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Childhood onset hereditary spastic paraplegia v8.17 ATL1 Achchuthan Shanmugasundram reviewed gene: ATL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18446315, 22378671, 24473461, 25193411, 26888483, 34808209, 35925862, 37927245, 39003427; Phenotypes: Spastic paraplegia 3A, autosomal dominant, OMIM:182600, hereditary spastic paraplegia 3A, MONDO:0008437; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.11 PPOX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 13 October 2025.
Cutaneous photosensitivity with a likely genetic cause v3.11 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata 176200; Variegate porphyria (Acute neuropathic porphyrias) to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Cutaneous photosensitivity with a likely genetic cause v3.10 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to
Cutaneous photosensitivity with a likely genetic cause v3.9 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Possible mitochondrial disorder - nuclear genes v4.15 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata, 176200 to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Possible mitochondrial disorder - nuclear genes v4.14 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to 9540991; 10870850; 25778941; 30476629; 32247286; 33159949
Possible mitochondrial disorder - nuclear genes v4.13 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Hereditary neuropathy or pain disorder v7.20 PPOX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 13 October 2025.
Hereditary neuropathy or pain disorder v7.20 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577
Hereditary neuropathy or pain disorder v7.19 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata, OMIM:176200; Sensory neuropathy, HP:0000763 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577
Hereditary neuropathy or pain disorder v7.18 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Variegate porphyria v1.3 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Variegate porphyria v1.3 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to
Variegate porphyria v1.2 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Mitochondrial disorders v9.32 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Adult onset neurodegenerative disorder v8.7 SPTLC2 Achchuthan Shanmugasundram Classified gene: SPTLC2 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v8.7 SPTLC2 Achchuthan Shanmugasundram Gene: sptlc2 has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v8.6 SPTLC2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SPTLC2.
Adult onset neurodegenerative disorder v8.6 SPTLC1 Achchuthan Shanmugasundram Classified gene: SPTLC1 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v8.6 SPTLC1 Achchuthan Shanmugasundram Gene: sptlc1 has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v8.5 SPTLC1 Achchuthan Shanmugasundram Phenotypes for gene: SPTLC1 were changed from Juvenile ALS to Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285; amyotrophic lateral sclerosis 27, juvenile, MONDO:0859529
Adult onset neurodegenerative disorder v8.4 SPTLC1 Achchuthan Shanmugasundram Publications for gene: SPTLC1 were set to 34059824; 34459874; 35627278; 35900868
Adult onset neurodegenerative disorder v8.3 SPTLC1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SPTLC1.
Tag Q3_25_NHS_review tag was added to gene: SPTLC1.
Intellectual disability v9.127 FICD Arina Puzriakova changed review comment from: Paper by Perera et al 2022 has now been published (PMID: 36704923).

An additional 6 unrelated families have been reported with biallelic variants in this gene presenting with motor neuron disease. Unlike the cases reported by Perera et al, these individuals did not display any significant cognitive deficits (PMID: 36136088; 40062579); to: Paper by Perera et al 2022 has now been published (PMID: 36704923).

An additional 6 unrelated families have been reported with biallelic variants in this gene presenting with motor neuron disease. Unlike the cases reported by Perera et al, these individuals did not display any significant cognitive deficits (PMID: 36136088; 40062579). Therefore maintaining the Amber rating on this panel.
Intellectual disability v9.127 FICD Arina Puzriakova commented on gene: FICD
Monogenic diabetes v3.5 FICD Arina Puzriakova Classified gene: FICD as Amber List (moderate evidence)
Monogenic diabetes v3.5 FICD Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 6 families with diabetes mellitus and biallelic variants at the Arg371 or Arg374 residue of this gene (PMID: 36704923; 36136088; 40062579)
Monogenic diabetes v3.5 FICD Arina Puzriakova Gene: ficd has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.17 FICD Arina Puzriakova Tag recurrent-variant tag was added to gene: FICD.
Monogenic diabetes v3.4 FICD Arina Puzriakova Tag recurrent-variant tag was added to gene: FICD.
Monogenic diabetes v3.4 FICD Arina Puzriakova gene: FICD was added
gene: FICD was added to Monogenic diabetes. Sources: Literature
Q3_25_promote_green tags were added to gene: FICD.
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36704923; 36136088; 40062579
Phenotypes for gene: FICD were set to Spastic paraplegia 92, autosomal recessive, OMIM:620911; diabetes mellitus, MONDO:0005015; Neonatal insulin-dependent diabetes mellitus, HP:0000857
Review for gene: FICD was set to GREEN
Added comment: - PMID: 36704923 (2022) - infantile diabetes and neurodevelopmental delay associated with a single variant p.Arg371Ser, in three consanguineous families, two of which shared a common haplotype

- PMID: 36136088 (2022) - four unrelated families from different ethnic backgrounds, all harboured the same p.Arg374His variant, which was homozygous in all but one case where the variant was present in a compound heterozygous state with a frameshift variant, p.Gly370GlufsTer53. Haplotype analysis did indicate that there is a shared haplotype in all patients with the p.Arg374His variant, strongly suggesting a founder effect. Affected individuals presented with severe motor neuron disease and one patient from this cohort also had diabetes mellitus.

- PMID: 40062579 (2025) - an additional four individuals from two families with variants affecting the Arg374 residue, who presented with complicated HSP and diabetes mellitus, merging these two previously distinct presentations.
The report describes one Serbian family, comprising 2 sibs with cHSP (age of onset: 5 and 6) and diabetes mellitus (age of diagnosis: 25 and 27). The sibs had the recurrent homozygous variant p.Arg374His - however, the haplotype identified in the previous report was not found in this family, suggesting that this is an independent event.
The second was a consanguineous family from Saudi Arabia with 2 sibs affected by progressive HSP and diabetes (one prediabetic) - age of onset unclear but paediatric. This family harboured a novel homozygous variant, p.Arg374Cys. No cognitive deficits were reported in either family.

The coexistence of motor neuron disease and diabetes suggests a broader range of neurological and metabolic effects of FICD dysfunction which does warrant further investigation. It is possible that these presentations may be more related than initially thought - individuals diagnosed with infancy-onset diabetes mellitus may develop spasticity later in life, and vice versa.
Sources: Literature
Neonatal diabetes v5.4 FICD Arina Puzriakova Phenotypes for gene: FICD were changed from Spastic paraplegia 92, autosomal recessive, OMIM:620911; Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities to Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities
Neonatal diabetes v5.3 FICD Arina Puzriakova commented on gene: FICD
Childhood onset hereditary spastic paraplegia v8.17 FICD Arina Puzriakova Publications for gene: FICD were set to 36136088
Childhood onset hereditary spastic paraplegia v8.16 FICD Arina Puzriakova edited their review of gene: FICD: Added comment: This gene was reassessed in light of the amber review by John Taylor, highlighting that two distinct phenotypes linked to similar variants located in the catalytic motif of FICD have been assessed differently.

FICD was rated amber on Neonatal diabetes (293) in context of infantile diabetes and neurodevelopmental delay associated with a single variant p.Arg371Ser, in three consanguineous families, two of which shared a common haplotype (PMID: 36704923).

A separate association with severe motor neuron disease (rated green on this panel) is based on four unrelated families from different ethnic backgrounds, who all harbour the p.Arg374His variant, which was homozygous in all but one case where the variant was present in a compound heterozygous state with a frameshift variant, p.Gly370GlufsTer53. One patient from this cohort also had diabetes mellitus. Haplotype analysis did indicate that there is a shared haplotype in all patients with the p.Arg374His variant, strongly suggesting a founder effect (PMID: 36136088).

Recently, an additional four individuals from two families were reported (PMID: 40062579) with variants affecting the Arg374 residue, who presented with complicated HSP and diabetes mellitus, merging these two previously distinct presentations.
The report describes one Serbian family, comprising 2 sibs with cHSP (age of onset: 5 and 6) and diabetes mellitus (age of diagnosis: 25 and 27). The sibs had the recurrent homozygous variant p.Arg374His - however, the haplotype identified in the previous report was not found in this family, suggesting that this is an independent event.
The second was a consanguineous family from Saudi Arabia with 2 sibs affected by progressive HSP and diabetes (one prediabetic) - age of onset unclear but paediatric. This family harboured a novel homozygous variant, p.Arg374Cys. No cognitive deficits were reported in either family.

The coexistence of motor neuron disease and diabetes suggests a broader range of neurological and metabolic effects of FICD dysfunction which does warrant further investigation. It is possible that these presentations may be more related than initially thought - individuals diagnosed with infancy-onset diabetes mellitus may develop spasticity later in life, and vice versa.

Overall the recent report does lend additional support for inclusion of FICD on this panel. This gene will also be added to the Monogenic diabetes (472) panel to cover the diabetes phenotype with later onset than the initial report which was reviewed on the Neonatal diabetes (293) panel.; Changed publications to: 36704923, 36136088, 40062579; Changed phenotypes to: Spastic paraplegia 92, autosomal recessive, OMIM:620911
Possible mitochondrial disorder - nuclear genes v4.13 PPOX Ida Ertmanska commented on gene: PPOX: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Possible mitochondrial disorder - nuclear genes.
Possible mitochondrial disorder - nuclear genes v4.13 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 8290408, 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.18 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms - including neuropathy. As reported by previous reviewers, 3 individuals with biallelic variants in PPOX presented with sensory neuropathy (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift). Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Hereditary neuropathy or pain disorder.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms - including neuropathy. As reported by previous reviewers, 3 individuals with biallelic variants in PPOX presented with sensory neuropathy (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift). Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.18 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 8290408, 10870850, 11286631; Phenotypes: Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Non-acute porphyrias v1.26 PPOX Ida Ertmanska commented on gene: PPOX: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood (PMIDs: 19460837, 38940544). PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should be rated Green for Non-acute porphyrias.
Mitochondrial disorders v9.32 PPOX Ida Ertmanska edited their review of gene: PPOX: Added comment: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should remain Green for Mitochondrial disorders.; Changed phenotypes to: Variegate porpComment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408, 9811936, 2004012, 35164799, 37879139, 40114189). PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should remain Green for Variegate porphyria.hyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577
Variegate porphyria v1.1 PPOX Ida Ertmanska commented on gene: PPOX: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on the available evidence, this gene should remain Green for Variegate porphyria.
Mitochondrial disorders v9.32 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.9 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Variegate porphyria.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Cutaneous photosensitivity with a likely genetic cause.
Neonatal diabetes v5.3 FICD Arina Puzriakova Phenotypes for gene: FICD were changed from Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities. to Spastic paraplegia 92, autosomal recessive, OMIM:620911; Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities
Cutaneous photosensitivity with a likely genetic cause v3.9 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Variegate porphyria v1.1 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' for Variegate porphyria.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Variegate porphyria.
Variegate porphyria v1.1 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Non-acute porphyrias v1.26 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed publications to: 9811936, 10486317, 19460837, 33159949, 35584894, 37879139, 38940544, 40114189
Non-acute porphyrias v1.26 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, variegate porphyria, MONDO:0008297; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neonatal diabetes v5.2 FICD Arina Puzriakova Publications for gene: FICD were set to
Intellectual disability v9.127 FICD Arina Puzriakova Publications for gene: FICD were set to
Variegate porphyria v1.1 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v8.3 SPTLC2 Ida Ertmanska commented on gene: SPTLC2: Comment on list classification: There are at least 10 unrelated patients reported with juvenile onset ALS with monoallelic variants in SPTLC2 (9 de novo, 1 familial case with demonstrated autosomal dominant inheritance). Based on the available evidence, this gene should be rated Green for Adult onset neurodegenerative disorder.
Adult onset neurodegenerative disorder v8.3 SPTLC2 Ida Ertmanska changed review comment from: Monoallelic variants in SPTLC2 have been associated with juvenile-onset ;amyotrophic lateral sclerosis:
PMID: 38041679 Syeda 2024 - 6 unrelated patients with a recurrent de novo variant p.Glu260Lys
PMID: 38316966 Naruse 2024 - 2 unrelated families - p.Ala71Val, p.Met68Arg
PMID: 38041684 Dohrn 2024 - 2 unrelated patients with the same de novo variant p.Met68Argetc
Sources: Literature; to: Monoallelic variants in SPTLC2 have been associated with juvenile-onset amyotrophic lateral sclerosis:

PMID: 38041679 Syeda 2024 - 6 unrelated patients with a recurrent de novo variant p.Glu260Lys - trio WES/WGS. Phenotype: early-childhood-onset spasticity, followed by rapidly progressive weakness involving upper and lower extremities, bulbar muscles, tongue fasciculations and eventual respiratory insufficiency. Onset: congenital - 4 years of age.

PMID: 38316966 Naruse 2024 - 2 unrelated Japanese families with early-onset ALS - p.Ala71Val, p.Met68Arg. Method: WES. Onset of symptoms: 22-31 years.

PMID: 38041684 Dohrn 2024 - 2 unrelated patients (one African American and one Turkish-Bulgarian) with the same de novo variant p.Met68Arg. Childhood onset. Method: WGS/WES +Sanger confirmation.

SPTLC2 is associated with Neuropathy, hereditary sensory and autonomic, type IC in OMIM (613640) - accessed 13th Oct 2025).
DDG2P v6.8 PDE6H Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Ronnie Wright, this gene does not fit into the scope of developmental disorders, particularly in the context of R27 Paediatric disorders clinical indication. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Hence, the rating with stay green, pending updates from G2P.; to: Comment on list classification: As reviewed by Ronnie Wright, this gene does not fit into the scope of developmental disorders, particularly in the context of R27 Paediatric disorders clinical indication. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Hence, the rating should stay green, pending updates from G2P.
Childhood onset hereditary spastic paraplegia v8.16 TBCB Arina Puzriakova Classified gene: TBCB as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.16 TBCB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the Genomics England Clinical Team. Some functional data that indicates disruption of the gene, however this does not provide conclusive support for pathogenicity of the founder variant. Additional functional evidence or corroborative cases would allow verification of this gene-disease association and future review of the classification on this panel.
Childhood onset hereditary spastic paraplegia v8.16 TBCB Arina Puzriakova Gene: tbcb has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v8.3 SPTLC2 Ida Ertmanska gene: SPTLC2 was added
gene: SPTLC2 was added to Adult onset neurodegenerative disorder. Sources: Literature
Mode of inheritance for gene: SPTLC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTLC2 were set to 38041684; 38041679; 38316966
Phenotypes for gene: SPTLC2 were set to Neuropathy, hereditary sensory and autonomic, type IC, OMIM:613640; amyotrophic lateral sclerosis 27, juvenile, MONDO:0859529
Review for gene: SPTLC2 was set to GREEN
Added comment: Monoallelic variants in SPTLC2 have been associated with juvenile-onset ;amyotrophic lateral sclerosis:
PMID: 38041679 Syeda 2024 - 6 unrelated patients with a recurrent de novo variant p.Glu260Lys
PMID: 38316966 Naruse 2024 - 2 unrelated families - p.Ala71Val, p.Met68Arg
PMID: 38041684 Dohrn 2024 - 2 unrelated patients with the same de novo variant p.Met68Argetc
Sources: Literature
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska edited their review of gene: SPTLC1: Changed phenotypes to: Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285, amyotrophic lateral sclerosis 27, juvenile, MONDO:0859529
Autoinflammatory disorders v2.32 ITCH Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ITCH.
Tag Q3_25_NHS_review tag was added to gene: ITCH.
Autoinflammatory disorders v2.32 ITCH Achchuthan Shanmugasundram Phenotypes for gene: ITCH were changed from Autoimmune disease, multisystem, with facial dysmorphism, 613385 to Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385; syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska commented on gene: SPTLC1: Comment on list classification: There are at least 11 unrelated cases with juvenile-onset ALS with monoallelic SPTLC1 variants (age of onset between 3-16 years). Variants were confirmed as de novo in 9/11 families. According to functional studies, ALS causing variants tend to cluster in the N-terminal transmembrane domain. Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.
Autoinflammatory disorders v2.31 ITCH Achchuthan Shanmugasundram Publications for gene: ITCH were set to PMID: 36338154
Autoinflammatory disorders v2.30 ITCH Achchuthan Shanmugasundram Classified gene: ITCH as Amber List (moderate evidence)
Autoinflammatory disorders v2.30 ITCH Achchuthan Shanmugasundram Gene: itch has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.126 PPOX Arina Puzriakova Mode of inheritance for gene: PPOX was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.125 PPOX Arina Puzriakova Phenotypes for gene: PPOX were changed from Porphyria variegata, 176200 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297
DDG2P v6.8 LBX1 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: LBX1.
Intellectual disability v9.124 PPOX Arina Puzriakova Publications for gene: PPOX were set to
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska changed review comment from: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4:
Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025).

Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.; to: As reviewed by James Polke, SPTLC1 variants are associated with juvenile-onset amyotrophic lateral sclerosis. There are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), none of them present in gnomAD v4. Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser (2 patients), p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1 ALS-related alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neurons. ALS causing variants tend to cluster in the N-terminal transmembrane domain (TMD); variants in the cytosolic domain are largely associated with HSAN1.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025).
Central congenital hypoventilation v1.5 LBX1 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: LBX1.
Intellectual disability v9.123 PPOX Arina Puzriakova Classified gene: PPOX as Amber List (moderate evidence)
Intellectual disability v9.123 PPOX Arina Puzriakova Gene: ppox has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.122 PPOX Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PPOX.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska edited their review of gene: ITCH: Changed publications to: 18727493, 20170897, 30705142, 31091003, 33894394, 36338154
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska edited their review of gene: ITCH: Changed phenotypes to: Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385, syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska edited their review of gene: ITCH: Changed publications to: 20170897, 30705142, 31091003, 33894394, 36338154
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient-derived ITCH-deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.
Childhood onset hereditary spastic paraplegia v8.15 OGDHL Arina Puzriakova Classified gene: OGDHL as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.15 OGDHL Arina Puzriakova Gene: ogdhl has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska commented on gene: ITCH: Comment on list classification:
There are at least 14 patients from 5 unrelated families with biallelic variants in ITCH. ITCH deficiency may result in multi-systemic immune dysregulation (present in 9/14 reported patients), dysmorphic features (14/14), developmental delay (14/14), relative macrocephaly (13/14), chronic lung disease (13/14), hepatomegaly/splenomegaly (10/14), and hypotonia (8/14). Based on available evidence, ITCH should be rated Green for autoinflammatory disorders.
Childhood onset hereditary spastic paraplegia v8.14 OGDHL Arina Puzriakova Phenotypes for gene: OGDHL were changed from Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221 to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: OGDHL.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR), flux through fatty acid oxidation, and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
Hereditary neuropathy or pain disorder v7.18 XPNPEP3 Arina Puzriakova Phenotypes for gene: XPNPEP3 were changed from Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy, MONDO:0005244 to Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy, MONDO:0005244; myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MONDO:0859322
Acute rhabdomyolysis v2.4 XPNPEP3 Arina Puzriakova gene: XPNPEP3 was added
gene: XPNPEP3 was added to Acute rhabdomyolysis. Sources: Literature
Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPNPEP3 were set to 40953058
Phenotypes for gene: XPNPEP3 were set to myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MONDO:0859322
Review for gene: XPNPEP3 was set to RED
Added comment: Biallelic variants in this gene are associated with nephronophthisis, a progressive cystic kidney disorder that leads to end-stage renal disease (OMIM:613159). Extra-renal manifestations have only been reported in a subset of cases - neurological features have been reported in at least 4 unrelated families including tremor, dystonia, rhabdomyolysis, peripheral neuropathy, sensorineural hearing loss, epilepsy and cardiomyopathy. Kidney disease was present in all (PMID: 20179356; 38035175), except one case (PMID: 40953058).

A recent report (PMID: 40953058) included the first case of mitochondrial myopathy presenting with a purely metabolic phenotype, manifesting as exertional symptoms and rhabdomyolysis associated with a homozygous XPNPEP3 variant (c.1153dup, p.(Tyr385LeufsTer13)) - however, this individual did not have any typical renal features and therefore it's worth monitoring for similar reports. In the meantime rating as Red awaiting further corroborating cases.
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v5.10 XPNPEP3 Arina Puzriakova gene: XPNPEP3 was added
gene: XPNPEP3 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPNPEP3 were set to 40953058
Phenotypes for gene: XPNPEP3 were set to myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MONDO:0859322
Review for gene: XPNPEP3 was set to RED
Added comment: Biallelic variants in this gene are associated with nephronophthisis, a progressive cystic kidney disorder that leads to end-stage renal disease (OMIM:613159). Extra-renal manifestations have only been reported in a subset of cases - neurological features have been reported in at least 4 unrelated families including tremor, dystonia, rhabdomyolysis, peripheral neuropathy, sensorineural hearing loss, epilepsy and cardiomyopathy. Kidney disease was present in all (PMID: 20179356; 38035175), except one case (PMID: 40953058).

A recent report (PMID: 40953058) included the first case of mitochondrial myopathy presenting with a purely metabolic phenotype, manifesting as exertional symptoms and rhabdomyolysis associated with a homozygous XPNPEP3 variant (c.1153dup, p.(Tyr385LeufsTer13)) - however, this individual did not have any typical renal features and therefore it's worth monitoring for similar reports. In the meantime rating as Red awaiting further corroborating cases.
Sources: Literature
DDG2P v6.8 PDE1B Arina Puzriakova Tag curated_removed tag was added to gene: PDE1B.
Hereditary neuropathy or pain disorder v7.17 XPNPEP3 Arina Puzriakova Phenotypes for gene: XPNPEP3 were changed from Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy to Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy, MONDO:0005244
Hereditary neuropathy or pain disorder v7.16 XPNPEP3 Arina Puzriakova Phenotypes for gene: XPNPEP3 were changed from Nephronopthisis; brain white matter lesions; sensory axonal neuropathy; recurrent rhabdomyolysis; cardiomyopathy; ataxia; hearing loss to Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy
Hereditary neuropathy or pain disorder v7.15 XPNPEP3 Arina Puzriakova Publications for gene: XPNPEP3 were set to 40953058
Hereditary neuropathy or pain disorder v7.14 XPNPEP3 Arina Puzriakova Classified gene: XPNPEP3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.14 XPNPEP3 Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in this gene are associated with nephronophthisis, a progressive cystic kidney disorder that leads to end-stage renal disease (OMIM:613159). Extra-renal manifestations have only been reported in a subset of cases - neurological features have been reported in at least 4 unrelated families including tremor, dystonia, rhabdomyolysis, peripheral neuropathy, sensorineural hearing loss, epilepsy and cardiomyopathy. Kidney disease was present in all (PMID: 20179356; 38035175), except one case (PMID: 40953058).

In the literature, there are 2 cases with peripheral neuropathy and biallelic variants in this gene (PMID: 38035175; 40953058), however, this is not a common manifestation for this gene. One case did not have any typical renal features and therefore it's worth monitoring for similar reports. In the meantime rating as Amber awaiting further corroborating cases.
Hereditary neuropathy or pain disorder v7.14 XPNPEP3 Arina Puzriakova Gene: xpnpep3 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska edited their review of gene: ITCH: Changed publications to: 20170897, 30705142, 31091003, 36338154
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR), flux through fatty acid oxidation, and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
DDG2P v6.8 LBX1 Achchuthan Shanmugasundram commented on gene: LBX1: The DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). This gene has been added with amber rating on R333 Central congenital hypoventilation panel (https://panelapp.genomicsengland.co.uk/panels/1314/gene/LBX1/) as this phenotype clearly fits into the scope of R333 clinical indication.

The 'curated_removed' tag has been added so that this gene won't be relevant on this panel until it is added to the DD panel on G2P resource.
DDG2P v6.8 LBX1 Achchuthan Shanmugasundram Deleted their comment
DDG2P v6.8 LBX1 Achchuthan Shanmugasundram Publications for gene: LBX1 were set to PMID: 30487221
DDG2P v6.7 LBX1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 13 October 2025
DDG2P v6.7 LBX1 Achchuthan Shanmugasundram Phenotypes for gene: LBX1 were changed from to ?Central hypoventilation syndrome, congenital, 3, OMIM:619483; central hypoventilation syndrome, congenital, 3, MONDO:0030539
DDG2P v6.6 LBX1 Achchuthan Shanmugasundram Tag curated_removed tag was added to gene: LBX1.
DDG2P v6.6 LBX1 Achchuthan Shanmugasundram commented on gene: LBX1
Central congenital hypoventilation v1.5 LBX1 Achchuthan Shanmugasundram Classified gene: LBX1 as Amber List (moderate evidence)
Central congenital hypoventilation v1.5 LBX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one published family and mouse model available in support of the association. Hence, this gene should be rated amber with the current evidence.
Central congenital hypoventilation v1.5 LBX1 Achchuthan Shanmugasundram Gene: lbx1 has been classified as Amber List (Moderate Evidence).
Central congenital hypoventilation v1.4 LBX1 Achchuthan Shanmugasundram Publications for gene: LBX1 were set to PMID: 30487221
Central congenital hypoventilation v1.3 LBX1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #619483). This OMIM record has been accessed on 13 October 2025.
Central congenital hypoventilation v1.3 LBX1 Achchuthan Shanmugasundram Phenotypes for gene: LBX1 were changed from to ?Central hypoventilation syndrome, congenital, 3, OMIM:619483; central hypoventilation syndrome, congenital, 3, MONDO:0030539
Central congenital hypoventilation v1.2 LBX1 Achchuthan Shanmugasundram reviewed gene: LBX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30487221; Phenotypes: ?Central hypoventilation syndrome, congenital, 3, OMIM:619483, central hypoventilation syndrome, congenital, 3, MONDO:0030539; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Central congenital hypoventilation v1.2 LBX1 Achchuthan Shanmugasundram Entity copied from DDG2P v6.6
Central congenital hypoventilation v1.2 LBX1 Achchuthan Shanmugasundram gene: LBX1 was added
gene: LBX1 was added to Central congenital hypoventilation. Sources: Expert Review
Mode of inheritance for gene: LBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LBX1 were set to PMID: 30487221
Penetrance for gene: LBX1 were set to Complete
Monogenic hearing loss v5.31 KIAA0391 Achchuthan Shanmugasundram Classified gene: KIAA0391 as Amber List (moderate evidence)
Monogenic hearing loss v5.31 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are at least four unrelated families reported with sensorineural hearing loss, this gene can be promoted to green rating in the next GMS update.
Monogenic hearing loss v5.31 KIAA0391 Achchuthan Shanmugasundram Gene: kiaa0391 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.30 KIAA0391 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: KIAA0391.
Monogenic hearing loss v5.30 KIAA0391 Achchuthan Shanmugasundram commented on gene: KIAA0391: The 'new-gene-name' tag has been added as the official gene symbol for KIAA0391 is PRORP. It is also known as MRPP3.
Monogenic hearing loss v5.30 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 10 October 2025.
Monogenic hearing loss v5.30 KIAA0391 Achchuthan Shanmugasundram Phenotypes for gene: KIAA0391 were changed from Combined oxidative phosphorylation deficiency 54, OMIM:619737 to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Monogenic hearing loss v5.29 KIAA0391 Achchuthan Shanmugasundram gene: KIAA0391 was added
gene: KIAA0391 was added to Monogenic hearing loss. Sources: Literature
new-gene-name tags were added to gene: KIAA0391.
Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0391 were set to 34715011; 37558808
Phenotypes for gene: KIAA0391 were set to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Review for gene: KIAA0391 was set to GREEN
Added comment: PMID:34715011 (2021) reported four unrelated families with multisystem disease and identified with biallelic variants (either homozygous or compound heterozygous) in PRORP (KIAA0391) gene. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss (SNHL), primary ovarian insufficiency, developmental delay, and brain white matter changes. SNHL was reported in three of the four families. There is also functional evidence available from fibroblasts from affected individuals in two families.

PMID:37558808 (2023) reported three additional unrelated patients with homozygous missense PRORP variants and with pleiotropic phenotypes consistent with the previously reported cases from PMID:34715011. SNHL was reported in one these cases, while another proband did not pass neonatal hearing screening (althoughjt formal hearing test was not performed and patient died at 19 months of age).
Sources: Literature
Deafness and congenital structural abnormalities v1.34 KIAA0391 Achchuthan Shanmugasundram Classified gene: KIAA0391 as Green List (high evidence)
Deafness and congenital structural abnormalities v1.34 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are at least four unrelated families reported with sensorineural hearing loss, this gene has been promoted to green rating on this panel.
Deafness and congenital structural abnormalities v1.34 KIAA0391 Achchuthan Shanmugasundram Gene: kiaa0391 has been classified as Green List (High Evidence).
Deafness and congenital structural abnormalities v1.33 KIAA0391 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: KIAA0391.
Deafness and congenital structural abnormalities v1.33 KIAA0391 Achchuthan Shanmugasundram commented on gene: KIAA0391: The 'new-gene-name' tag has been added as the official gene symbol for KIAA0391 is PRORP. It is also known as MRPP3.
Deafness and congenital structural abnormalities v1.33 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 10 October 2025.
Deafness and congenital structural abnormalities v1.33 KIAA0391 Achchuthan Shanmugasundram Phenotypes for gene: KIAA0391 were changed from Combined oxidative phosphorylation deficiency 54, OMIM:619737 to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Deafness and congenital structural abnormalities v1.32 KIAA0391 Achchuthan Shanmugasundram Phenotypes for gene: KIAA0391 were changed from Sensorineural hearing loss; primary ovarian insufficiency; leukodystrophy to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Deafness and congenital structural abnormalities v1.31 KIAA0391 Achchuthan Shanmugasundram Publications for gene: KIAA0391 were set to PMID:34715011; 37558808
Deafness and congenital structural abnormalities v1.30 KIAA0391 Achchuthan Shanmugasundram reviewed gene: KIAA0391: Rating: GREEN; Mode of pathogenicity: None; Publications: 34715011, 37558808; Phenotypes: Combined oxidative phosphorylation deficiency 54, OMIM:619737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska reviewed gene: ITCH: Rating: GREEN; Mode of pathogenicity: None; Publications: 20170897, 30705142, 31091003; Phenotypes: Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v4.7 UNC45A Ida Ertmanska changed review comment from: Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).

; to: Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM (accessed 10th Oct 2025) - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).
Cholestasis v3.10 UNC45A Ida Ertmanska changed review comment from: UNC45A has been linked to Aagenaes syndrome - a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. There are at least 28 affected individuals from 25 different families who presented with neonatal cholestasis and lymphedema (PMIDs:37328071;39887522). Based on the reported evidence, this gene should be rated Green for Cholestasis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).; to: UNC45A has been linked to Aagenaes syndrome - a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. There are at least 28 affected individuals from 25 different families who presented with neonatal cholestasis and lymphedema (PMIDs:37328071;39887522). Based on the reported evidence, this gene should be rated Green for Cholestasis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM (accessed 10th Oct 2025) - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).
Cholestasis v3.10 UNC45A Ida Ertmanska reviewed gene: UNC45A: Rating: GREEN; Mode of pathogenicity: None; Publications: 37328071, 39887522; Phenotypes: Osteootohepatoenteric syndrome, OMIM:619377, Aagenaes syndrome, MONDO:0008966; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v4.7 UNC45A Ida Ertmanska commented on gene: UNC45A: Comment on list classification: UNC45A has been linked to Aagenaes syndrome - a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. There are at least 28 affected individuals from 25 different families who presented with neonatal cholestasis and lymphedema (PMIDs:37328071;39887522). Based on the reported evidence, this gene should be rated Green for Primary lymphoedema.
Primary lymphoedema v4.7 UNC45A Ida Ertmanska edited their review of gene: UNC45A: Changed publications to: 37328071, 39887522
Primary lymphoedema v4.7 UNC45A Ida Ertmanska changed review comment from: PMID: 37328071 Almaas et al., 2023
Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.
26 patients from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.
Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls + CRISPR/Cas9-created cell model.; to: Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).
Primary lymphoedema v4.7 UNC45A Ida Ertmanska edited their review of gene: UNC45A: Changed phenotypes to: Osteootohepatoenteric syndrome, OMIM:619377, Aagenaes syndrome, MONDO:0008966
Primary lymphoedema v4.7 UNC45A Ida Ertmanska reviewed gene: UNC45A: Rating: GREEN; Mode of pathogenicity: None; Publications: 37328071; Phenotypes: Osteootohepatoenteric syndrome 619377; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
RASopathies v1.86 RREB1 Achchuthan Shanmugasundram Classified gene: RREB1 as Green List (high evidence)
RASopathies v1.86 RREB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated patients) in support of the disease association. Hence, this gene has been promoted to green rating on this panel.
RASopathies v1.86 RREB1 Achchuthan Shanmugasundram Gene: rreb1 has been classified as Green List (High Evidence).
RASopathies v1.85 RREB1 Achchuthan Shanmugasundram Phenotypes for gene: RREB1 were changed from Noonan syndrome-like disorder to RASopathy, MONDO:0021060
RASopathies v1.84 RREB1 Achchuthan Shanmugasundram Publications for gene: RREB1 were set to 32938917
RASopathies v1.83 RREB1 Achchuthan Shanmugasundram reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38332451, 40418122; Phenotypes: RASopathy, MONDO:0021060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.39 VSX2 Ida Ertmanska edited their review of gene: VSX2: Changed publications to: 8630490, 21976963, 23028343, 24001013, 35831950, 36264558, 38994775
Retinal disorders v8.39 VSX2 Ida Ertmanska changed review comment from: Biallelic VSX2 variants often result in microphthalmia, anophthalmia, coloboma (MAC):

PMID: 21976963 Reis et al., 2011
2 unrelated consanguineous families with AR isolated bilateral microphthalmia.
Pakistani family - affected individuals homozygous for c.668G>C (p.G223A).
Iranian family - affected individuals homozygous for c.249delG (p.Leu84SerfsX57). ERG performed on 2 sisters in this family showed inner retinal dysfunction in both.

As reviewed by Beisi Xu, there are also at least three different VSX2 variants reported in three unrelated patients with retinopathy and no reported MAC phenotype.

PMID: 36264558 Smirnov et al., 2022: 3 patients from 2 unrelated non-consanguineous Turkish families, harbouring homozygous missense variants: c.595C>T, p.(Arg199Cys) and c.698C>T, p.(Pro233Leu). All 3 patients presented with infantile nystagmus, low stable visual acuity, myopia and night blindness, cause by retinopathy with lens luxation.

PMID: 24001013 Khan et al., 2013: Case study - Female, 3yo, Saudi Arabian. Phenotype: Poor vision from birth, chorioretinal atrophy, retinal dysfunction; superior lens subluxation and smooth iris. Homozygous for c.773delA; p.(Lys258Serfs*44); variant heterozygous in unaffected brother and consanguineous parents. Homozygous frameshift BCAP29 variant also identified in patient - not much known about this gene.
Functional studies in mice and human retinal organoids indicate that the reported VSX2 variants have a variable effect on VSX2’s DNA binding properties, which may explain the phenotypic heterogeneity observed in patients (PMID: 23028343; 35831950; 38994775).

This gene is not yet associated with retinal disorders in OMIM or Gene2Phenotype.; to: Biallelic VSX2 (formerly CHX10) variants often result in microphthalmia, anophthalmia, coloboma (MAC).

PMID: 21976963 Reis et al., 2011
2 unrelated consanguineous families with AR isolated bilateral microphthalmia.
Pakistani family - affected individuals homozygous for c.668G>C (p.G223A).
Iranian family - affected individuals homozygous for c.249delG (p.Leu84SerfsX57). ERG performed on 2 sisters in this family showed inner retinal dysfunction in both.

As reviewed by Beisi Xu, there are also at least three different VSX2 variants reported in three unrelated patients with retinopathy and no reported MAC phenotype:

PMID: 36264558 Smirnov et al., 2022: 3 patients from 2 unrelated non-consanguineous Turkish families, harbouring homozygous missense variants: c.595C>T, p.(Arg199Cys) and c.698C>T, p.(Pro233Leu). All 3 patients presented with infantile nystagmus, low stable visual acuity, myopia and night blindness, cause by retinopathy with lens luxation.

PMID: 24001013 Khan et al., 2013: Case study - Female, 3yo, Saudi Arabian. Phenotype: Poor vision from birth, chorioretinal atrophy, retinal dysfunction; superior lens subluxation and smooth iris. Homozygous for c.773delA; p.(Lys258Serfs*44); variant heterozygous in unaffected brother and consanguineous parents. Homozygous frameshift BCAP29 variant also identified in patient - not much known about this gene.

Functional studies in mice and human retinal organoids indicate that the reported VSX2 variants have a variable effect on VSX2’s DNA binding properties, which may explain the phenotypic heterogeneity observed in patients (PMID: 23028343; 35831950; 38994775).
PMID: 8630490 Burmeister et al., 1996: Mice homozygous for a premature stop codon in VSX2/CHX10 are blind, with obvious microphthalmia, cataractous lens, a thin retina, and no optic nerve. Study notes that loss of VSX2CHX10 leads both to reduced proliferation of retinal progenitors and to a specific absence of differentiated bipolar cells - supportive of MAC / retinal degeneration phenotype seen in patients.

This gene is not yet associated with retinal disorders in OMIM or Gene2Phenotype.
Fetal hydrops v1.91 RASA1 Achchuthan Shanmugasundram Classified gene: RASA1 as Green List (high evidence)
Fetal hydrops v1.91 RASA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (~25 unrelated cases) for the promotion of this gene to green rating on this panel.
Fetal hydrops v1.91 RASA1 Achchuthan Shanmugasundram Gene: rasa1 has been classified as Green List (High Evidence).
Fetal hydrops v1.90 RASA1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 10 October 2025.
Fetal hydrops v1.90 RASA1 Achchuthan Shanmugasundram Phenotypes for gene: RASA1 were changed from capillary malformation-arteriovenous malformation-1 (CMAVM1, OMIM # 608354) to Capillary malformation-arteriovenous malformation 1, OMIM:608354; capillary malformation-arteriovenous malformation 1, MONDO:0020783
Fetal hydrops v1.89 RASA1 Achchuthan Shanmugasundram reviewed gene: RASA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36980822; Phenotypes: Capillary malformation-arteriovenous malformation 1, OMIM:608354, capillary malformation-arteriovenous malformation 1, MONDO:0020783; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.39 VSX2 Ida Ertmanska reviewed gene: VSX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21976963, 24001013, 36264558; Phenotypes: Microphthalmia, isolated 2, OMIM:610093, retinal disorder, MONDO:0005283; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.97 RASA1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 10 October 2025.
Fetal anomalies v6.97 RASA1 Achchuthan Shanmugasundram Phenotypes for gene: RASA1 were changed from PARKES WEBER SYNDROME; CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION to Capillary malformation-arteriovenous malformation 1, OMIM:608354; capillary malformation-arteriovenous malformation 1, MONDO:0020783
Respiratory ciliopathies including non-CF bronchiectasis v4.47 DNAH9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 10 October 2025.
Respiratory ciliopathies including non-CF bronchiectasis v4.47 DNAH9 Achchuthan Shanmugasundram Phenotypes for gene: DNAH9 were changed from Primary ciliary dyskinesia to Ciliary dyskinesia, primary, 40, OMIM:618300; ciliary dyskinesia, primary, 40, MONDO:0032664
Primary ciliary disorders v1.55 DNAH9 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (eight unrelated cases and functional studies) for the promotion of this gene to green rating in this panel.; to: Comment on list classification: There is sufficient evidence available (eight unrelated cases and functional studies) for the promotion of this gene to green rating on this panel.
Primary ciliary disorders v1.55 DNAH9 Achchuthan Shanmugasundram Classified gene: DNAH9 as Green List (high evidence)
Primary ciliary disorders v1.55 DNAH9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight unrelated cases and functional studies) for the promotion of this gene to green rating in this panel.
Primary ciliary disorders v1.55 DNAH9 Achchuthan Shanmugasundram Gene: dnah9 has been classified as Green List (High Evidence).
Primary ciliary disorders v1.54 DNAH9 Achchuthan Shanmugasundram Classified gene: DNAH9 as Green List (high evidence)
Primary ciliary disorders v1.54 DNAH9 Achchuthan Shanmugasundram Gene: dnah9 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.41 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Early onset or syndromic epilepsy. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes childhood-onset seizures / epilepsy.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Early onset or syndromic epilepsy. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Primary ciliary disorders v1.53 DNAH9 Achchuthan Shanmugasundram Phenotypes for gene: DNAH9 were changed from to Ciliary dyskinesia, primary, 40, OMIM:618300; ciliary dyskinesia, primary, 40, MONDO:0032664
Primary ciliary disorders v1.52 DNAH9 Achchuthan Shanmugasundram Publications for gene: DNAH9 were set to PMID: 30471717; 30471718
Primary ciliary disorders v1.51 DNAH9 Achchuthan Shanmugasundram reviewed gene: DNAH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30471717, 30471718; Phenotypes: Ciliary dyskinesia, primary, 40, OMIM:618300, ciliary dyskinesia, primary, 40, MONDO:0032664; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.28 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Monogenic hearing loss. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes hearing loss (at least 8 cases in total).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Monogenic hearing loss. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Ataxia and cerebellar anomalies - narrow panel v8.24 OGDHL Ida Ertmanska edited their review of gene: OGDHL: Changed publications to: 28017472, 34800363, 38031187; Changed phenotypes to: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221
Ataxia and cerebellar anomalies - narrow panel v8.24 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes neurological features such as gait ataxia.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Ataxia and cerebellar anomalies - narrow panel. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes neurological features such as ataxia (6 cases).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Ataxia and cerebellar anomalies - narrow panel. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Ataxia and cerebellar anomalies - narrow panel v8.24 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Ataxia and cerebellar anomalies - narrow panel. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes neurological features such as gait ataxia.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Ataxia and cerebellar anomalies - narrow panel. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska commented on gene: OGDHL: Comment on list classification: This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly heterogeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska changed review comment from: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature; to: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a childhood-onset complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

PMIDs: 28017472; 34800363: 10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome. Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska gene: OGDHL was added
gene: OGDHL was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 28017472; 34800363; 38031187
Phenotypes for gene: OGDHL were set to Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221
Review for gene: OGDHL was set to GREEN
Added comment: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature
Primary ciliary disorders v1.51 OFD1 Achchuthan Shanmugasundram Classified gene: OFD1 as Green List (high evidence)
Primary ciliary disorders v1.51 OFD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating.
Primary ciliary disorders v1.51 OFD1 Achchuthan Shanmugasundram Gene: ofd1 has been classified as Green List (High Evidence).
Primary ciliary disorders v1.50 OFD1 Achchuthan Shanmugasundram Mode of inheritance for gene: OFD1 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary ciliary disorders v1.49 OFD1 Achchuthan Shanmugasundram Publications for gene: OFD1 were set to
Primary ciliary disorders v1.48 OFD1 Achchuthan Shanmugasundram Phenotypes for gene: OFD1 were changed from ciliopathies to Simpson-Golabi-Behmel syndrome, type 2, OMIM:300209; ?Retinitis pigmentosa 23 , OMIM:300424; Joubert syndrome 10, OMIM:300804; Orofaciodigital syndrome I, OMIOM:311200
Primary ciliary disorders v1.47 OFD1 Achchuthan Shanmugasundram reviewed gene: OFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31366608, 31373179; Phenotypes: Simpson-Golabi-Behmel syndrome, type 2, OMIM:300209, ?Retinitis pigmentosa 23 , OMIM:300424, Joubert syndrome 10, OMIM:300804, Orofaciodigital syndrome I, OMIOM:311200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v8.41 OGDHL Ida Ertmanska reviewed gene: OGDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28017472, 34800363, 38031187; Phenotypes: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.28 OGDHL Ida Ertmanska edited their review of gene: OGDHL: Changed rating: GREEN; Changed publications to: 28017472, 34800363, 38031187; Changed phenotypes to: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.28 OGDHL Ida Ertmanska commented on gene: OGDHL
Ataxia and cerebellar anomalies - narrow panel v8.24 OGDHL Ida Ertmanska reviewed gene: OGDHL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: 28017472, 34800363, 38031187; Mode of inheritance: None
Intellectual disability v9.122 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: neurodevelopmental disorder, neurodegeneration, infantile-onset epileptic encephalopathy, skeletal dysplasia, childhood-onset epilepsy, multiple congenital anomalies, dysmorphism, non-syndromic hearing loss, neuromuscular disorders, and congenital heart defects. 9/14 reported patients had developmental delay/intellectual disability. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.122 NAA60 Ida Ertmanska gene: NAA60 was added
gene: NAA60 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA60 were set to 38480682
Phenotypes for gene: NAA60 were set to Basal ganglia calcification, idiopathic, 9, autosomal recessive, 620786; basal ganglia calcification, idiopathic, 9, autosomal recessive, MONDO:0968977
Review for gene: NAA60 was set to RED
Added comment: PMID: 38480682 Chelban et al., 2024
Report of 7 unrelated families with homozygous variants in NAA60 with primary familial brain calcifications. Families originated from UK, France/Algeria, France/Morocco, UK/India, Turkey, and Saudi Arabia. 5/7 families had reported consanguinity. Sequencing method: WGS, WES.
Variants reported: c.321_327del, (p.Arg108Thrfs*3); c.338-1G>C, p.(Gly113Valfs*32); c.391C>T, (p.His131Tyr); c.130C>T, (p.Arg44Cys); c.50T>G, (p.Leu17Arg); c.428A>C, (p.Asn143Thr). No homozygotes reported in gnomAD v4.
9/10 patients had some motor features: extrapyramidal, pyramidal, cerebellar syndrome, dystonia - onset mostly in 20s-30s, one individual had symptoms from age 10 years. 3/10 individuals had mild intellectual disability, 3/10 had developmental delay from birth. 5/10 patients had some dysmorphic features. All 10 patients had some cognitive features (mostly mild): cognitive impairment (adult-onset), mild frontal syndrome, learning difficulties.
CT and brain MRI confirmed the presence of brain calcifications in all reported adult cases (9).
Phenotype and age of onset was variable, even in individuals who harboured the same variant - e.g. siblings in Family 2, homozygous for the same variant: sib II-2 had no motor features, only presented with mild frontal syndrome in her early 30s; sib II-1 presented with global developmental delay from birth, with onset of motor symptoms at age 20 - extrapyramidal and cerebellar syndrome, dystonia.

NAA60 is associated with AR Basal ganglia calcification, idiopathic, 9, autosomal recessive, 620786 in OMIM (accessed 10th Oct 2025).
In summary, while some individuals presented with intellectual disability and cognitive impairment, their symptoms were mild. Thus, these cases do not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Based on the available evidence, this gene should be rated Red for Intellectual disability.
Sources: Literature
Skeletal dysplasia v8.17 SIK3 Sarah Graham reviewed gene: SIK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30232230, 22318228; Phenotypes: Spondyloepimetaphyseal dysplasia, Krakow type, OMIM:618162; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska changed review comment from: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4:
Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400.
Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.; to: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4:
Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025).

Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.
Hereditary neuropathy or pain disorder v7.13 TDP1 Achchuthan Shanmugasundram edited their review of gene: TDP1: Added comment: As reviewed before, PMID:31182267 reported three unrelated probands (two Omani families and one Saudi Arabian family) with homozygous missense variant in TDP1 gene - p.His493Arg, which has been confirmed by haplotype analysis as a founder variant. However, the allele count for this variant in gnomAD v4.1.0 is 13 and it is not found in homozygous state in any of those individuals. In addition, there is also function evidence available that showed that cells expressing TDP1 gene with H493R variant promotes mitochondrial dysfunction and mitophagy.

PMID:39576382 reported a female patient from a Pakistani family with autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1, who presented with additional clinical features including congenital onset of disease, This patient was identified with novel missense variant in TDP1 - p.His478Tyr. via WES and autosomal recessive segregation was confirmed by Sanger sequencing. The allele count for this variant in gnomAD v4.1.0 is 10, of which eight were from South Asian ancestry - however, it is absent in homozygous state in the database.

As reviewed by Ian Berry and Lauren Turton, there is an additional case reported in with p.His493Arg variant and a likely LoF splicing variant, who had early adulthood onset progressive ataxia and axonal neuropathy.; Changed rating: GREEN; Changed publications to: 12244316, 15920477, 17948061, 31182267, 31723605, 39576382; Changed phenotypes to: ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, MONDO:0011801
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska reviewed gene: SPTLC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34059824, 34459874, 35900868, 40027730; Phenotypes: Amyotrophic lateral sclerosis 27, juvenile, 620285, amyotrophic lateral sclerosis 27, juvenile MONDO:0859529; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v6.6 PDE6H Achchuthan Shanmugasundram Classified gene: PDE6H as Green List (high evidence)
DDG2P v6.6 PDE6H Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ronnie Wright, this gene does not fit into the scope of developmental disorders, particularly in the context of R27 Paediatric disorders clinical indication. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Hence, the rating with stay green, pending updates from G2P.
DDG2P v6.6 PDE6H Achchuthan Shanmugasundram Gene: pde6h has been classified as Green List (High Evidence).
DDG2P v6.5 PDE6H Achchuthan Shanmugasundram edited their review of gene: PDE6H: Changed rating: AMBER
Tubulointerstitial kidney disease v3.6 JAG1 John Sayer gene: JAG1 was added
gene: JAG1 was added to Tubulointerstitial kidney disease. Sources: Expert list
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to PMID: 41061854
Phenotypes for gene: JAG1 were set to tubulointersitial kidney disease; kidney failure
Penetrance for gene: JAG1 were set to Incomplete
Mode of pathogenicity for gene: JAG1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: JAG1 was set to GREEN
Added comment: JAG1 causes Alagile syndrome but new evidence shows it can give renal limited phenotypes resembling ADTKD
Sources: Expert list
Adult onset neurodegenerative disorder v8.3 DNAJC7 Cassandra Smith changed review comment from: One report of biallelic inheritance

PMID:40802071 - three affected sibling with homozygous frameshift variant. Parents unaffected; to: One report of biallelic inheritance

PMID:40802071 - three affected siblings with homozygous frameshift variant. Phenotype is ALS. Parents unaffected
Adult onset neurodegenerative disorder v8.3 DNAJC7 Cassandra Smith reviewed gene: DNAJC7: Rating: ; Mode of pathogenicity: None; Publications: 40802071; Phenotypes: ; Mode of inheritance: None
Paediatric or syndromic cardiomyopathy v7.91 MT-ND5 Achchuthan Shanmugasundram changed review comment from: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the while mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.; to: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.
Hypertrophic cardiomyopathy v5.12 MT-ND5 Achchuthan Shanmugasundram changed review comment from: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the while mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.; to: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram changed review comment from: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with ncomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.; to: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with incomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram Classified gene: PDE6H as Amber List (moderate evidence)
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ronnie Wright, the rating for this gene should remain amber. This is because there is only one variant reported across multiple unrelated patients displaying phenotypic variability and without compelling functional evidence.
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram Gene: pde6h has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.38 PDE6H Achchuthan Shanmugasundram commented on gene: PDE6H: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with ncomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.
Retinal disorders v8.38 PDE6H Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 09 September 2025.
Retinal disorders v8.38 PDE6H Achchuthan Shanmugasundram Phenotypes for gene: PDE6H were changed from Achromatopsia 6, OMIM:610024; achromatopsia 6, MONDO:0800197 to Achromatopsia 6, OMIM:610024; achromatopsia 6, MONDO:0800197
Retinal disorders v8.37 PDE6H Achchuthan Shanmugasundram Phenotypes for gene: PDE6H were changed from Retinal Cone Dystrophy 3, 610024; Achromatopsia 6, 610024; Eye Disorders; Achromatopsia, Cone, and Cone-rod Dystrophy to Achromatopsia 6, OMIM:610024; achromatopsia 6, MONDO:0800197
Retinal disorders v8.36 PDE6H Achchuthan Shanmugasundram Publications for gene: PDE6H were set to 15629837; 22901948; 25739440
Retinal disorders v8.35 PDE6H Achchuthan Shanmugasundram reviewed gene: PDE6H: Rating: AMBER; Mode of pathogenicity: None; Publications: 22901948, 25739440, 27472364, 35567543, 36980963; Phenotypes: Achromatopsia 6, OMIM:610024, achromatopsia 6, MONDO:0800197; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.342 FGF14 Arina Puzriakova commented on gene: FGF14
Palmoplantar keratoderma and erythrokeratodermas v1.34 FAM83G Arina Puzriakova Publications for gene: FAM83G were set to
Palmoplantar keratoderma and erythrokeratodermas v1.33 FAM83G Arina Puzriakova Classified gene: FAM83G as Amber List (moderate evidence)
Palmoplantar keratoderma and erythrokeratodermas v1.33 FAM83G Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber inline with expert review by Tom Cullup (GOSH) to facilitate further gathering of data where appropriate which could potentially support future promotion to Green. Already Amber on GMS equivalent panels (R166 and R165)
Palmoplantar keratoderma and erythrokeratodermas v1.33 FAM83G Arina Puzriakova Gene: fam83g has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.122 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from HEREDITARY FOLATE MALABSORPTION (HFM) to Folate malabsorption, hereditary, OMIM:229050
Likely inborn error of metabolism v8.60 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary; Hereditary folate malabsorption (Disorders of folate metabolism and transport) to Folate malabsorption, hereditary, OMIM:229050; Hereditary folate malabsorption (Disorders of folate metabolism and transport)
Childhood onset dystonia, chorea or related movement disorder v7.12 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary, 229050 to Folate malabsorption, hereditary, OMIM:229050
Adult onset dystonia, chorea or related movement disorder v5.2 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary, 229050; Dystonia to Folate malabsorption, hereditary, OMIM:229050
Fetal anomalies v6.96 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from HEREDITARY FOLATE MALABSORPTION to Folate malabsorption, hereditary, OMIM:229050
Undiagnosed metabolic disorders v1.634 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Hereditary folate malabsorption (Disorders of folate metabolism and transport); Folate malabsorption, hereditary to Folate malabsorption, hereditary, OMIM:229050; Hereditary folate malabsorption (Disorders of folate metabolism and transport)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.44 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary 229050; Defects of Vitamin B12 and Folate metabolism; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Combined immunodeficiencies with associated or syndromic features to Folate malabsorption, hereditary, OMIM:229050; Defects of Vitamin B12 and Folate metabolism; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Combined immunodeficiencies with associated or syndromic features
COVID-19 research v1.145 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary 229050; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Defects of Vitamin B12 and Folate metabolism; Combined immunodeficiencies with associated or syndromic features to Folate malabsorption, hereditary, OMIM:229050; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Defects of Vitamin B12 and Folate metabolism; Combined immunodeficiencies with associated or syndromic features
Cerebral folate deficiency v1.3 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary 229050 to Folate malabsorption, hereditary, OMIM:229050
Cytopenias and congenital anaemias v1.120 SLC46A1 Arina Puzriakova Classified gene: SLC46A1 as Green List (high evidence)
Cytopenias and congenital anaemias v1.120 SLC46A1 Arina Puzriakova Added comment: Comment on list classification: New gene added as Green. At least 5 unrelated individuals with biallelic variants in this gene and hereditary folate malabsorption which can progress to severe pancytopenia (PMID: 11807405; 17446347; 21333572; 40937236). This is a key feature of this condition and warrants inclusion on the panel.
Cytopenias and congenital anaemias v1.120 SLC46A1 Arina Puzriakova Gene: slc46a1 has been classified as Green List (High Evidence).
Cytopenia - NOT Fanconi anaemia v4.24 SLC46A1 Arina Puzriakova Classified gene: SLC46A1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.24 SLC46A1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green. At least 5 unrelated individuals with biallelic variants in this gene and hereditary folate malabsorption which can progress to severe pancytopenia (PMID: 11807405; 17446347; 21333572; 40937236). This is a key feature of this condition and warrants inclusion on the panel.
Cytopenia - NOT Fanconi anaemia v4.24 SLC46A1 Arina Puzriakova Gene: slc46a1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.23 SLC46A1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SLC46A1.
Tag Q3_25_NHS_review tag was added to gene: SLC46A1.
Cytopenia - NOT Fanconi anaemia v4.23 SLC46A1 Arina Puzriakova Entity copied from Cytopenias and congenital anaemias v1.119
Cytopenia - NOT Fanconi anaemia v4.23 SLC46A1 Arina Puzriakova gene: SLC46A1 was added
gene: SLC46A1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert Review,Literature
Mode of inheritance for gene: SLC46A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC46A1 were set to 21333572; 17446347; 29390264; 11804211; 17641272
Phenotypes for gene: SLC46A1 were set to Folate malabsorption, hereditary, OMIM:229050; anemia; pancytopenia
Cytopenias and congenital anaemias v1.119 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption; anemia; pancytopenia to Folate malabsorption, hereditary, OMIM:229050; anemia; pancytopenia
Publications for gene: SLC46A1 were updated from PMID: 21333572; 17446347; 29390264; 11804211; 17641272 to 21333572; 17446347; 29390264; 11804211; 17641272
Intellectual disability v9.121 SF1 Achchuthan Shanmugasundram Classified gene: SF1 as Amber List (moderate evidence)
Intellectual disability v9.121 SF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are fifteen unrelated patients reported with monoallelic SF1 variants and a neurodevelopmental disorder, of which four patients had intellectual disability of moderate severity. Hence, this gene can be promoted to green rating in the next update.
Intellectual disability v9.121 SF1 Achchuthan Shanmugasundram Gene: sf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.120 SF1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.; to: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v4.1.0 non-UK Biobank, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Intellectual disability v9.120 SF1 Achchuthan Shanmugasundram Phenotypes for gene: SF1 were changed from to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.119 SF1 Achchuthan Shanmugasundram Publications for gene: SF1 were set to PMID: 40987292
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram Tag Q3_25_NHS_review tag was added to gene: SF1.
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SF1.
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.; to: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram reviewed gene: SF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40987292; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v7.13 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from hepatic dysfunction; sensory axonal neuropathy to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; hepatic dysfunction; sensory axonal neuropathy
Hereditary neuropathy or pain disorder v7.12 DLD Arina Puzriakova Classified gene: DLD as Red List (low evidence)
Hereditary neuropathy or pain disorder v7.12 DLD Arina Puzriakova Added comment: Comment on list classification: Several cases reported with Dihydrolipoamide dehydrogenase deficiency (OMIM:246900) but only a single report linking this to a reversible sensory neuropathy (PMID:40888368). It is worth noting that neuropathy occurred without lactic acidosis or secondary vitamin deficiencies, coupled with lipid deposition in peripheral nerve biopsies. This requires validation through additional corroborative cases and therefore rating as Red until such cases emerge.
Hereditary neuropathy or pain disorder v7.12 DLD Arina Puzriakova Gene: dld has been classified as Red List (Low Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.11 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoamide dehydrogenase deficiency, 246900 to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
Mitochondrial disorders v9.32 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoamide dehydrogenase deficiency, 246900; Leigh syndrome to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; Leigh syndrome
Intellectual disability v9.118 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoamide dehydrogenase deficiency, 246900; DIHYDROLIPOAMIDE DEHYDROGENASE (E3) DEFICIENCY to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
Fetal anomalies v6.95 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from DIHYDROLIPOAMIDE DEHYDROGENASE (E3) DEFICIENCY; LEIGH SYNDROME to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
Likely inborn error of metabolism v8.59 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoyl dehydrogenase deficiency (Disorders of pyruvate metabolism); Leigh syndrome; Dihydrolipoamide dehydrogenase deficiency, 246900 to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; Dihydrolipoyl dehydrogenase deficiency (Disorders of pyruvate metabolism); Leigh syndrome
Possible mitochondrial disorder - nuclear genes v4.13 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY, 246900 to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
Undiagnosed metabolic disorders v1.633 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoyl dehydrogenase deficiency (Disorders of pyruvate metabolism); Dihydrolipoamide dehydrogenase deficiency, 246900; Leigh syndrome to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; Dihydrolipoyl dehydrogenase deficiency (Disorders of pyruvate metabolism); Leigh syndrome
Pyruvate dehydrogenase (PDH) deficiency v1.37 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY OMIM:246900; pyruvate dehydrogenase E3 deficiency MONDO:0009529 to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; pyruvate dehydrogenase E3 deficiency MONDO:0009529
Paediatric or syndromic cardiomyopathy v7.91 RPL3L Arina Puzriakova Tag Q3_24_NHS_review tag was added to gene: RPL3L.
Tag Q3_25_promote_green tag was added to gene: RPL3L.
Tag Q3_25_expert_review tag was added to gene: RPL3L.
Paediatric or syndromic cardiomyopathy v7.91 RPL3L Arina Puzriakova Publications for gene: RPL3L were set to 32514796; 32870709
Dilated and arrhythmogenic cardiomyopathy v3.9 RPL3L Arina Puzriakova Publications for gene: RPL3L were set to 32514796; 32870709
Dilated and arrhythmogenic cardiomyopathy v3.8 RPL3L Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RPL3L.
Tag Q3_25_expert_review tag was added to gene: RPL3L.
Paediatric or syndromic cardiomyopathy v7.90 RPL3L Arina Puzriakova Classified gene: RPL3L as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.90 RPL3L Arina Puzriakova Added comment: Comment on list classification: There are now at least 14 individuals from 11 families with severe early-onset dilated cardiomyopathy. Almost all attributed to compound heterozygous missense variants (also 3 frameshift and 1 splice-site) but the underlying mechanism remains poorly understood. Notably, RPL3L knockout in mice did not result in any severe heart defects. (PMID: 32514796; 32870709; 36291431; 35323613; 37308880; 39803500; 40820268)

The number of cases reported supports inclusion on this panel as Green, but given that mouse models are conflicting and this addition was rejected in a previous GMS panel release, tagging for additional GMS expert review to determine the appropriate rating.
Paediatric or syndromic cardiomyopathy v7.90 RPL3L Arina Puzriakova Gene: rpl3l has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v3.8 RPL3L Arina Puzriakova Classified gene: RPL3L as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v3.8 RPL3L Arina Puzriakova Added comment: Comment on list classification: There are now at least 14 individuals from 11 families with severe early-onset dilated cardiomyopathy. Almost all attributed to compound heterozygous missense variants (also 3 frameshift and 1 splice-site) but the underlying mechanism remains poorly understood. Notably, RPL3L knockout in mice did not result in any severe heart defects. (PMID: 32514796; 32870709; 36291431; 35323613; 37308880; 39803500; 40820268)

The number of cases reported supports inclusion on this panel as Green, but given that mouse models are conflicting and this addition was rejected in a previous GMS panel release, tagging for additional GMS expert review to determine the appropriate rating.
Dilated and arrhythmogenic cardiomyopathy v3.8 RPL3L Arina Puzriakova Gene: rpl3l has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.89 RPL3L Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype listed in OMIM: Cardiomyopathy, dilated, 2D, OMIM:619371 (accessed on 09-10-2025)
Paediatric or syndromic cardiomyopathy v7.89 RPL3L Arina Puzriakova Phenotypes for gene: RPL3L were changed from Neonatal dilated cardiomyopathy; dilated cardiomyopathy, MONDO:0005021 to Cardiomyopathy, dilated, 2D, OMIM:619371
Dilated and arrhythmogenic cardiomyopathy v3.7 RPL3L Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype listed in OMIM: Cardiomyopathy, dilated, 2D, OMIM:619371 (accessed on 09-10-2025)
Dilated and arrhythmogenic cardiomyopathy v3.7 RPL3L Arina Puzriakova Phenotypes for gene: RPL3L were changed from Neonatal dilated cardiomyopathy; dilated cardiomyopathy, MONDO:0005021 to Cardiomyopathy, dilated, 2D, OMIM:619371
Adult onset hereditary spastic paraplegia v6.3 AP5Z1 Arina Puzriakova Classified gene: AP5Z1 as Green List (high evidence)
Adult onset hereditary spastic paraplegia v6.3 AP5Z1 Arina Puzriakova Gene: ap5z1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.41 LSS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

Hence, clinical opinion is being sought on whether there is sufficient evidence available for the promotion of this gene to green rating.; to: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

After seeking clinical opinion, it has been decided to recommend this gene for promotion to green rating in the next GMS update.
Skeletal dysplasia v8.17 SIK3 Eleanor Williams Classified gene: SIK3 as Amber List (moderate evidence)
Skeletal dysplasia v8.17 SIK3 Eleanor Williams Added comment: Comment on list classification: Promoted to amber since there is one published case plus a supportive mouse model. Following up with evidence from UK NHS cases and the rating maybe reviewed.
Skeletal dysplasia v8.17 SIK3 Eleanor Williams Gene: sik3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.94 SIK3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 8th October 2025
Fetal anomalies v6.94 SIK3 Eleanor Williams Phenotypes for gene: SIK3 were changed from Spondyloepimetaphyseal dysplasia, Krakow type, 618162 to ?Spondyloepimetaphyseal dysplasia, Krakow type, OMIM:618162; spondyloepimetaphyseal dysplasia, Krakow type, MONDO:0032571
Skeletal dysplasia v8.16 SIK3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 8th October 2025
Skeletal dysplasia v8.16 SIK3 Eleanor Williams Phenotypes for gene: SIK3 were changed from to ?Spondyloepimetaphyseal dysplasia, Krakow type, OMIM:618162; spondyloepimetaphyseal dysplasia, Krakow type, MONDO:0032571
Skeletal dysplasia v8.15 SIK3 Eleanor Williams Classified gene: SIK3 as Amber List (moderate evidence)
Skeletal dysplasia v8.15 SIK3 Eleanor Williams Gene: sik3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.117 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Intellectual disability.
Intellectual disability v9.117 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.117 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.117 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years; not associated with intellectual disability).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.117 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.117 LGI1 Ida Ertmanska edited their review of gene: LGI1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.117 LGI1 Arina Puzriakova Mode of inheritance for gene: LGI1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with severe developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.116 PPOX Ida Ertmanska commented on gene: PPOX: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163; 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.116 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed publications to: 8290408, 9811936, 2004012, 35164799, 37879139, 40114189
Early onset or syndromic epilepsy v8.41 LGI1 Arina Puzriakova Publications for gene: LGI1 were set to 15079010; 11810107; 22496201
Early onset or syndromic epilepsy v8.40 LGI1 Arina Puzriakova Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1 600512 to Epilepsy, familial temporal lobe, 1, OMIM:600512; developmental and epileptic encephalopathy, MONDO:0100620
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163; 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Early onset or syndromic epilepsy v8.39 LGI1 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: LGI1.
Intellectual disability v9.116 LGI1 Arina Puzriakova Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1 600512; AUTOSOMAL DOMINANT PARTIAL EPILEPSY WITH AUDITORY FEATURES to Epilepsy, familial temporal lobe, 1, OMIM:600512; developmental and epileptic encephalopathy, MONDO:0100620
Intellectual disability v9.115 PPOX Ida Ertmanska changed review comment from: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.115 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 6143163, 8290408, 9811936, 2004012, 35164799, 37879139, 40114189; Phenotypes: Variegate porphyria, childhood-onset, 620483, variegate porphyria, MONDO:0008297; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v9.115 LGI1 Arina Puzriakova Publications for gene: LGI1 were set to 0
Intellectual disability v9.114 LGI1 Arina Puzriakova Mode of inheritance for gene: LGI1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Monogenic hearing loss v5.28 TBX2 Arina Puzriakova Tag watchlist was removed from gene: TBX2.
Monogenic hearing loss v5.28 TBX2 Arina Puzriakova Tag microdeletion tag was added to gene: TBX2.
Monogenic hearing loss v5.28 TBX2 Arina Puzriakova Classified gene: TBX2 as Amber List (moderate evidence)
Monogenic hearing loss v5.28 TBX2 Arina Puzriakova Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.27 TBX2 Arina Puzriakova Tag watchlist tag was added to gene: TBX2.
Early onset or syndromic epilepsy v8.39 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.113 LGI1 Ida Ertmanska commented on gene: LGI1: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.; to: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - later-onset epilepsy, not associated with intellectual disability / developmental delay (PMID: 26773249). Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in those patients, LGI1 should be rated RED for Intellectual disability.; to: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.
Intellectual disability v9.113 LGI1 Ida Ertmanska reviewed gene: LGI1: Rating: RED; Mode of pathogenicity: None; Publications: 26773249, 40455867, 41000458; Phenotypes: developmental and epileptic encephalopathy MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.39 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.39 EMX2 Arina Puzriakova Phenotypes for gene: EMX2 were changed from Schizencephaly, 269160 to Schizencephaly, OMIM:269160
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska edited their review of gene: LGI1: Added comment: Comment on mode of inheritance: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; Changed publications to: 26773249, 40455867, 41000458
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4

Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.

Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form); to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40455867, 41000458; Phenotypes: Epilepsy, familial temporal lobe, 600512, developmental and epileptic encephalopathy MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOPI has been updated to 'BIALLELIC, autosomal or pseudoautosomal' and the rating has been changes to amber with the current evidence.; to: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOI and rating have been updated to 'BIALLELIC, autosomal or pseudoautosomal' and amber respectively.
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram Classified gene: ADCY5 as Amber List (moderate evidence)
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOPI has been updated to 'BIALLELIC, autosomal or pseudoautosomal' and the rating has been changes to amber with the current evidence.
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram Gene: adcy5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.112 ADCY5 Achchuthan Shanmugasundram Mode of inheritance for gene: ADCY5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.111 ADCY5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: ADCY5 was changed from Other - please provide details in the comments to None
Intellectual disability v9.110 ADCY5 Achchuthan Shanmugasundram Publications for gene: ADCY5 were set to 28511835
Intellectual disability v9.109 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Biallelic variants in ADCY5 gene has been associated with 'Neurodevelopmental disorder with hyperkinetic movements and dyskinesia' phenotype in OMIM (MIM #619651, OMIM accessed on 06 October 2025).
Intellectual disability v9.109 ADCY5 Achchuthan Shanmugasundram Phenotypes for gene: ADCY5 were changed from Dyskinesia, familial, with facial myokymia, 606703 to Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651; neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211
Intellectual disability v9.108 ADCY5 Achchuthan Shanmugasundram reviewed gene: ADCY5: Rating: AMBER; Mode of pathogenicity: None; Publications: 33704598, 34631954; Phenotypes: Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651, neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.108 KCND3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 5th October 2025
Intellectual disability v9.108 KCND3 Eleanor Williams Phenotypes for gene: KCND3 were changed from Spinocerebellar ataxia 19, 607346 to Spinocerebellar ataxia 19, OMIM: 607346; spinocerebellar ataxia type 19/22, MONDO:0011819
Intellectual disability v9.107 KCND3 Eleanor Williams Publications for gene: KCND3 were set to
Intellectual disability v9.106 KCND3 Eleanor Williams Classified gene: KCND3 as Amber List (moderate evidence)
Intellectual disability v9.106 KCND3 Eleanor Williams Added comment: Comment on list classification: Promoting to amber as there are some cases with intellectual disability/cognitive impairment however this appears to be at the milder end of the phenotypic spectrum.
Intellectual disability v9.106 KCND3 Eleanor Williams Gene: kcnd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Tag dd_review tag was added to gene: KCND3.
Tag Q3_25_promote_green tag was added to gene: KCND3.
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Classified gene: KCND3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Gene: kcnd3 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.10 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least four unrelated families reported with biallelic ADCY5 variants and with childhood-onset movement disorder.

As there is sufficient evidence available for the association of both monoallelic and biallelic ADCY5 variants with the phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Childhood onset dystonia, chorea or related movement disorder v7.10 ADCY5 Achchuthan Shanmugasundram Mode of inheritance for gene: ADCY5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v7.9 ADCY5 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: ADCY5.
Childhood onset dystonia, chorea or related movement disorder v7.9 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 04 October 2025.
Childhood onset dystonia, chorea or related movement disorder v7.9 ADCY5 Achchuthan Shanmugasundram Phenotypes for gene: ADCY5 were changed from Dyskinesia, familial, with facial myokymia, 606703; dystonia; Familial dyskinesia, 606703 to Dyskinesia with orofacial involvement, autosomal dominant, OMIM:606703; dyskinesia with orofacial involvement, autosomal dominant, MONDO:0800028; Dyskinesia with orofacial involvement, autosomal recessive, OMIM:619647; dyskinesia with orofacial involvement, autosomal recessive, MONDO:0030625; Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651; neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211
Childhood onset dystonia, chorea or related movement disorder v7.8 ADCY5 Achchuthan Shanmugasundram Publications for gene: ADCY5 were set to 11310626; 24700542
Childhood onset dystonia, chorea or related movement disorder v7.7 ADCY5 Achchuthan Shanmugasundram changed review comment from: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).; to: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).
Childhood onset dystonia, chorea or related movement disorder v7.7 ADCY5 Achchuthan Shanmugasundram edited their review of gene: ADCY5: Changed publications to: 28971144, 30975617, 33704598, 34631954
Childhood onset dystonia, chorea or related movement disorder v7.7 ADCY5 Achchuthan Shanmugasundram commented on gene: ADCY5: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).
Childhood onset dystonia, chorea or related movement disorder v7.7 ADCY5 Achchuthan Shanmugasundram reviewed gene: ADCY5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskinesia with orofacial involvement, autosomal dominant, OMIM:606703, dyskinesia with orofacial involvement, autosomal dominant, MONDO:0800028, Dyskinesia with orofacial involvement, autosomal recessive, OMIM:619647, dyskinesia with orofacial involvement, autosomal recessive, MONDO:0030625, Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651, neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v6.5 NRXN2 Achchuthan Shanmugasundram edited their review of gene: NRXN2: Added comment: This gene has now been downgraded to 'limited' rating on the DD panel in Gene2Phenotype resource. So, it will be demoted to red on this panel in the next GMS update.; Changed rating: RED; Changed phenotypes to: AUTISM, OMIM:209850, NRXN2-related autism
DDG2P v6.5 GSPT2 Achchuthan Shanmugasundram edited their review of gene: GSPT2: Added comment: This gene has now been downgraded to 'limited' rating on the DD panel in Gene2Phenotype resource. So, it will be demoted to red on this panel in the next GMS update.; Changed rating: RED; Changed phenotypes to: GSPT2-related intellectual disability
DDG2P v6.5 GIGYF1 Achchuthan Shanmugasundram edited their review of gene: GIGYF1: Added comment: This gene has now been downgraded to 'limited' rating on the DD panel in Gene2Phenotype resource. So, it will be demoted to red on this panel in the next GMS update.; Changed rating: RED; Changed phenotypes to: GIGYF1-related developmental disorder
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Knock-in mice (p.Phe227del equivalent) displayed defects in motor coordination and balance, and neuroinflammation. Knock-out Kcnd3 -/- mice showed no observable phenotype. Molecular evidence suggests that the misfolded protein induces a trafficking defect in the Golgi apparatus - a dominant negative effect (PMID: 39562497).
Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28947073, 32823520, 32921676, 39562497
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493; 28947073; 32823520; 32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient.
Knock-in mice (p.Phe227del equivalent) displayed defects in motor coordination and balance, and neuroinflammation. Knock-out Kcnd3 -/- mice showed no observable phenotype. Molecular evidence suggests that the misfolded protein induces a trafficking defect in the Golgi apparatus - a dominant negative effect (PMID: 39562497).
Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28895081, 32823520, 31293010, 32921676, 39562497
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

Functional evidence: PMID: 39562497 Hung et al., 2025
A mouse model with a p.Phe227del-equivalent Kcnd3 knock-in displayed defects in motor coordination and balance, neuroinflammation, trafficking defect due to accumulation in the golgi apparatus, and a transcriptional effect: downregulation of genes involved in neurogenesis. Meanwhile, Kcnd3 knockout mice showed no observable phenotype. This evidence suggests a dominant negative effect of the mutation, and supports the association of KCND3 and neurodevelopmental disorders.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska commented on gene: KCND3: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28947073, 32823520, 32921676
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.


PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and childhood onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures.
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.


PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska gene: KCND3 was added
gene: KCND3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: KCND3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCND3 were set to 26189493; 28895081; 32823520; 31293010; 32921676
Phenotypes for gene: KCND3 were set to Spinocerebellar ataxia 19 (OMIM: 607346); spinocerebellar ataxia type 19/22, MONDO:0011819
Review for gene: KCND3 was set to GREEN
Added comment: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and childhood onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures.
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with childhood onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed phenotypes to: Spinocerebellar ataxia 19 (OMIM: 607346), spinocerebellar ataxia type 19/22, MONDO:0011819
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy.
Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy.
Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are at least 4 published reports of individuals with early onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, their cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28895081, 32823520, 31293010, 32921676
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 32823520 – Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Added comment: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are at least 4 published reports of individuals with early onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, their cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; Changed publications to: 26189493, 28895081, 32823520, 32921676
Intellectual disability v9.105 KCND3 Ida Ertmanska reviewed gene: KCND3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 19 (OMIM: 607346); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v8.13 TBCB Arina Puzriakova gene: TBCB was added
gene: TBCB was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
watchlist, founder-effect tags were added to gene: TBCB.
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 (2025) - 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with the same homozygous founder variant (c.589T>A, p.(Tyr197Asn)) in TBCB. Affected individuals presented during infancy with motor or speech delays and developed late-childhood-onset spastic paraparesis (onset around 9-12 years old), global developmental delay (formal assessment done in 5 individuals, indicating mild ID), and autism spectrum. Brain MRI showed corpus collosum thinning in 3, and decreased white matter in 2.

The c.589T>A (GRCh38: 19-36125492-T-A) variant has an AF of 0.006485 in the Ashkenazi Jewish population in gnomAD v4 with 0 homozygotes. Classified as VUS in ClinVar based on 1 submission.

TBCB protein levels were reduced in patient fibroblasts. Drosophila melanogaster model showed reduced survival and impaired climbing ability.
Sources: Literature
DDG2P v6.5 FGF5 Eleanor Williams Tag curated_removed tag was added to gene: FGF5.
Arthrogryposis v9.11 ERCC1 Eleanor Williams Added comment: Comment on phenotypes: Phenotype data access in OMIM on 2nd October 2025
Arthrogryposis v9.11 ERCC1 Eleanor Williams Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, OMIM:610758 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Deleted their comment
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams edited their review of gene: DST: Changed rating: RED
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Tag curated_removed tag was added to gene: DST.
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Classified gene: DST as No list
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Added comment: Comment on list classification: Removing from this panel. Since the presentation is syndromic it is better suited to the Paediatric or syndromic cardiomyopathy panel (panel ID 749)
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Gene: dst has been removed from the panel.
Dilated and arrhythmogenic cardiomyopathy v3.5 DST Eleanor Williams Classified gene: DST as Red List (low evidence)
Dilated and arrhythmogenic cardiomyopathy v3.5 DST Eleanor Williams Gene: dst has been classified as Red List (Low Evidence).
Fetal anomalies v6.93 DST Eleanor Williams Publications for gene: DST were set to 37431644; 40497796; 35942699
Fetal anomalies v6.92 DST Eleanor Williams Phenotypes for gene: DST were changed from Arthrogryposis multiplex congenita to Arthrogryposis multiplex congenita, MONDO:0015168; arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Fetal anomalies v6.91 DST Eleanor Williams Publications for gene: DST were set to 37431644
Fetal anomalies v6.90 DST Eleanor Williams reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: None; Publications: 40497796, 35942699; Phenotypes: arthrogryposis, MONDO:0859248, cardiomyopathy, MONDO:0004994, congenital myopathy, MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams changed review comment from: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS approval.; to: Comment on list classification: Promoting to amber but checking with the clinical team whether this is the right panel for this gene.
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams Tag Q3_25_promote_green was removed from gene: DST.
Paediatric or syndromic cardiomyopathy v7.88 DST Eleanor Williams Classified gene: DST as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.88 DST Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.
Paediatric or syndromic cardiomyopathy v7.88 DST Eleanor Williams Gene: dst has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.87 DST Eleanor Williams gene: DST was added
gene: DST was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Q3_25_promote_green tags were added to gene: DST.
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to 40497796; 35942699
Phenotypes for gene: DST were set to arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Review for gene: DST was set to GREEN
Added comment: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Created: 30 Sep 2025, 5:18 p.m. | Last Modified: 30 Sep 2025, 5:18 p.m.
Sources: Literature
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams changed review comment from: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Sources: Literature; to: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Sources: Literature
Arthrogryposis v9.10 DST Eleanor Williams changed review comment from: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.; to: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Congenital myopathy v6.38 DST Eleanor Williams changed review comment from: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.; to: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Intellectual disability v9.105 SF1 Mike Spiller gene: SF1 was added
gene: SF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF1 were set to PMID: 40987292
Review for gene: SF1 was set to GREEN
Added comment: Gene-disease associated reported in PMID: 40987292.
15 patients with varying levels of global developmental delay and ASD. One of these is intronic with gnomad AC = 9 so can be disregarded.
Of the remaining 14 almost all are de novo. 13 absent from gnomad, 1 with AC = 1.
7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations. 6/7 missenses at conserved residues within missense-constrained regions, but no hotspot cluster..

NMD variants show the most consistent phenotype of mild-moderate ID/GDD.
Of the total 14 cases ID/GDD mild in 5, moderate in 4, level not stated in 5. Language delays most consistent characteristic..

Functional studies using SF1 knockdown in neural progenitor cells show substantial effects on gene regulation and alternative splicing, consistent with SF1 loss of function. However paper does not record if this led to any effects on NPC function.

Gene constrained for LOF (gnomad v4 o/e 0.12, LOEUF 0.22).
Sources: Literature
Arthrogryposis v9.10 ERCC1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ERCC1.
Arthrogryposis v9.10 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Arthrogryposis v9.10 ERCC1 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but this gene could be promoted to Green at the next GMS panel update.

Two unrelated individuals with biallelic ERCC1 variants have been reported who had cerebrooculofacioskeletal syndrome which includes contractures. Both died in early childhood. Cells from both individuals showed sensitivity to UV-induced DNA damage (PMID: 17273966; 23623389).

Rated Green on other GMS panels for this phenotype (Intellectual disability, Fetal anomalies) based on the same evidence. Number of cases is likely to be small due to severity of the condition.
Arthrogryposis v9.10 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.10 ERCC1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

PMID: 40684071 - liver dysfunction was reported in all affected individuals with ERCC1-hepatorenal syndrome, with three children requiring liver transplants.

Progressive cholestatic liver disease was found in 3 individuals (PV50LD, PV46LD, XE28CH). Individual CA16LD also developed neonatal cholestasis which resolved, and XE1AH developed liver disease later than others in the cohort but showed signs suggestive of chronic cholestatic disease.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - liver dysfunction was reported in all affected individuals with ERCC1-hepatorenal syndrome, with three children requiring liver transplants.

Progressive cholestatic liver disease was found in 3 individuals (PV50LD, PV46LD, XE28CH). Individual CA16LD also developed neonatal cholestasis which resolved, and XE1AH developed liver disease later than others in the cohort but showed signs suggestive of chronic cholestatic disease (PMID: 40684071)
Paediatric disorders - additional genes v7.10 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from hepatorenal syndrome, MONDO:0001382 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758; hepatorenal syndrome, MONDO:0001382
Renal tubulopathies v5.8 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Renal tubulopathies v5.8 ERCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - renal dysfunction was reported in all affected individuals with ERCC1-hepatorenal syndrome.

Renal involvement is variable, including tubular dysfunction (5/7) and nephrocalcinosis (2/7). The two oldest individuals progressed to end-stage renal disease in adolescence.
Renal tubulopathies v5.8 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.9 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.9 ERCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 5 unrelated cases with a multisystem phenotype characteristic of a DNA repair disorder which is relevant for inclusion on the Paediatric disorders super panel.
Paediatric disorders - additional genes v7.9 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.10 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Cholestasis v3.10 ERCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

PMID: 40684071 - liver dysfunction was reported in all affected individuals with ERCC1-hepatorenal syndrome, with three children requiring liver transplants.

Progressive cholestatic liver disease was found in 3 individuals (PV50LD, PV46LD, XE28CH). Individual CA16LD also developed neonatal cholestasis which resolved, and XE1AH developed liver disease later than others in the cohort but showed signs suggestive of chronic cholestatic disease.
Cholestasis v3.10 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v5.7 ERCC1 Arina Puzriakova gene: ERCC1 was added
gene: ERCC1 was added to Renal tubulopathies. Sources: Literature
Q3_25_promote_green tags were added to gene: ERCC1.
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to 40684071
Phenotypes for gene: ERCC1 were set to hepatorenal syndrome, MONDO:0001382
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 is associated with a spectrum of DNA repair disorders from severe neonatal conditions (Cerebrooculofacioskeletal syndrome 4, OMIM:610758) to multisystem disorders (Xeroderma Pigmentosum) that can extend into adolescence and early adulthood.

A recent study (PMID: 40684071) identified seven individuals from five families carrying biallelic ERCC1 variants, who exhibited a distinct clinical phenotype including growth restriction, photosensitivity, and kidney and liver dysfunction. Hepatocellular carcinoma developed in four children, resulting in death in two. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Most reported individuals have c.466 C > T (p.Arg156Trp) on at least one allele, often with a LOF variant in trans. Functional assays using patient-derived fibroblasts demonstrated significant destabilisation of the ERCC1-XPF complex and defects in NER and ICL repair.
Sources: Literature
Paediatric disorders - additional genes v7.8 ERCC1 Arina Puzriakova gene: ERCC1 was added
gene: ERCC1 was added to Paediatric disorders - additional genes. Sources: Literature
Q3_25_promote_green tags were added to gene: ERCC1.
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to 40684071
Phenotypes for gene: ERCC1 were set to hepatorenal syndrome, MONDO:0001382
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 is associated with a spectrum of DNA repair disorders from severe neonatal conditions (Cerebrooculofacioskeletal syndrome 4, OMIM:610758) to multisystem disorders (Xeroderma Pigmentosum) that can extend into adolescence and early adulthood.

A recent study (PMID: 40684071) identified seven individuals from five families carrying biallelic ERCC1 variants, who exhibited a distinct clinical phenotype including growth restriction, photosensitivity, and kidney and liver dysfunction. Hepatocellular carcinoma developed in four children, resulting in death in two. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Most reported individuals have c.466 C > T (p.Arg156Trp) on at least one allele, often with a LOF variant in trans. Functional assays using patient-derived fibroblasts demonstrated significant destabilisation of the ERCC1-XPF complex and defects in NER and ICL repair.
Sources: Literature
Cholestasis v3.9 ERCC1 Arina Puzriakova gene: ERCC1 was added
gene: ERCC1 was added to Cholestasis. Sources: Literature
Q3_25_promote_green tags were added to gene: ERCC1.
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to 40684071
Phenotypes for gene: ERCC1 were set to hepatorenal syndrome, MONDO:0001382
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 is associated with a spectrum of DNA repair disorders from severe neonatal conditions (Cerebrooculofacioskeletal syndrome 4, OMIM:610758) to multisystem disorders (Xeroderma Pigmentosum) that can extend into adolescence and early adulthood.

A recent study (PMID: 40684071) identified seven individuals from five families carrying biallelic ERCC1 variants, who exhibited a distinct clinical phenotype including growth restriction, photosensitivity, and kidney and liver dysfunction. Hepatocellular carcinoma developed in four children, resulting in death in two. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Most reported individuals have c.466 C > T (p.Arg156Trp) on at least one allele, often with a LOF variant in trans. Functional assays using patient-derived fibroblasts demonstrated significant destabilisation of the ERCC1-XPF complex and defects in NER and ICL repair.
Sources: Literature
Childhood solid tumours v5.6 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Childhood solid tumours v5.6 ERCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 individuals from 3 families with childhood-onset hepatocellular carcinoma due to biallelic variants in this gene. Diagnosis may have treatment implications due to heightened sensitivity of individuals with ERCC1 variants to DNA-damaging agents.
Childhood solid tumours v5.6 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v5.5 ERCC1 Arina Puzriakova Publications for gene: ERCC1 were set to
Childhood solid tumours v5.4 ERCC1 Arina Puzriakova Tag dd_review tag was added to gene: ERCC1.
Tag Q3_25_promote_green tag was added to gene: ERCC1.
Childhood solid tumours v5.4 ERCC1 Arina Puzriakova reviewed gene: ERCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40684071; Phenotypes: xeroderma pigmentosum, MONDO:0019600, hepatorenal syndrome, MONDO:0001382; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult solid tumours cancer susceptibility v2.34 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from xeroderma pigmentosum, MONDO:0019600 to hepatocellular carcinoma, MONDO:0007256
Adult solid tumours cancer susceptibility v2.33 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Red List (low evidence)
Adult solid tumours cancer susceptibility v2.33 ERCC1 Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red as typically childhood onset. Could only identify one report (conference abstract) describing "First Report of ERCC1-Associated Adult-Onset Hepatocellular Carcinoma, Ataxia, and Cognitive Decline" due to a homozygous variant c.466 C>T, p.(Arg156Trp) in exon 4 - https://www.mdsabstracts.org/abstract/first-report-of-ercc1-associated-adult-onset-hepatocellular-carcinoma-ataxia-and-cognitive-decline/
Adult solid tumours cancer susceptibility v2.33 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Red List (Low Evidence).
Childhood solid tumours cancer susceptibility v1.29 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from xeroderma pigmentosum, MONDO:0019600 to xeroderma pigmentosum, MONDO:0019600; hepatorenal syndrome, MONDO:0001382
Childhood solid tumours v5.4 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from xeroderma pigmentosum, MONDO:0019600 to xeroderma pigmentosum, MONDO:0019600; hepatorenal syndrome, MONDO:0001382
Adult solid tumours cancer susceptibility v2.32 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa to xeroderma pigmentosum, MONDO:0019600
Childhood solid tumours cancer susceptibility v1.28 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa to xeroderma pigmentosum, MONDO:0019600
Childhood solid tumours v5.3 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa to xeroderma pigmentosum, MONDO:0019600
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.6 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosum; ERCC1-Hepatorenal Syndrome to xeroderma pigmentosum, MONDO:0019600; hepatorenal syndrome, MONDO:0001382
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.5 ERCC1 Arina Puzriakova Added comment: Comment on publications: PMID: 23623389 - homozygous missense variant reported in a patient with Cockayne syndrome
PMID: 17273966 - ERCC1 deficiency in a patient with cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure
PMID: 40684071 - hepatorenal syndrome identified in seven individuals from five families carrying biallelic ERCC1 variants. All individuals presented with skin and/or ocular photosensitivity, among other features such as growth restriction, café-au-lait macules, kidney impairment, progressive cholestatic liver disease, and hepatocellular carcinoma.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.5 ERCC1 Arina Puzriakova Publications for gene: ERCC1 were set to 23623389 - homozygous missense variant reported in a patient with Cockayne syndrome; 17273966 - ERCC1 deficiency in a patient with cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.4 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosum to Xeroderma Pigmentosum; ERCC1-Hepatorenal Syndrome
Anophthalmia or microphthalmia v1.55 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, 610758 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Anophthalmia or microphthalmia v1.54 ERCC1 Arina Puzriakova Mode of inheritance for gene: ERCC1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.90 EMX2 Ida Ertmanska commented on gene: EMX2: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other schizencephaly cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Fetal anomalies.
Fetal anomalies v6.90 EMX2 Ida Ertmanska reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 8528262, 9153481, 9359037, 17506092, 18409201, 20157829; Phenotypes: Schizencephaly, OMIM:269160, schizencephaly, MONDO:0010011; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Corneal dystrophy v4.3 PRDX3 Eleanor Williams changed review comment from: The 'founder-effect' tag has been added as the same variant has been identified in multiple families from the same populations.; to: The 'founder-effect' tag has been added as the same variant has been identified in multiple families from the same ethnic background.
Corneal dystrophy v4.3 PRDX3 Eleanor Williams commented on gene: PRDX3: The 'founder-effect' tag has been added as the same variant has been identified in multiple families from the same populations.
Corneal dystrophy v4.3 PRDX3 Eleanor Williams Tag founder-effect tag was added to gene: PRDX3.
Adult onset neurodegenerative disorder v8.3 ANXA11 Eleanor Williams commented on gene: ANXA11
Adult onset neurodegenerative disorder v8.3 ANXA11 Eleanor Williams Tag founder-effect tag was added to gene: ANXA11.
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams Classified gene: DST as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS approval.
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams Gene: dst has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v3.3 DST Eleanor Williams gene: DST was added
gene: DST was added to Dilated and arrhythmogenic cardiomyopathy. Sources: Literature
Q3_25_promote_green tags were added to gene: DST.
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to 40497796; 35942699
Phenotypes for gene: DST were set to arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Review for gene: DST was set to GREEN
Added comment: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Sources: Literature
Arthrogryposis v9.9 DST Eleanor Williams Tag Q3_25_promote_green tag was added to gene: DST.
Congenital myopathy v6.38 DST Eleanor Williams Tag Q3_25_promote_green tag was added to gene: DST.
Arthrogryposis v9.9 DST Eleanor Williams Entity copied from Congenital myopathy v6.38
Arthrogryposis v9.9 DST Eleanor Williams gene: DST was added
gene: DST was added to Arthrogryposis. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to 40497796; 35942699
Phenotypes for gene: DST were set to arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Congenital myopathy v6.38 DST Eleanor Williams Phenotypes for gene: DST were changed from to arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Congenital myopathy v6.37 DST Eleanor Williams Publications for gene: DST were set to 40497796
Congenital myopathy v6.36 DST Eleanor Williams Classified gene: DST as Amber List (moderate evidence)
Congenital myopathy v6.36 DST Eleanor Williams Added comment: Comment on list classification: Promoting to amber but with a recommendation for green rating following GMS review since there are sufficient cases with plausible disease causing variants and an appropriate phenotype.
Congenital myopathy v6.36 DST Eleanor Williams Gene: dst has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.35 DST Eleanor Williams reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: None; Publications: 40497796, 35942699; Phenotypes: arthrogryposis, MONDO:0859248, cardiomyopathy, MONDO:0004994, congenital myopathy, MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v6.7 ANXA11 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: ANXA11.
Adult onset leukodystrophy v6.7 ANXA11 Achchuthan Shanmugasundram Classified gene: ANXA11 as Amber List (moderate evidence)
Adult onset leukodystrophy v6.7 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with ANXA11 variants and white matter abnormalities - however, all three families were identified with the same variant. What matter abnormalities were not reported in successive studies. Hence, this gene should be rated amber with the current evidence.
Adult onset leukodystrophy v6.7 ANXA11 Achchuthan Shanmugasundram Gene: anxa11 has been classified as Amber List (Moderate Evidence).
Adult onset leukodystrophy v6.6 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619733). OMIM was accessed on 30 September 2025.
Adult onset leukodystrophy v6.6 ANXA11 Achchuthan Shanmugasundram Phenotypes for gene: ANXA11 were changed from Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514 to Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514
Adult onset leukodystrophy v6.5 ANXA11 Achchuthan Shanmugasundram gene: ANXA11 was added
gene: ANXA11 was added to Adult onset leukodystrophy. Sources: Literature
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to 34048612
Phenotypes for gene: ANXA11 were set to Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514
Review for gene: ANXA11 was set to AMBER
Added comment: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy. Brain imaging from patients showed white matter abnormalities using diffusion tensor imaging. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene, suggesting it could be founder variant.

Although there were patients reported with variants affecting the Asp40 amino acid residue of ANXA11 gene and presenting with myopathy phenotype in successive studies (PMIDs: 36134701; 36651622; 40730020), there were no mentions of white matter abnormalities reported for these patients in these publications.
Sources: Literature
Adult onset neurodegenerative disorder v8.3 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 30 September 2025.
Adult onset neurodegenerative disorder v8.3 ANXA11 Achchuthan Shanmugasundram Phenotypes for gene: ANXA11 were changed from Amytrophic lateral sclerosis 23, OMIM:617839 to Amyotrophic lateral sclerosis 23, OMIM:617839
Intellectual disability v9.105 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from FANCONI ANEMIA to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Fetal anomalies v6.90 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from CEREBROOCULOFACIOSKELETAL SYNDROME 4; FANCONI ANEMIA to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Structural eye disease v4.30 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4 (includes microphthalmia), 610758; Cerebrooculofacioskeletal syndrome 4, 610758 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Arthrogryposis v9.8 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, 610758 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram changed review comment from: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.

The 'founder-effect' tag has been added as the same variant has been identified across populations.
Sources: Literature; to: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.

The 'founder-effect' tag has been added as the same variant has been identified in multiple families from the same populations.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram changed review comment from: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.
Sources: Literature; to: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.

The 'founder-effect' tag has been added as the same variant has been identified across populations.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: ANXA11.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram Classified gene: ANXA11 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in ANXA11 gene to limb-girdle syndrome. Hence, this gene can be promoted to green rating in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram Gene: anxa11 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.15 ANXA11 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ANXA11.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.15 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619733). OMIM was accessed on 30 September 2025.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.15 ANXA11 Achchuthan Shanmugasundram Phenotypes for gene: ANXA11 were changed from Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514 to Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514
Adult solid tumours cancer susceptibility v2.31 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa; Cerebrooculofacioskeletal syndrome 4, 610758 to Xeroderma Pigmentosa
Childhood solid tumours v5.2 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa; Cerebrooculofacioskeletal syndrome 4, 610758 to Xeroderma Pigmentosa
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.14 ANXA11 Achchuthan Shanmugasundram changed review comment from: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.
Sources: Literature; to: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.
Sources: Literature
Fetal anomalies v6.89 EMX2 Eleanor Williams Tag Q3_25_expert_review tag was added to gene: EMX2.
Intellectual disability v9.104 EMX2 Eleanor Williams Tag Q3_25_NHS_review tag was added to gene: EMX2.
Childhood onset dystonia, chorea or related movement disorder v7.7 CACNB4 Eleanor Williams Tag Q3_25_MOI tag was added to gene: CACNB4.
Childhood onset dystonia, chorea or related movement disorder v7.7 CACNB4 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotypes correct at 30th September 2025
Childhood onset dystonia, chorea or related movement disorder v7.7 CACNB4 Eleanor Williams Phenotypes for gene: CACNB4 were changed from ?Episodic ataxia, type 5, OMIM:613855; episodic ataxia type 5, MONDO:0013464; {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682; epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892; neurodevelopmental disorder, MONDO:0700092 to ?Episodic ataxia, type 5, OMIM:613855; episodic ataxia type 5, MONDO:0013464; {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682; epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892; neurodevelopmental disorder, MONDO:0700092
DDG2P v6.5 TSPAN7 Ida Ertmanska reviewed gene: TSPAN7: Rating: ; Mode of pathogenicity: None; Publications: 10655063, 12376945, 14735593, 12070254, 22511893, 26290131; Phenotypes: Intellectual developmental disorder, X-linked 58, OMIM:300210, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
DDG2P v6.5 TSPAN7 Ida Ertmanska Deleted their review
DDG2P v6.5 TSPAN7 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 7 unrelated individuals reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene should be rated Amber for Intellectual disability.; to: Comment on list classification: There are at least 7 unrelated individuals reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, we decided to demote this gene to Amber for Intellectual disability.
Fetal anomalies v6.89 EMX2 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 29th September 2025
Fetal anomalies v6.89 EMX2 Eleanor Williams Phenotypes for gene: EMX2 were changed from Schizencephaly, 269160 to Schizencephaly, OMIM:269160; schizencephaly, MONDO:0010011
Fetal anomalies v6.88 EMX2 Eleanor Williams Publications for gene: EMX2 were set to
Fetal anomalies v6.87 EMX2 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: EMX2.
Early onset or syndromic epilepsy v8.37 EMX2 Eleanor Williams commented on gene: EMX2
Intellectual disability v9.104 EMX2 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 29th September 2025
Intellectual disability v9.104 EMX2 Eleanor Williams Phenotypes for gene: EMX2 were changed from Schizencephaly 269160 to Schizencephaly, OMIM:269160; schizencephaly, MONDO:0010011
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.14 ANXA11 Achchuthan Shanmugasundram gene: ANXA11 was added
gene: ANXA11 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to 34048612; 36134701; 36651622; 40730020
Phenotypes for gene: ANXA11 were set to Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514
Review for gene: ANXA11 was set to GREEN
Added comment: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.
Sources: Literature
Retinal disorders v8.35 VSX2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: VSX2.
Retinal disorders v8.35 VSX2 Arina Puzriakova Classified gene: VSX2 as Amber List (moderate evidence)
Retinal disorders v8.35 VSX2 Arina Puzriakova Gene: vsx2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.34 VSX2 Arina Puzriakova Publications for gene: VSX2 were set to
Retinal disorders v8.33 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia/coloboma 3, OMIM:610092 to retinal disorder MONDO:0005283; Microphthalmia/coloboma 3, OMIM:610092
Retinal disorders v8.32 VSX2 Arina Puzriakova Mode of inheritance for gene: VSX2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.31 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Eye Disorders to Microphthalmia/coloboma 3, OMIM:610092
Bilateral congenital or childhood onset cataracts v7.3 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia, cataracts and iris abnormalities to Microphthalmia/coloboma 3, OMIM:610092
Ocular coloboma v1.50 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia with coloboma 3, 610092 to Microphthalmia/coloboma 3, OMIM:610092
Fetal anomalies v6.87 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from MICROPHTHALMIA WITH CATARACTS AND IRIS ABNORMALITIES; MICROPHTHALMIA ISOLATED WITH COLOBOMA TYPE 3; MICROPHTHALMIA ISOLATED TYPE 2 to Microphthalmia, isolated 2, OMIM:610093; Microphthalmia/coloboma 3, OMIM:610092
Anophthalmia or microphthalmia v1.53 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia with coloboma 3 to Microphthalmia, isolated 2, OMIM:610093; Microphthalmia/coloboma 3, OMIM:610092
Structural eye disease v4.29 VSX2 Arina Puzriakova Added comment: Comment on phenotypes: This gene is associated with Microphthalmia, isolated 2, OMIM:610093 and Microphthalmia/coloboma 3, OMIM:610092 (accessed on 30-09-2025)
Structural eye disease v4.29 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia with coloboma 3, 610092 to Microphthalmia, isolated 2, OMIM:610093; Microphthalmia/coloboma 3, OMIM:610092
Intellectual disability v9.103 EMX2 Eleanor Williams Publications for gene: EMX2 were set to 9359037; 24975717; 27125467; 9153481
Intellectual disability v9.102 EMX2 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: EMX2.
DDG2P v6.5 TSPAN7 Ida Ertmanska reviewed gene: TSPAN7: Rating: AMBER; Mode of pathogenicity: None; Publications: 10655063, 12376945, 14735593, 12070254, 22511893, 26290131; Phenotypes: Intellectual developmental disorder, X-linked 58, OMIM:300210, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hereditary neuropathy or pain disorder v7.11 TTC19 Achchuthan Shanmugasundram Classified gene: TTC19 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.11 TTC19 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there are three unrelated patents reported with biallelic TTC19 variants and motor neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.11 TTC19 Achchuthan Shanmugasundram Gene: ttc19 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.10 TTC19 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: TTC19.
Tag Q3_25_NHS_review tag was added to gene: TTC19.
Hereditary neuropathy or pain disorder v7.10 TTC19 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in both OMIM (MIM #615157, OMIM accessed on 30 September 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel).
Hereditary neuropathy or pain disorder v7.10 TTC19 Achchuthan Shanmugasundram Phenotypes for gene: TTC19 were changed from Ataxia; apraxia; dystonia; dysarthria; necrotic brain lesions; motor axonal neuropathy to Mitochondrial complex III deficiency, nuclear type 2, OMIM:615157; mitochondrial complex III deficiency nuclear type 2, MONDO:0014063
Hereditary neuropathy or pain disorder v7.9 TTC19 Achchuthan Shanmugasundram Publications for gene: TTC19 were set to 40946707; 37927170; 25652355
Hereditary neuropathy or pain disorder v7.8 TTC19 Achchuthan Shanmugasundram reviewed gene: TTC19: Rating: GREEN; Mode of pathogenicity: None; Publications: 25652355, 37927170, 40946707; Phenotypes: Mitochondrial complex III deficiency, nuclear type 2, OMIM:615157, mitochondrial complex III deficiency nuclear type 2, MONDO:0014063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: UGGT1.
Severe microcephaly v8.14 UGGT1 Achchuthan Shanmugasundram Classified gene: UGGT1 as Amber List (moderate evidence)
Severe microcephaly v8.14 UGGT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Severe microcephaly was only reported in five patients from four unrelated families. In addition, there is also phenotypic variability observed within the families where patients were reported with severe microcephaly. Hence, this gene should be rated amber with the current evidence.
Severe microcephaly v8.14 UGGT1 Achchuthan Shanmugasundram Gene: uggt1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.13 UGGT1 Achchuthan Shanmugasundram gene: UGGT1 was added
gene: UGGT1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to 40267907
Phenotypes for gene: UGGT1 were set to congenital disorder of glycosylation, MONDO:0015286
Review for gene: UGGT1 was set to AMBER
Added comment: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). However, severe secondary microcephaly (postnatal OFC beyond a Z-score < -3) was only reported in five patients from four families.

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with intellectual disability (six families with severe ID). Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with epilepsy (eight families and functional evidence). Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram changed review comment from: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available).

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.; to: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures (11 patients from eight unrelated families), characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available).

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram Entity copied from Intellectual disability v9.102
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram gene: UGGT1 was added
gene: UGGT1 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: UGGT1.
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to 40267907
Phenotypes for gene: UGGT1 were set to congenital disorder of glycosylation, MONDO:0015286
Congenital disorders of glycosylation v7.8 UGGT1 Achchuthan Shanmugasundram Classified gene: UGGT1 as Amber List (moderate evidence)
Congenital disorders of glycosylation v7.8 UGGT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (10 unrelated families and functional evidence) for the promotion of this gene to green rating in this panel on the next GMS update.
Congenital disorders of glycosylation v7.8 UGGT1 Achchuthan Shanmugasundram Gene: uggt1 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v7.7 UGGT1 Achchuthan Shanmugasundram Phenotypes for gene: UGGT1 were changed from intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys to congenital disorder of glycosylation, MONDO:0015286
Congenital disorders of glycosylation v7.6 UGGT1 Achchuthan Shanmugasundram Publications for gene: UGGT1 were set to PMID: 40267907
Congenital disorders of glycosylation v7.5 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UGGT1.
Tag Q3_25_NHS_review tag was added to gene: UGGT1.
Intellectual disability v9.102 UGGT1 Achchuthan Shanmugasundram Classified gene: UGGT1 as Amber List (moderate evidence)
Intellectual disability v9.102 UGGT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with intellectual disability (six families with severe ID). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.102 UGGT1 Achchuthan Shanmugasundram Gene: uggt1 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v4.3 PRDX3 Eleanor Williams changed review comment from: Comment on list classification: There are 5 cases with heterozygous variants in this gene and a corneal dystrophy phenotype. However, the same variant was found in all cases, and all had Spanish ancestry. WES was only performed in one family, with targetted sequencing in the others. Therefore rating Amber until a second variant is found.; to: Comment on list classification: There are 5 cases with heterozygous variants in this gene and a corneal dystrophy phenotype. However, the same variant was found in all cases, and all had Spanish ancestry. WES was only performed in one family, with targetted sequencing in the others. Therefore rating Amber until further supporting evidence is reported, such as functional data, or cases with different ethnicities.
Corneal dystrophy v4.3 PRDX3 Eleanor Williams changed review comment from: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same rare heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.

PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. No variants in the 3 genes were found in family 5. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4.
Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 identified the heterozygous in the proband revealed the PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature; to: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same rare heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.

PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. No variants in the 3 genes were found in family 5. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4.
Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but since the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 in the proband revealed the heterozygous PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature
Congenital disorders of glycosylation v7.5 UGGT1 Achchuthan Shanmugasundram reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40267907; Phenotypes: congenital disorder of glycosylation, MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.101 UGGT1 Achchuthan Shanmugasundram Phenotypes for gene: UGGT1 were changed from intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys to congenital disorder of glycosylation, MONDO:0015286
Intellectual disability v9.100 UGGT1 Achchuthan Shanmugasundram Publications for gene: UGGT1 were set to PMID: 40267907
Intellectual disability v9.99 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UGGT1.
Tag Q3_25_NHS_review tag was added to gene: UGGT1.
Intellectual disability v9.99 UGGT1 Achchuthan Shanmugasundram reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40267907; Phenotypes: congenital disorder of glycosylation, MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.6 LSS Achchuthan Shanmugasundram Classified gene: LSS as Amber List (moderate evidence)
Ectodermal dysplasia v4.6 LSS Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Eleanor Williams, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Ectodermal dysplasia v4.6 LSS Achchuthan Shanmugasundram Gene: lss has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v4.5 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LSS.
Ectodermal dysplasia v4.5 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM (MIMs #618275 & #618840) and Gene2Phenotype (LSS-related hypotrichosis & LSS-related palmoplantar keratoderma-congenital alopecia syndrome with 'limited' rating on Skin panel).

OMIM phenotypes have been last accessed on 29 September 2025.
Ectodermal dysplasia v4.5 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Hypotrichosis 14 OMIM:618275; hypotrichosis 14 MONDO:0032649 to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009; Hypotrichosis 14, OMIM:618275; hypotrichosis 14, MONDO:0032649
Ectodermal dysplasia v4.4 LSS Achchuthan Shanmugasundram reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alopecia-intellectual disability syndrome 4, OMIM:618840, alopecia-intellectual disability syndrome 4, MONDO:0030009, Hypotrichosis 14, OMIM:618275, hypotrichosis 14, MONDO:0032649; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LSS.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Classified gene: LSS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

Hence, clinical opinion is being sought on whether there is sufficient evidence available for the promotion of this gene to green rating.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Gene: lss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 September 2025.
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009 to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Early onset or syndromic epilepsy v8.34 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 September 2025.
Early onset or syndromic epilepsy v8.34 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia; Abnormality of the skin; Microcephaly; Cataract 44, 616509, Hypotrichosis 14, 618275; Seizures; Abnormality of the genital system; Hypotonia; Intellectual disability; Global developmental delay to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram edited their review of gene: LSS: Changed publications to: 30723320, 37157980
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram changed review comment from: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.; to: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram changed review comment from: PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.; to: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: 37157980; Phenotypes: Alopecia-intellectual disability syndrome 4, OMIM:618840, alopecia-intellectual disability syndrome 4, MONDO:0030009; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Corneal dystrophy v4.3 PRDX3 Eleanor Williams changed review comment from: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.


PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. Variants in the 3 genes were not found in family 4. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4. Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 identified the heterozygous in the proband revealed the PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature; to: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same rare heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.

PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. No variants in the 3 genes were found in family 5. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4.
Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 identified the heterozygous in the proband revealed the PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature
Ichthyosis and erythrokeratoderma v4.6 LSS Achchuthan Shanmugasundram Classified gene: LSS as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v4.6 LSS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least seven unrelated patients reported with ichthyosis and/ or erythroderma. Hence, this gene can be promoted to green rating in the next GMS update.
Ichthyosis and erythrokeratoderma v4.6 LSS Achchuthan Shanmugasundram Gene: lss has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v4.5 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LSS.
Ichthyosis and erythrokeratoderma v4.5 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #618840) and Gene2Phenotype (LSS-related palmoplantar keratoderma-congenital alopecia syndrome with 'limited' rating on Skin panel).

The OMIM phenotype was accessed on 29 September 2025.
Ichthyosis and erythrokeratoderma v4.5 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009 to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Ichthyosis and erythrokeratoderma v4.4 LSS Achchuthan Shanmugasundram gene: LSS was added
gene: LSS was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 30723320; 35830358
Phenotypes for gene: LSS were set to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Review for gene: LSS was set to GREEN
Added comment: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while ichthyosis and/ or erythroderma were found in eight of these individuals from six families.

PMID:35830358 (2022) reported a 4-day-old female patient who presented with alopecia and a previously unreported dermatologic manifestation of congenital localized hyperpigmentation. Examination of the patient also revealed features consistent with ichthyosis. The patient was identified with two variants in LSS gene and a de novo pathogenic variant in SPTAN1 gene. The SPTAN1 variant is associated with neurodevelopmental phenotypes including early infantile epileptic encephalopathy. There are no known cutaneous manifestations of SPTAN1 variant.
Sources: Literature
Corneal dystrophy v4.3 PRDX3 Eleanor Williams Classified gene: PRDX3 as Amber List (moderate evidence)
Corneal dystrophy v4.3 PRDX3 Eleanor Williams Added comment: Comment on list classification: There are 5 cases with heterozygous variants in this gene and a corneal dystrophy phenotype. However, the same variant was found in all cases, and all had Spanish ancestry. WES was only performed in one family, with targetted sequencing in the others. Therefore rating Amber until a second variant is found.
Corneal dystrophy v4.3 PRDX3 Eleanor Williams Gene: prdx3 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v4.2 PRDX3 Eleanor Williams gene: PRDX3 was added
gene: PRDX3 was added to Corneal dystrophy. Sources: Literature
Mode of inheritance for gene: PRDX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRDX3 were set to 31782998; 34369396
Phenotypes for gene: PRDX3 were set to Corneal dystrophy, punctiform and polychromatic pre-Descemet, OMIM:619871; corneal dystrophy, punctiform and polychromatic pre-descemet, MONDO:0859248
Review for gene: PRDX3 was set to AMBER
Added comment: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.


PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. Variants in the 3 genes were not found in family 4. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4. Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 identified the heterozygous in the proband revealed the PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v7.6 CACNB4 Achchuthan Shanmugasundram changed review comment from: PMID:10762541 (2000) reported the identification of two different monoallelic variants (p.Arg482Ter and p.Cys104Phe) in CACNB4 gene in three unrelated families. The p.Arg482Ter variant was reported in a patient with juvenile myoclonic epilepsy. The missense p.Cys104Phe variant was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia.

There are no other patients reported with monoallelic CACNB4 variants in published scientific literature.

Monoallelic CACNB4 variants have been associated with both episodic ataxia and epilepsy phenotypes in OMIM (MIMs #613855 & #607682, phenotypes accessed on 29 September 2025) and with CACNB4-related juvenile myoclonic epilepsy in Gene2Phenotype (with 'limited' rating on the DD panel).

PMID:32176688 (2020) reported two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy. They were identified with rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. The authors identified using in silico tools, animal model, clinical, and genetic data that the p.Leu126Pro variant in CACNB4 gene to be likely pathogenic.

Biallelic CACNB4 variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:10762541 (2000) reported the identification of two different monoallelic variants (p.Arg482Ter and p.Cys104Phe) in CACNB4 gene in three unrelated families. The p.Arg482Ter variant was reported in a patient with juvenile myoclonic epilepsy. The missense p.Cys104Phe variant was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. In addition, p.Cys104Phe has been identified in over 1,000 alleles in gnomAD - https://gnomad.broadinstitute.org/variant/2-151880879-C-A?dataset=gnomad_r4.

There are no other patients reported with monoallelic CACNB4 variants in published scientific literature.

Monoallelic CACNB4 variants have been associated with both episodic ataxia and epilepsy phenotypes in OMIM (MIMs #613855 & #607682, phenotypes accessed on 29 September 2025) and with CACNB4-related juvenile myoclonic epilepsy in Gene2Phenotype (with 'limited' rating on the DD panel).

PMID:32176688 (2020) reported two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy. They were identified with rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. The authors identified using in silico tools, animal model, clinical, and genetic data that the p.Leu126Pro variant in CACNB4 gene to be likely pathogenic.

Biallelic CACNB4 variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Childhood onset dystonia, chorea or related movement disorder v7.6 CACNB4 Achchuthan Shanmugasundram Classified gene: CACNB4 as Green List (high evidence)
Childhood onset dystonia, chorea or related movement disorder v7.6 CACNB4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one family reported with monoallelic CACNB4 variants and episodic ataxia. Other two families were reported with epilepsy. There is also one family reported with biallelic CACNB4 variants and a phenotype including movement disorder. Hence, this gene should be recommended for demotion from green to red in the next GMS update.

In addition, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Childhood onset dystonia, chorea or related movement disorder v7.6 CACNB4 Achchuthan Shanmugasundram Gene: cacnb4 has been classified as Green List (High Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.5 CACNB4 Achchuthan Shanmugasundram Phenotypes for gene: CACNB4 were changed from EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 9; EPISODIC ATAXIA, TYPE 5 to ?Episodic ataxia, type 5, OMIM:613855; episodic ataxia type 5, MONDO:0013464; {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682; epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892; neurodevelopmental disorder, MONDO:0700092
Childhood onset dystonia, chorea or related movement disorder v7.4 CACNB4 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: CACNB4.
Tag Q3_25_demote_red tag was added to gene: CACNB4.
Childhood onset dystonia, chorea or related movement disorder v7.4 CACNB4 Achchuthan Shanmugasundram reviewed gene: CACNB4: Rating: RED; Mode of pathogenicity: None; Publications: 10762541, 32176688; Phenotypes: ?Episodic ataxia, type 5, OMIM:613855, episodic ataxia type 5, MONDO:0013464, {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682, {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682, epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other schizencephaly cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have also been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829). No other cases with EMX2 variants were published in literature since 1997. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated and conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have also been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly (SCH) - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the articles, published in 1996-1997, are limited by their sequencing method (EMX2 targeted gene sequencing):

PMID: 8528262 Brunelli et al., 1996
Method: SSCP analysis on PCR amplification products of 4 genes: EMX1, EMX2, OTX1, OTX2. No variants were detected in EMX1, OTX1, or OTX2. 7/8 schizencephaly patients harboured heterozygous EMX2 variants, of which 3 were de novo and predicted to be pathogenic:
c.407-4G>T – spliceAI benign, 1 allele reported in European population in gnomAD v4.1
c.407-1G>A – spliceAI splice-altering Strong, not in gnomAD v4.1
c.575_576insA p.(Ser192Argfs*41) – not in gnomAD v4.1

PMID: 9153481 Granata et al., 1997 - two brothers aged 8 and 10 with severe bilateral schizencephaly, carrying an identical point mutation in EMX2. Phenotype: severe neurologic deficits and mental retardation. No access to full article
PMID: 9359037 Faiella et al., 1997 – same two brothers? Variant c.407G>T (p.Gly136Val) – Revel score 0.46 (Uncertain); not in gnomAD v4.1

Supporting evidence: https://iamg.in/genetic_clinics/full_textdfc6.html?id=212 – Clinical Vignette, Indian Academy of Medical Genetics – NO PMID.
Case report: 7 year old boy, bilateral schizencephaly, non-consanguineous parents; heterozygous for a de novo EMX2 variant: c.473G>A, (p.Arg158Gln) – Revel score 0.63, not found in gnomAD v4.1; method: trio sequencing of EMX2 exons only.
Phenotype: Severe developmental delay noticed at age 3-4 months. At 5 years old, the developmental age was 4 months. No meaningful speech was present. History of seizures since 4 years of age. Microcornea, widely spaced teeth, severe spasticity in all limbs.

CONTRADICTING EVIDENCE:
Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations:

PMID: 17506092 Tietjen et al., 2007
EMX2 genotyping of 84 affected probands with Schizencephaly – no EMX2 mutations detected.

PMID: 18409201 Merello et al., 2008
EMX2 sequencing in 39 SCH patients detected no pathogenic mutations. Only sequenced EMX2. Authors claimed that diagnostic testing of EMX2 is not justified, as any results would be uninterpretable.

PMID: 20157829 – Hehr et al., 2010
52 patients with SCH, no EMX2 mutations detected. Sequenced EMX2 (all 52 cases) as well SHH, SIX3 and ZIC2 in some of the individuals. SIX3 and SHH variants are reported as causative instead.

EMX2 is associated with Schizencephaly in OMIM (269160, accessed 29th Sep 2025) & classified as Limited for Schizencephaly in ClinGen (Epilepsy GCEP, 2024).

No other cases with EMX2 variants were published in literature since 1997. Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly (SCH) - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the articles, published in 1996-1997, are limited by their sequencing method (EMX2 targeted gene sequencing):

PMID: 8528262 Brunelli et al., 1996
Method: SSCP analysis on PCR amplification products of 4 genes: EMX1, EMX2, OTX1, OTX2. No variants were detected in EMX1, OTX1, or OTX2. 7/8 schizencephaly patients harboured heterozygous EMX2 variants, of which 3 were de novo and predicted to be pathogenic:
c.407-4G>T – spliceAI benign, 1 allele reported in European population in gnomAD v4.1
c.407-1G>A – spliceAI splice-altering Strong, not in gnomAD v4.1
c.575_576insA p.(Ser192Argfs*41) – not in gnomAD v4.1

PMID: 9153481 Granata et al., 1997 - two brothers aged 8 and 10 with severe bilateral schizencephaly, carrying an identical point mutation in EMX2. Phenotype: severe neurologic deficits and mental retardation. No access to full article
PMID: 9359037 Faiella et al., 1997 – same two brothers? Variant c.407G>T (p.Gly136Val) – Revel score 0.46 (Uncertain); not in gnomAD v4.1

Supporting evidence: https://iamg.in/genetic_clinics/full_textdfc6.html?id=212 – Clinical Vignette, Indian Academy of Medical Genetics – NO PMID.
Case report: 7 year old boy, bilateral schizencephaly, non-consanguineous parents; heterozygous for a de novo EMX2 variant: c.473G>A, (p.Arg158Gln) – Revel score 0.63, not found in gnomAD v4.1; method: trio sequencing of EMX2 exons only.
Phenotype: Severe developmental delay noticed at age 3-4 months. At 5 years old, the developmental age was 4 months. No meaningful speech was present. History of seizures since 4 years of age. Microcornea, widely spaced teeth, severe spasticity in all limbs.

CONTRADICTING EVIDENCE:
Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations:

PMID: 17506092 Tietjen et al., 2007
EMX2 genotyping of 84 affected probands with Schizencephaly – no EMX2 mutations detected.

PMID: 18409201 Merello et al., 2008
EMX2 sequencing in 39 SCH patients detected no pathogenic mutations. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more. Thus, authors claimed that diagnostic testing of EMX2 is not justified, as any results would be uninterpretable.

PMID: 20157829 – Hehr et al., 2010
52 patients with SCH, no EMX2 mutations detected. Sequenced EMX2 (all 52 cases) as well SHH, SIX3 and ZIC2 in some of the individuals. SIX3 and SHH variants are reported as causative instead.

EMX2 is associated with Schizencephaly in OMIM (269160, accessed 29th Sep 2025) & classified as Limited for Schizencephaly in ClinGen (Epilepsy GCEP, 2024).

No other cases with EMX2 variants were published in literature since 1997. Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska commented on gene: EMX2: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829). No other cases with EMX2 variants were published in literature since 1997. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated and conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska edited their review of gene: EMX2: Changed publications to: 8528262, 9153481, 9359037, 17506092, 18409201, 20157829
Intellectual disability v9.99 EMX2 Ida Ertmanska reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Schizencephaly, OMIM:269160, schizencephaly, MONDO:0010011; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v7.7 CHAF1A Arina Puzriakova Classified gene: CHAF1A as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.7 CHAF1A Arina Puzriakova Added comment: Comment on list classification: Rating Amber as additional evidence, such as additional cases or functional data, is required to corroborate this new gene-disease association. There is also debate on whether OAVS is a monogenic condition which should be taken into account.
Paediatric disorders - additional genes v7.7 CHAF1A Arina Puzriakova Gene: chaf1a has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.6 CHAF1A Arina Puzriakova gene: CHAF1A was added
gene: CHAF1A was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: CHAF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHAF1A were set to 39333427
Phenotypes for gene: CHAF1A were set to Oculo-auriculo-vertebral spectrum
Review for gene: CHAF1A was set to AMBER
Added comment: PMID: 39333427 (2025) - 8 individuals from 5 families with Oculo-auriculo-vertebral spectrum (OAVS) and heterozygous predicted LOF variants. No functional studies. Cases were selected through Genematcher and Decipher and were sequencing by WES or WGS.

This gene-disease association is not yet represented in other resources such as PanelApp Australia, Gene2Phenotype or OMIM.
Sources: Literature
Fetal anomalies v6.86 PDE12 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: PDE12.
Tag Q3_25_expert_review was removed from gene: PDE12.
Fetal anomalies v6.86 PDE12 Arina Puzriakova commented on gene: PDE12: Maintaining Amber rating following further consultation with the expert group - The concern is that the two prenatal presentations are very different. There is no link between brain anomalies and hydrops. The panel want to see more evidence that the gene is causing a prenatal phenotype and there is not another cause of these abnormalities in these families.
Fetal anomalies v6.86 NDUFB7 Arina Puzriakova Phenotypes for gene: NDUFB7 were changed from Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135; Mitochondrial complex I deficiency, nuclear type 39 to Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135
Fetal anomalies v6.85 NDUFB7 Arina Puzriakova Tag Q1_25_ expert_review was removed from gene: NDUFB7.
Tag Q3_25_NHS_review tag was added to gene: NDUFB7.
Fetal anomalies v6.85 NDUFB7 Arina Puzriakova commented on gene: NDUFB7: Following further consultation with the expert group, it was decided that this gene should be rated Green on this panel as there is sufficient evidence to support an association with a prenatal phenotype.
Fetal anomalies v6.85 FLII Arina Puzriakova Tag Q3_25_promote_green was removed from gene: FLII.
Tag Q3_25_expert_review was removed from gene: FLII.
Tag Q3_25_NHS_review was removed from gene: FLII.
Fetal anomalies v6.85 FLII Arina Puzriakova commented on gene: FLII: Maintaining as Amber following further consultation with the expert group - this gene causes isolated cardiac anomalies which is not an indication for R21 fetal anomaly testing. However, we do want to monitor in case of new reports where it is not isolated.
Intellectual disability v9.99 KCND3 Nour Elkhateeb reviewed gene: KCND3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32823520, 32921676, 26189493, 28895081, 40140957; Phenotypes: Developmental delay, intellectual disability, ataxia, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v3.2 PRDM16 Jesse Hayesmoore reviewed gene: PRDM16: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23768516, PMID: 24454898, PMID: 37395136, PMID: 33500567, PMID: 29367541, PMID: 35893073, PMID: 29447731, PMID: 30847666, PMID: 33082984, PMID: 32183154, PMID: 34540771, PMID: 34350506, PMID: 34935411, PMID: 38113297, PMID: 31965688, PMID: 40935858, PMID: 21343612, PMID: 32083975, PMID: 33086060, PMID: 34915728; Phenotypes: LVNC, DCM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Limb disorders v7.12 NTN1 Eleanor Williams Phenotypes for gene: NTN1 were changed from to polydactyly, MONDO:0021003
Limb disorders v7.11 NTN1 Eleanor Williams Classified gene: NTN1 as Red List (low evidence)
Limb disorders v7.11 NTN1 Eleanor Williams Gene: ntn1 has been classified as Red List (Low Evidence).
Monogenic hearing loss v5.27 NTN1 Eleanor Williams Phenotypes for gene: NTN1 were changed from to sensorineural hearing loss disorder, MONDO:0020678
Monogenic hearing loss v5.26 NTN1 Eleanor Williams Publications for gene: NTN1 were set to
Monogenic hearing loss v5.25 NTN1 Eleanor Williams Mode of inheritance for gene: NTN1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v5.24 NTN1 Eleanor Williams Classified gene: NTN1 as Amber List (moderate evidence)
Monogenic hearing loss v5.24 NTN1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber as there is 1 case plus some functional data supporting the association with hearing loss.
Monogenic hearing loss v5.24 NTN1 Eleanor Williams Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.99 OGDHL Ida Ertmanska changed review comment from: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly heterogeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 OGDHL Ida Ertmanska changed review comment from: Comment on list classifcation: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 OGDHL Ida Ertmanska commented on gene: OGDHL: Comment on list classifcation: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 OGDHL Ida Ertmanska reviewed gene: OGDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28017472, 34800363, 38031187; Phenotypes: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v1.144 UNC119 Arina Puzriakova Phenotypes for gene: UNC119 were changed from Immunodeficiency 13 615518; Combined immunodeficiency; Immunodeficiency 13/ UNC119 deficiency to ?Immunodeficiency 13, OMIM:615518
Primary immunodeficiency or monogenic inflammatory bowel disease v8.43 UNC119 Arina Puzriakova Phenotypes for gene: UNC119 were changed from Immunodeficiency 13/ UNC119 deficiency; Combined immunodeficiency; Immunodeficiency 13 615518 to ?Immunodeficiency 13, OMIM:615518
Structural eye disease v4.28 UNC119 Arina Puzriakova Phenotypes for gene: UNC119 were changed from Cone-rod dystrophy; Immunodeficiency 13, 615518; Eye Disorders to Cone-rod dystrophy 24, OMIM:620342
Retinal disorders v8.30 UNC119 Arina Puzriakova Phenotypes for gene: UNC119 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Eye Disorders; Cone-Rod Dystrophy, Dominant; CD4 lymphopenia, idiopathic (Gorska (2012) Blood 119, 1399) to Cone-rod dystrophy 24, OMIM:620342; retinal disorder, MONDO:0005283
Retinal disorders v8.29 UNC119 Arina Puzriakova Publications for gene: UNC119 were set to 11006213; 23563732; 27079236
Retinal disorders v8.28 UNC119 Arina Puzriakova Tag Q3_25_demote_amber tag was added to gene: UNC119.
Ataxia and cerebellar anomalies - narrow panel v8.24 CDK5 Arina Puzriakova Publications for gene: CDK5 were set to 25560765, 15067135
Ataxia and cerebellar anomalies - narrow panel v8.23 CDK5 Arina Puzriakova Classified gene: CDK5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.23 CDK5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype comprising lissencephaly with cerebellar hypoplasia and supportive animal models. Other lissencephaly genes also included on this panel (RELN, TUBA1A)
Ataxia and cerebellar anomalies - narrow panel v8.23 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.22 CDK5 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: CDK5.
Ataxia and cerebellar anomalies - narrow panel v8.22 CDK5 Arina Puzriakova reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 25560765, 40186457, 28854363, 8855328; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.80 CDK5 Arina Puzriakova Publications for gene: CDK5 were set to 25560765, 15067135
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype comprising lissencephaly with seizures and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.
Malformations of cortical development v7.8 CDK5 Arina Puzriakova Classified gene: CDK5 as Amber List (moderate evidence)
Malformations of cortical development v7.8 CDK5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype comprising lissencephaly and supportive animal models.
Malformations of cortical development v7.8 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Amber List (Moderate Evidence).
Cerebellar hypoplasia v1.79 CDK5 Arina Puzriakova Classified gene: CDK5 as Green List (high evidence)
Cerebellar hypoplasia v1.79 CDK5 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Green - 2 unrelated families with the same severe phenotype comprising lissencephaly and supportive animal models.
Cerebellar hypoplasia v1.79 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.78 CDK5 Arina Puzriakova reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 25560765, 40186457, 28854363, 8855328; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Classified gene: CDK5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.32 CDK5 Arina Puzriakova gene: CDK5 was added
gene: CDK5 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: CDK5.
Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK5 were set to 25560765; 40186457; 28854363; 8855328
Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Review for gene: CDK5 was set to GREEN
Added comment: - PMID: 25560765 (2015) - Homozygous splice site variant g.IVS8+1G>A p.V162SfsX19 segregated with a lethal form of lissencephaly with cerebellar hypoplasia in 4 patients and 25 healthy relatives from one consanguineous family. Affected newborns had dysmorphic facial features, HC in normal-low range, lymphedema, arthrogryposis multiplex, and intractable seizures. Functional studies of the variant showed loss-of-function of the gene product.

- PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.

Animal models:
Brains of Cdk5-null mice lacked cortical laminar structure and cerebellar foliation (PMID: 8855328). Cdk5 knockout in the ferret cerebral cortex also markedly impaired cortical folding (PMID: 28854363).
Sources: Literature
Malformations of cortical development v7.7 CDK5 Arina Puzriakova gene: CDK5 was added
gene: CDK5 was added to Malformations of cortical development. Sources: Literature
Q3_25_promote_green tags were added to gene: CDK5.
Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK5 were set to 25560765; 40186457; 28854363; 8855328
Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Review for gene: CDK5 was set to GREEN
Added comment: - PMID: 25560765 (2015) - Homozygous splice site variant g.IVS8+1G>A p.V162SfsX19 segregated with a lethal form of lissencephaly with cerebellar hypoplasia in 4 patients and 25 healthy relatives from one consanguineous family. Affected newborns had dysmorphic facial features, HC in normal-low range, lymphedema, arthrogryposis multiplex, and intractable seizures. Functional studies of the variant showed loss-of-function of the gene product.

- PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.

Animal models:
Brains of Cdk5-null mice lacked cortical laminar structure and cerebellar foliation (PMID: 8855328). Cdk5 knockout in the ferret cerebral cortex also markedly impaired cortical folding (PMID: 28854363).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.22 RARS2 Arina Puzriakova Phenotypes for gene: RARS2 were changed from epilepsy; Pontocerebellar hypoplasia, type 6, 611523; Pontocerebellar Hypoplasia type 6; Pontocerebellar hypoplasia; Pontocerebellar Hypoplasia to Pontocerebellar hypoplasia, type 6, OMIM:611523
Monogenic hearing loss v5.23 NTN1 Ida Ertmanska commented on gene: NTN1: Comment on list classification: There is one patient reported in literature with sensorineural hearing loss, heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had hearing impairment. Morpholino gene knockdown of ntn1a in zebrafish embryos resulted in sensory hair cell defects, supporting the gene's role in hearing. Based on the available evidence, NTN1 should be rated Amber for Monogenic hearing loss.
Monogenic hearing loss v5.23 NTN1 Ida Ertmanska reviewed gene: NTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28945198, 39648562; Phenotypes: sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v5.23 TBX2 Ida Ertmanska changed review comment from: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset, 4-40 years old). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.; to: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset, 4-40 years old). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.
Monogenic hearing loss v5.23 TBX2 Ida Ertmanska changed review comment from: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.; to: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset, 4-40 years old). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.
Monogenic hearing loss v5.23 TBX2 Ida Ertmanska commented on gene: TBX2: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.
Monogenic hearing loss v5.23 TBX2 Ida Ertmanska gene: TBX2 was added
gene: TBX2 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX2 were set to 15459098; 20206336; 21271665; 22052739; 35508658
Phenotypes for gene: TBX2 were set to hearing loss disorder, MONDO:0005365
Review for gene: TBX2 was set to AMBER
Added comment: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple.

A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS.

Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern.

Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood.

Functional data:
Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss.

TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss.
Sources: Literature
Limb disorders v7.10 NTN1 Ida Ertmanska edited their review of gene: NTN1: Added comment: Comment on list classification: There is one patient reported in literature with a limb disorder (right hand polydactyly), heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had no polydcatyly. Based on the available evidence, NTN1 should be rated Red for Limb disorders.; Changed phenotypes to: polydactyly, MONDO:0021003
Limb disorders v7.10 NTN1 Ida Ertmanska gene: NTN1 was added
gene: NTN1 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NTN1 were set to 28945198; 39648562
Review for gene: NTN1 was set to RED
Added comment: PMID: 39648562 (Toms et al., 2024) reports a patient with right hand polydactyly, heterozygous for a de novo variant in NTN1: NM_004822.3:c.1483T>A p.(Tyr495Asn). Sequencing method: WGS.The patient (Female, 30 years old, White British) also had chorioretinal coloboma and microphthalmia, and bilateral sensorineural hearing loss. The C-terminus variant is not found in gnomAD v4.1.0; in silico prediction tools: Revel score = 0.5 (Uncertain), AlphaMissense score = 0.806 (Deleterious Supporting); predicted NMD escape (https://www.deciphergenomics.org/gene/NTN1/overview/protein-genomic-info)

Confoundingly, patients with congenital mirror movements from 3 families reported in PMID: 28945198 (Meneret et al., 2017) who also harboured heterozygous NTN1 variants at the C-terminal end (p.Cys601Arg, p.Ile518del, p.Cys601Ser) had normal eyesight, no oculomotor abnormalities, and no hearing impairment.

This gene appears to be intolerant to LoF variants (NTN1 pLI score = 1). NTN1 is associated with Mirror movements 4, OMIM:618264 (OMIM entry accessed 10th Sep 2025).

Based on the available evidence, this gene can only be rated Red for Limb disorders.
Sources: Literature
Fetal anomalies v6.85 CCT6A Arina Puzriakova Tag gene-checked tag was added to gene: CCT6A.
Intellectual disability v9.99 CCT6A Arina Puzriakova Tag gene-checked tag was added to gene: CCT6A.
Intellectual disability v9.99 CCT6A Arina Puzriakova Classified gene: CCT6A as Amber List (moderate evidence)
Intellectual disability v9.99 CCT6A Arina Puzriakova Added comment: Comment on list classification: This gene can be promoted to Green at the next GMS panel update. Phenotype is quite variable and unspecific - DD/ID is the most common feature observed among affected individuals so worth adding to this panel to enable capture of variants in this gene.
Intellectual disability v9.99 CCT6A Arina Puzriakova Gene: cct6a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.98 CCT6A Arina Puzriakova gene: CCT6A was added
gene: CCT6A was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: CCT6A.
Mode of inheritance for gene: CCT6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCT6A were set to 39480921
Phenotypes for gene: CCT6A were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: CCT6A was set to GREEN
Added comment: PMID: 39480921 (2024) - 5 unrelated individuals with variants in the CCT6A gene, including 4 de novo (4 LoF, 2 missense), presenting with neurodevelopmental disorders. Main clinical features include DD/ID (4/5), pyramidal/cerebellar signs (3/4), variable brain abnormalities (3/5), microcephaly (2/5 - severe only in one) seizures (2/4), visual impairment (2/5).
Sources: Literature
Neurological ciliopathies v6.3 EVC2 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: EVC2.
Fetal anomalies v6.85 EVC2 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: EVC2.
Clefting v6.11 CTGF Arina Puzriakova Classified gene: CTGF as Amber List (moderate evidence)
Clefting v6.11 CTGF Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated cases supported by a recapitulated phenotype in an animal model.
Clefting v6.11 CTGF Arina Puzriakova Gene: ctgf has been classified as Amber List (Moderate Evidence).
Clefting v6.10 CTGF Arina Puzriakova gene: CTGF was added
gene: CTGF was added to Clefting. Sources: Literature
new-gene-name, Q3_25_promote_green tags were added to gene: CTGF.
Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTGF were set to 39506047; 39414788; 12736220
Phenotypes for gene: CTGF were set to Kyphomelic dysplasia, OMIM:211350; kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
Review for gene: CTGF was set to GREEN
Added comment: PMID: 39506047 (2025) reported three individuals from two unrelated families with different homozygous CCN2 variants and kyphomelic dysplasia - all had cleft palate or bifid uvula as part of their phenotype. Ccn2-deficient mice also show skeletal dysmorphisms as well as secondary cleft palate, supporting this association.

Individuals with monoallelic variants in this gene do not exhibit dysmorphic facial phenotypes such as cleft palate (PMID: 39414788).
Sources: Literature
Fetal anomalies v6.85 CTGF Arina Puzriakova Phenotypes for gene: CTGF were changed from kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510 to Kyphomelic dysplasia, OMIM:211350; kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
Skeletal dysplasia v8.14 CTGF Arina Puzriakova Phenotypes for gene: CTGF were changed from kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510 to Kyphomelic dysplasia, OMIM:211350; kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
Intellectual disability v9.97 TSPAN7 Eleanor Williams Phenotypes for gene: TSPAN7 were changed from ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0010266 X-linked 58, to ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, X-linked 58, MONDO:0010266
Intellectual disability v9.96 TSPAN7 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype term accessed on 22nd September 2025
Intellectual disability v9.96 TSPAN7 Eleanor Williams Phenotypes for gene: TSPAN7 were changed from Mental retardation, X-linked 58, 300210; MENTAL RETARDATION X-LINKED TYPE 58 to ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0010266 X-linked 58,
Intellectual disability v9.95 TSPAN7 Eleanor Williams Publications for gene: TSPAN7 were set to
Intellectual disability v9.94 TSPAN7 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: TSPAN7.
Skeletal dysplasia v8.13 CTGF Arina Puzriakova Tag watchlist_moi tag was added to gene: CTGF.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Supporting evidence - variants in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing: IQ<50, global developmental delay, childhood onset. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.; to: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska commented on gene: TSPAN7: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing: IQ<50, global developmental delay, childhood onset. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska edited their review of gene: TSPAN7: Changed rating: AMBER
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska reviewed gene: TSPAN7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10655063, 12376945, 14735593, 12070254, 22511893, 26290131; Phenotypes: Intellectual developmental disorder, X-linked 58, OMIM:300210, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.
Intellectual disability v9.94 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.
Intellectual disability v9.94 BHLHE22 Arina Puzriakova Classified gene: BHLHE22 as Amber List (moderate evidence)
Intellectual disability v9.94 BHLHE22 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.
Intellectual disability v9.94 BHLHE22 Arina Puzriakova Gene: bhlhe22 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova Classified gene: BHLHE22 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova Gene: bhlhe22 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.3 EVC2 Eleanor Williams Added comment: Comment on phenotypes: Phenotypes accessed in OMIM on 22nd September 2025
Neurological ciliopathies v6.3 EVC2 Eleanor Williams Phenotypes for gene: EVC2 were changed from Ellis-van Creveld syndrome, 225500; Weyers acrofacial dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500; Weyers acrofacial dysostosis, OMIM:193530
Neurological ciliopathies v6.2 EVC2 Eleanor Williams Publications for gene: EVC2 were set to
Skeletal ciliopathies v6.3 EVC2 Eleanor Williams Publications for gene: EVC2 were set to 38531627; 23220543; 19810119; 16404586
Skeletal ciliopathies v6.2 EVC2 Eleanor Williams Added comment: Comment on phenotypes: Phenotypes accessed in OMIM on 22nd September 2025
Skeletal ciliopathies v6.2 EVC2 Eleanor Williams Phenotypes for gene: EVC2 were changed from Ellis-van Creveld syndrome, 225500; Weyers acrofacial dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500; Weyers acrofacial dysostosis, OMIM:193530
Skeletal ciliopathies v6.2 EVC2 Eleanor Williams Publications for gene: EVC2 were set to
Skeletal ciliopathies v6.1 EVC2 Eleanor Williams Tag Q3_25_MOI tag was added to gene: EVC2.
Fetal anomalies v6.84 EVC2 Eleanor Williams Publications for gene: EVC2 were set to
Fetal anomalies v6.83 EVC2 Eleanor Williams Added comment: Comment on phenotypes: Phenotypes accessed in OMIM on 22nd September 2025
Fetal anomalies v6.83 EVC2 Eleanor Williams Phenotypes for gene: EVC2 were changed from ELLIS-VAN CREVELD SYNDROME; ACROFACIAL DYSOSTOSIS WEYERS TYPE to Ellis-van Creveld syndrome, OMIM:225500 Weyers acrofacial dysostosis, OMIM:193530
Skeletal dysplasia v8.13 EVC2 Eleanor Williams Mode of inheritance for gene: EVC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v8.12 EVC2 Eleanor Williams Added comment: Comment on phenotypes: Phenotypes accessed from OMIM 22nd September 2025.
Skeletal dysplasia v8.12 EVC2 Eleanor Williams Phenotypes for gene: EVC2 were changed from Ellis-van Creveld syndrome 225500; Weyers acrofacial dysostosis 193530 to Ellis-van Creveld syndrome, OMIM:225500; Weyers acrofacial dysostosis, OMIM:193530
Skeletal dysplasia v8.11 EVC2 Eleanor Williams Publications for gene: EVC2 were set to
Skeletal dysplasia v8.10 EVC2 Eleanor Williams Mode of inheritance for gene: EVC2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v8.9 EVC2 Eleanor Williams Tag Q3_25_MOI tag was added to gene: EVC2.
Structural eye disease v4.27 NTN1 Ida Ertmanska edited their review of gene: NTN1: Changed phenotypes to: microphthalmia, isolated, with coloboma, MONDO:0000170
Structural eye disease v4.27 NTN1 Ida Ertmanska changed review comment from: As reviewed by Hannah Knight, PMID: 39648562 (Toms et al., 2024) reports a patient with chorioretinal coloboma and microphthalmia, heterozygous for NM_004822.3:c.1483T>A p.(Tyr495Asn). The patient (Female, 30 years old, White British) also had bilateral sensorineural hearing loss and right hand polydactyly. The C-terminus variant is not found in gnomAD v4.1.0; in silico prediction tools: Revel score = 0.5 (Uncertain), AlphaMissense score = 0.806 (Deleterious Supporting); predicted NMD escape (https://www.deciphergenomics.org/gene/NTN1/overview/protein-genomic-info).

Confoundingly, patients with congenital mirror movements from 3 families reported in PMID: 28945198 (Meneret et al., 2017) who also harboured heterozygous NTN1 variants at the C-terminal end (p.Cys601Arg, p.Ile518del, p.Cys601Ser) had normal eyesight, no oculomotor abnormalities, and no hearing impairment.

Mouse, chick, and zebrafish models provide good evidence for NTN1's function in optic fissure fusion:
In PMID: 39648562, morpholino knockdown of ntn1a in zebrafish (86% gene similarity to human ortholog) had ocular coloboma and sensory hair cell defects.
PMID: 31162046 (Hardy et al.,2019): Gene knockdown in zebrafish, using sgRNA targeting the first exon of ntn1. Homozygous knockouts were phenotypic; meanwhile heterozygous fish had no ocular abnormalities. Ntn1-/- mice also displayed highly penetrant ocular coloboma (10/11). Transcriptomic profiling in chick embryos showed that NTN1 is expressed in the chick optic fissure closure.

This gene appears to be intolerant to LoF variants (NTN1 pLI score = 1). NTN1 is associated with Mirror movements 4, OMIM:618264 (OMIM entry accessed 10th Sep 2025).

Based on the available evidence, this gene can only be rated Amber for Structural eye disease.; to: As reviewed by Hannah Knight, PMID: 39648562 (Toms et al., 2024) reports a patient with chorioretinal coloboma and microphthalmia, heterozygous for a de novo variant in NTN1: NM_004822.3:c.1483T>A p.(Tyr495Asn). Sequencing method: WGS.The patient (Female, 30 years old, White British) also had bilateral sensorineural hearing loss and right hand polydactyly. The C-terminus variant is not found in gnomAD v4.1.0; in silico prediction tools: Revel score = 0.5 (Uncertain), AlphaMissense score = 0.806 (Deleterious Supporting); predicted NMD escape (https://www.deciphergenomics.org/gene/NTN1/overview/protein-genomic-info).

Confoundingly, patients with congenital mirror movements from 3 families reported in PMID: 28945198 (Meneret et al., 2017) who also harboured heterozygous NTN1 variants at the C-terminal end (p.Cys601Arg, p.Ile518del, p.Cys601Ser) had normal eyesight, no oculomotor abnormalities, and no hearing impairment.

Mouse, chick, and zebrafish models provide good evidence for NTN1's function in optic fissure fusion:
In PMID: 39648562, morpholino knockdown of ntn1a in zebrafish (86% gene similarity to human ortholog) had ocular coloboma and sensory hair cell defects.
PMID: 31162046 (Hardy et al.,2019): Gene knockdown in zebrafish, using sgRNA targeting the first exon of ntn1. Homozygous knockouts were phenotypic; meanwhile heterozygous fish had no ocular abnormalities. Ntn1-/- mice also displayed highly penetrant ocular coloboma (10/11). Transcriptomic profiling in chick embryos showed that NTN1 is expressed in the chick optic fissure closure.

This gene appears to be intolerant to LoF variants (NTN1 pLI score = 1). NTN1 is associated with Mirror movements 4, OMIM:618264 (OMIM entry accessed 10th Sep 2025).

Based on the available evidence, this gene can only be rated Amber for Structural eye disease.
Structural eye disease v4.27 NTN1 Eleanor Williams Phenotypes for gene: NTN1 were changed from microphthalmia, isolated, with coloboma, MONDO:0000170 to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129
Structural eye disease v4.26 NTN1 Eleanor Williams Phenotypes for gene: NTN1 were changed from Chorioretinal Coloboma; Sensorineural Hearing Loss; Polydactyly to microphthalmia, isolated, with coloboma, MONDO:0000170
Structural eye disease v4.25 NTN1 Eleanor Williams Publications for gene: NTN1 were set to PMID: 39648562
Structural eye disease v4.24 NTN1 Eleanor Williams Classified gene: NTN1 as Amber List (moderate evidence)
Structural eye disease v4.24 NTN1 Eleanor Williams Added comment: Comment on list classification: Updating the rating to amber. One case with a relevant phenotype plus some functional data from zebrafish. Note that there are cases reported with missense variants in the C-terminus of this gene, that do not exhibit the eye phenotype.
Structural eye disease v4.24 NTN1 Eleanor Williams Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.11 BHLHE22 Arina Puzriakova gene: BHLHE22 was added
gene: BHLHE22 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: BHLHE22.
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BHLHE22 was set to GREEN
Added comment: PMID: 39502664 - 11 individuals from 9 unrelated families with BHLHE22 variants, presenting with a neurodevelopmental disorder including absent or limited speech, impaired motor function, intellectual disability, involuntary movements, autistic traits, abnormal muscle tone. Most had partial or complete agenesis of the corpus callosum, and some also showed epilepsy, dysmorphic features, and eye anomalies.

Four individuals had de novo missense variants within the helix-loop-helix domain, and seven carried a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum, recapitulating the structural anomalies seen in affected humans.
Sources: Literature
Intellectual disability v9.93 BHLHE22 Arina Puzriakova gene: BHLHE22 was added
gene: BHLHE22 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: BHLHE22.
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BHLHE22 was set to GREEN
Added comment: PMID: 39502664 - 11 individuals from 9 unrelated families with BHLHE22 variants, presenting with a neurodevelopmental disorder including absent or limited speech, impaired motor function, intellectual disability, involuntary movements, autistic traits, abnormal muscle tone. Most had partial or complete agenesis of the corpus callosum, and some also showed epilepsy, dysmorphic features, and eye anomalies.

Four individuals had de novo missense variants within the helix-loop-helix domain, and seven carried a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum, recapitulating the structural anomalies seen in affected humans.
Sources: Literature
Hereditary neuropathy or pain disorder v7.8 TTC19 Alexander Rossor gene: TTC19 was added
gene: TTC19 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: TTC19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC19 were set to 40946707; 37927170; 25652355
Phenotypes for gene: TTC19 were set to Ataxia; apraxia; dystonia; dysarthria; necrotic brain lesions; motor axonal neuropathy
Penetrance for gene: TTC19 were set to Complete
Review for gene: TTC19 was set to GREEN
Added comment: Evidence of motor axonal neuropathy in 3 unrelated individuals.
Sources: Expert list
Hereditary neuropathy or pain disorder v7.8 XPNPEP3 Alexander Rossor gene: XPNPEP3 was added
gene: XPNPEP3 was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPNPEP3 were set to 40953058
Phenotypes for gene: XPNPEP3 were set to Nephronopthisis; brain white matter lesions; sensory axonal neuropathy; recurrent rhabdomyolysis; cardiomyopathy; ataxia; hearing loss
Penetrance for gene: XPNPEP3 were set to Complete
Review for gene: XPNPEP3 was set to AMBER
Added comment: Currently sensory axonal neuropathy only reported in a single case.
Sources: Other
Hereditary neuropathy or pain disorder v7.8 TDP1 Lauren Turton reviewed gene: TDP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia with axonal neuropathy (OMIM: 607250); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
DDG2P v6.5 PDE6H Ronnie Wright reviewed gene: PDE6H: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.28 PDE6H Ronnie Wright reviewed gene: PDE6H: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 22901948; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.28 CYP2U1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: CYP2U1.
Retinal disorders v8.28 CYP2U1 Arina Puzriakova Phenotypes for gene: CYP2U1 were changed from to Spastic paraplegia 56, autosomal recessive, OMIM:615030; retinal disorder, MONDO:0005283
Retinal disorders v8.27 CYP2U1 Arina Puzriakova Publications for gene: CYP2U1 were set to 26914923; 34828401; 39605873
Retinal disorders v8.26 CYP2U1 Arina Puzriakova Classified gene: CYP2U1 as Amber List (moderate evidence)
Retinal disorders v8.26 CYP2U1 Arina Puzriakova Gene: cyp2u1 has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.5 FLG Arina Puzriakova Classified gene: FLG as Red List (low evidence)
Rare genetic inflammatory skin disorders v4.5 FLG Arina Puzriakova Gene: flg has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v4.4 FLG Arina Puzriakova Mode of inheritance for gene: FLG was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v4.3 FLG Arina Puzriakova Publications for gene: FLG were set to 16550169
Rare genetic inflammatory skin disorders v4.2 FLG Arina Puzriakova Phenotypes for gene: FLG were changed from Eczema; Ichthyosis vulgaris 146700; Ichthyosis vulgaris to Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM:605803; hereditary palmoplantar keratoderma, MONDO:0019272
Palmoplantar keratodermas v4.3 FLG Arina Puzriakova Phenotypes for gene: FLG were changed from ICHTHYOSIS VULGARIS to Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM:605803; hereditary palmoplantar keratoderma, MONDO:0019272
Palmoplantar keratodermas v4.2 FLG Arina Puzriakova Publications for gene: FLG were set to 16444271; 16815158; 17030239; 17291859
Palmoplantar keratodermas v4.1 FLG Arina Puzriakova Tag Q3_25_MOI tag was added to gene: FLG.
Ichthyosis and erythrokeratoderma v4.3 FLG Arina Puzriakova Phenotypes for gene: FLG were changed from Ichthyosis vulgaris, OMIM:146700 to Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM:605803; ichthyosis vulgaris, MONDO:0024304
Ichthyosis and erythrokeratoderma v4.2 FLG Arina Puzriakova Publications for gene: FLG were set to 16444271; 16815158; 17030239; 17291859
Ichthyosis and erythrokeratoderma v4.1 FLG Arina Puzriakova Tag Q3_25_MOI tag was added to gene: FLG.
Congenital myopathy v6.35 PNPLA2 Anna Sarkozy edited their review of gene: PNPLA2: Added comment: variants in this gene have now been reported in young individuals presenting with progressive skeletal myopathy, raised CK, and sometimes cardiomyopathy and liver dysfunction. these findings suggest that variants in this gene can be associated with an early onset form of myopathy, supporting green rating of this gene.; Changed rating: GREEN; Changed publications to: PMID: 21544567, PMID: 40919432, PMID: 37620213
Congenital myopathy v6.35 CASQ1 Anna Sarkozy commented on gene: CASQ1: Calsequestrin (CASQ) is the main Ca2+ buffer in the terminal cisternae, part of the so called Triad. Other forms of congenital myopathies are caused by genetic defects in components of the triad such as RYR1, ORAI1, STIM1 and now also CASQ1. patients with CASQ1 pathogenic variants usually present with high CK levels, mild proximal weakness, and myalgia. variable age at onset, mostly in adult life. muscle biopsy findings were typically myopathic with vacuolar inclusions strongly react with antibodies against SR calcium–machinery proteins and also tubular aggregates. These features are in part similar and overlapping what seen in association with other diseases associated with the triad.
Congenital myopathy v6.35 CASQ1 Anna Sarkozy edited their review of gene: CASQ1: Added comment: Calsequestrin (CASQ) is the main Ca2+ buffer in the terminal cisternae, part of the so called Triad. Other forms of congenital myopathies are caused by genetic defects in components of the triad such as RYR1, ORAI1, STIM1 and now also CASQ1. patients with CASQ1 pathogenic variants usually present with high CK levels, mild proximal weakness, and myalgia. variable age at onset, mostly in adult life. muscle biopsy findings were typically myopathic with vacuolar inclusions strongly react with antibodies against SR calcium–machinery proteins and also tubular aggregates. These features are in part similar and overlapping what seen in association with other diseases associated with the triad.; Changed rating: GREEN; Changed publications to: PMID: 30258016; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v6.35 VWA1 Anna Sarkozy reviewed gene: VWA1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:39502942, PMID: 33459760; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Structural eye disease v4.23 MYH10 Achchuthan Shanmugasundram Classified gene: MYH10 as Amber List (moderate evidence)
Structural eye disease v4.23 MYH10 Achchuthan Shanmugasundram Added comment: Comment on list classification: Four of six patients from three unrelated families were reported with monoallelic MYH10 variants and ocular coloboma. In addition, functional evidence from patient fibroblasts and delayed eye development in zebrafish model support the association.

However, this gene should be currently rated amber as coloboma was not consistently reported in all six patents from PMID:40044823 and was entirely absent in the previously reported cohort with neurodevelopmental phenotype (PMID:35980381).

The 'watchlist' tag has been added to review this gene for any new evidence in the future.
Structural eye disease v4.23 MYH10 Achchuthan Shanmugasundram Gene: myh10 has been classified as Amber List (Moderate Evidence).
Structural eye disease v4.22 MYH10 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: MYH10.
Structural eye disease v4.22 MYH10 Achchuthan Shanmugasundram Phenotypes for gene: MYH10 were changed from Autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features to neurodevelopmental disorder, MONDO:0700092; coloboma, MONDO:0001476
Structural eye disease v4.21 MYH10 Achchuthan Shanmugasundram edited their review of gene: MYH10: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, coloboma, MONDO:0001476
Structural eye disease v4.21 MYH10 Achchuthan Shanmugasundram Publications for gene: MYH10 were set to PMID: 40044823
Structural eye disease v4.20 MYH10 Achchuthan Shanmugasundram Deleted their comment
Structural eye disease v4.20 MYH10 Achchuthan Shanmugasundram changed review comment from: PMID:35980381 (2022) reported a cohort of 16 individuals with 14 unique heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders. Eye-related phenotypes were relatively minor with ptosis in 3 patients, refractive errors in four and chorioretinal lacunae in one patient.

PMID:40044823 (2025) reported six individuals from three unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features, and identified with 3 novel heterozygous variants (one of missense, splice site and one AA deletion) in the tail domain of MYH10 gene via exome or genome sequencing. However, no neurodevelopmental disorders as usually observed in this syndrome were detected. Iris and choreoretinal coloboma was reported in four of six individuals from three unrelated families (2/3 patients from family 1, 1/2 patients from family 2 and the only patient from family 3). Heterozygous variant in HOXD13 gene was identified in both mother and son from family 2, which was reported to explain their extremities anomalies. In addition, MYH10 dysfunction led to delayed development of the eye and muscular phenotype in the zebrafish model.

This gene has been currently rated Amber on Anophthalmia_Microphthalmia_Coloboma panel (https://panelapp-aus.org/panels/42/gene/MYH10/) in PanelApp Australia based on the evidence from PMID:40044823. This gene has also been rated 'moderate' on the DD panel based on the neurodevelopmental phenotype. However, it has not yet been associated with any relevant phenotypes in OMIM>; to: PMID:35980381 (2022) reported a cohort of 16 individuals with 14 unique heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders. Eye-related phenotypes were relatively minor with ptosis in 3 patients, refractive errors in four and chorioretinal lacunae in one patient.

PMID:40044823 (2025) reported six individuals from three unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features, and identified with 3 novel heterozygous variants (one of missense, splice site and one AA deletion) in the tail domain of MYH10 gene via exome or genome sequencing. However, no neurodevelopmental disorders as usually observed in this syndrome were detected. Iris and choreoretinal coloboma was reported in four of six individuals from three unrelated families (2/3 patients from family 1, 1/2 patients from family 2 and the only patient from family 3). Heterozygous variant in HOXD13 gene was identified in both mother and son from family 2, which was reported to explain their extremities anomalies. In addition, MYH10 dysfunction led to delayed development of the eye and muscular phenotype in the zebrafish model.

This gene has been currently rated Amber on Anophthalmia_Microphthalmia_Coloboma panel (https://panelapp-aus.org/panels/42/gene/MYH10/) in PanelApp Australia based on the evidence from PMID:40044823. This gene has also been rated 'moderate' on the DD panel based on the neurodevelopmental phenotype. However, it has not yet been associated with any relevant phenotypes in OMIM.
Structural eye disease v4.20 MYH10 Achchuthan Shanmugasundram commented on gene: MYH10: PMID:35980381 (2022) reported a cohort of 16 individuals with 14 unique heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders. Eye-related phenotypes were relatively minor with ptosis in 3 patients, refractive errors in four and chorioretinal lacunae in one patient.

PMID:40044823 (2025) reported six individuals from three unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features, and identified with 3 novel heterozygous variants (one of missense, splice site and one AA deletion) in the tail domain of MYH10 gene via exome or genome sequencing. However, no neurodevelopmental disorders as usually observed in this syndrome were detected. Iris and choreoretinal coloboma was reported in four of six individuals from three unrelated families (2/3 patients from family 1, 1/2 patients from family 2 and the only patient from family 3). Heterozygous variant in HOXD13 gene was identified in both mother and son from family 2, which was reported to explain their extremities anomalies. In addition, MYH10 dysfunction led to delayed development of the eye and muscular phenotype in the zebrafish model.

This gene has been currently rated Amber on Anophthalmia_Microphthalmia_Coloboma panel (https://panelapp-aus.org/panels/42/gene/MYH10/) in PanelApp Australia based on the evidence from PMID:40044823. This gene has also been rated 'moderate' on the DD panel based on the neurodevelopmental phenotype. However, it has not yet been associated with any relevant phenotypes in OMIM>
Structural eye disease v4.20 MYH10 Achchuthan Shanmugasundram reviewed gene: MYH10: Rating: AMBER; Mode of pathogenicity: None; Publications: 35980381, 40044823; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).
PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).
PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska edited their review of gene: FLG: Added comment: Comment on list classification: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; Changed publications to: 16444271, 16550169, 24940654, 22409988, 33807935, 36716921, 36751330
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska commented on gene: FLG: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska changed review comment from: Comment on list classification: There are at least 17 unrelated patients with variants in FLG with palmoplantar keratoderma (PPK). PPK is frequently seen in combination with ichthyosis.
PMID:36308042 (Clabbers et al., 2022): 22 Dutch patients with palmoplantar keratoderma were found to carry mono- or bi-allelic variants in FLG. In 17/22 of the patients, variants in other known PPK genes were excluded through an exome sequencing panel. Ten patients were heterozygous, six homozygous, and six compound heterozygous, including nonsense and frameshift mutations. Phenotypes: diffuse PPK (100% of patients), palmoplantar erythema (82%), palmar hyperlinearity (91%), transgrediens (62%), and generalized xerosis cutis (100%).
Functional studies: Newborn Flg(-/-) mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).; to: Comment on list classification: There are at least 17 unrelated patients with variants in FLG with palmoplantar keratoderma (PPK). PPK is frequently seen in combination with ichthyosis.

PMID:36308042 (Clabbers et al., 2022): 22 Dutch patients with palmoplantar keratoderma were found to carry mono- or bi-allelic variants in FLG. In 17/22 of the patients, variants in other known PPK genes were excluded through an exome sequencing panel. Ten patients were heterozygous, six homozygous, and six compound heterozygous, including nonsense and frameshift mutations. Phenotypes: diffuse PPK (100% of patients), palmoplantar erythema (82%), palmar hyperlinearity (91%), transgrediens (62%), and generalized xerosis cutis (100%).

Functional studies: Newborn Flg(-/-) mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Palmoplantar keratodermas.
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska edited their review of gene: FLG: Added comment: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Both monoallelic and biallelic variants in FLG may cause palmoplantar keratoderma - PPK is frequently seen in combination with ichthyosis (PMID:36308042 Clabbers et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).; Changed publications to: 16444271, 16550169, 22409988, 36308042
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 22409988, 36308042; Phenotypes: Ichthyosis vulgaris, OMIM:146700, Dermatitis, atopic, susceptibility to, 2, OMIM: 605803, hereditary palmoplantar keratoderma, MONDO:0019272; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16444271, 16550169; Phenotypes: Ichthyosis vulgaris, OMIM:146700, Dermatitis, atopic, susceptibility to, 2, OMIM: 605803, ichthyosis vulgaris, MONDO:0024304; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.10 FICD John Taylor reviewed gene: FICD: Rating: AMBER; Mode of pathogenicity: None; Publications: 36136088, 36704923; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital hyperinsulinism v3.5 AKT2 Achchuthan Shanmugasundram Deleted their review
Congenital hyperinsulinism v3.5 GPC3 Achchuthan Shanmugasundram Deleted their review
Congenital hyperinsulinism v3.5 AKT2 Achchuthan Shanmugasundram changed review comment from: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before demoting this gene to red.; to: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before demoting this gene to amber.
Congenital hyperinsulinism v3.5 AKT2 Achchuthan Shanmugasundram commented on gene: AKT2
Congenital hyperinsulinism v3.5 AKT2 Achchuthan Shanmugasundram Deleted their review
Rare genetic inflammatory skin disorders v4.1 FLG Ida Ertmanska changed review comment from: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' at the next update.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).; to: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).
Rare genetic inflammatory skin disorders v4.1 FLG Ida Ertmanska edited their review of gene: FLG: Added comment: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' at the next update.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).; Changed publications to: 16444271, 16550169
Rare genetic inflammatory skin disorders v4.1 FLG Ida Ertmanska changed review comment from: As reviewed by Ronnie Wright, FLG is associated with Ichthyosis vulgaris, which does not fit into the current scope of the Rare genetic inflammatory skin disorders panel. It should be rated Red based on the available evidence.

The gene is already rated Green on the following panels: Ichthyosis and erythrokeratoderma and Palmoplantar keratodermas.

FLG is associated with Ichthyosis vulgaris (AD &AR) OMIM:146700 and {Dermatitis, atopic, susceptibility to, 2} AD OMIM: 605803 in OMIM (accessed 18th Sep 2025).; to: Comment on list classification: As reviewed by Ronnie Wright, FLG is associated with Ichthyosis vulgaris, which does not fit into the current scope of the Rare genetic inflammatory skin disorders panel. It should be rated Red based on the available evidence.

The gene is already rated Green on the following panels: Ichthyosis and erythrokeratoderma and Palmoplantar keratodermas.

FLG is associated with Ichthyosis vulgaris (AD &AR) OMIM:146700 and {Dermatitis, atopic, susceptibility to, 2} AD OMIM: 605803 in OMIM (accessed 18th Sep 2025).
Rare genetic inflammatory skin disorders v4.1 FLG Ida Ertmanska reviewed gene: FLG: Rating: RED; Mode of pathogenicity: None; Publications: 16444271; Phenotypes: Ichthyosis vulgaris, OMIM:146700, Dermatitis, atopic, susceptibility to, 2, OMIM: 605803, ichthyosis vulgaris, MONDO:0024304; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v5.12 MT-ND5 Jesse Hayesmoore reviewed gene: MT-ND5: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 14520659, PMID: 23847141, PMID: 37318682, PMID: 25681084, PMID: 12624137, PMID: 14730434, PMID: 36104228, PMID: 22759514, PMID: 30587702, PMID: 23628297, PMID: 19473338; Phenotypes: Leigh syndrome, LHON, MELAS; Mode of inheritance: MITOCHONDRIAL
Paediatric or syndromic cardiomyopathy v7.86 MT-ND5 Jesse Hayesmoore reviewed gene: MT-ND5: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 14520659, PMID: 23847141, PMID: 37318682, PMID: 25681084, PMID: 12624137, PMID: 14730434, PMID: 36104228, PMID: 22759514, PMID: 30587702, PMID: 23628297, PMID: 19473338; Phenotypes: Leigh syndrome, LHON, MELAS; Mode of inheritance: MITOCHONDRIAL
Retinal disorders v8.25 CYP2U1 Ida Ertmanska commented on gene: CYP2U1: Comment on list classification: As reviewed by Cassandra Smith, individuals with biallelic variants in CYP2U1 may present with retinal abnormalities, which fits into the scope of this panel - there at least 8 unrelated individuals reported in literature. The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases), sometimes appearing as the first symptom, before spasticity. Based on the available evidence, CYP2U1 should be rated Green for Retinal disorders.
Retinal disorders v8.25 CYP2U1 Ida Ertmanska edited their review of gene: CYP2U1: Changed publications to: 23176821, 26914923, 29034544, 33107650, 34546337, 34828401, 38058766, 39605873
Retinal disorders v8.25 CYP2U1 Ida Ertmanska edited their review of gene: CYP2U1: Changed publications to: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873
Retinal disorders v8.25 CYP2U1 Ida Ertmanska Deleted their comment
Retinal disorders v8.25 CYP2U1 Ida Ertmanska commented on gene: CYP2U1: CYP2U1 is known to cause hereditary spastic paraplegia, with a variable spectrum of other symptoms being reported: intellectual disability, dystonia, pseudoxanthoma elasticum, and visual impairments (pigmentary degenerative maculopathy, loss of visual acuity, photophobia). There are at least 8 unrelated individuals with retinal abnormalities with biallelic variants in CYP2U1, harbouring missense, stop-gained, splice-altering, and frameshift variants (PMID: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873). The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases) – sometimes appearing as the first symptom, before spasticity (e.g. PMID:26914923, 39605873).

FUNCTIONAL EVIDENCE: A Cyp2u1−/− mouse model recapitulated the retinal impairments observed in patients – mice exhibited a late-onset (18 mo) ophthalmologic phenotype characterized by a cone dystrophy (PMID: 34546337 Pujol et al., 2021). Skin fibroblasts of an individual with c.61_73del, p.(Leu21Trpfs∗19) in CYP2U1 showed reduced oxygen consumption compared to controls, as well as structural abnormalities of the mitochondrial membrane (PMID: 23176821 Tesson et al., 2012). Expressing CYP2U1 with missense variants in HEK293T cells demonstrated that most missense variants were functionally inactive, due to loss of proper heme binding or destabilization of the protein structure (PMID: 29034544 Durand et al., 2018). Thus, the proposed disease mechanism is LoF leading to mitochondrial dysfunction - a common driver for degenerative retinal disease. Based on the available evidence, CYP2U1 should be rated Green for Retinal disorders.

The gene is associated with Spastic paraplegia 56, autosomal recessive (OMIM:615030, accessed 17th Sep 2025). It is also Definitive for CYP2U1-related spastic paraplegia in G2P (G2P00349).
Retinal disorders v8.25 CYP2U1 Ida Ertmanska reviewed gene: CYP2U1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873; Phenotypes: Spastic paraplegia 56, autosomal recessive, OMIM:615030, retinal disorder, MONDO:0005283; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v4.1 VIPAS39 Achchuthan Shanmugasundram Tag Q1_23_promote_green was removed from gene: VIPAS39.
Tag Q3_25_promote_green tag was added to gene: VIPAS39.
Intellectual disability v9.92 UGGT1 Karen Stals gene: UGGT1 was added
gene: UGGT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to PMID: 40267907
Phenotypes for gene: UGGT1 were set to intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys
Review for gene: UGGT1 was set to GREEN
gene: UGGT1 was marked as current diagnostic
Added comment: Dardas et al report biallelic UGGT1 variants in 10 families (15 individuals), with more severe phenotypes seen with biallelic loss of function variants. UGGT1 variants were shown to impair UGGT1 glycosylation and catalytic activity.
Sources: Literature
Congenital disorders of glycosylation v7.5 UGGT1 Karen Stals gene: UGGT1 was added
gene: UGGT1 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to PMID: 40267907
Phenotypes for gene: UGGT1 were set to intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys
Review for gene: UGGT1 was set to GREEN
gene: UGGT1 was marked as current diagnostic
Added comment: Dardas et al report biallelic UGGT1 variants in 10 families (15 individuals), with more severe phenotypes seen with biallelic loss of function variants. UGGT1 variants were shown to impair UGGT1 glycosylation and catalytic activity.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.86 RPL3L Riyaad Aungraheeta reviewed gene: RPL3L: Rating: ; Mode of pathogenicity: Other; Publications: PMID: 40820268; Phenotypes: Neonatal dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.8 DLD Alexander Rossor gene: DLD was added
gene: DLD was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: DLD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLD were set to 40888368
Phenotypes for gene: DLD were set to hepatic dysfunction; sensory axonal neuropathy
Penetrance for gene: DLD were set to Complete
Review for gene: DLD was set to AMBER
Added comment: Single case reporting sensory axonal neuropathy therefore should be amber for now
Sources: Other
Retinal disorders v8.25 UNC119 Ida Ertmanska commented on gene: UNC119: Comment on list classification: There are three cone-rod dystrophy patients from three unrelated families reported with heterozygous UNC119 variants. However, there is conflicting evidence regarding pathogenicity of the variants. Due to conflicting evidence, this gene should be demoted to Amber for retinal disorders.
Retinal disorders v8.25 UNC119 Ida Ertmanska reviewed gene: UNC119: Rating: AMBER; Mode of pathogenicity: None; Publications: 11006213, 23563732, 35947183, 30910914; Phenotypes: retinal disorder, MONDO:0005283, Cone-rod dystrophy 24, OMIM:620342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v7.4 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Movement disorders
(dystonia (8/14), choreoathetosis (3/14)) were reported in several individuals with biallelic variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Movement disorders such as dystonia (8/14) and choreoathetosis (3/14) were reported in several individuals with biallelic variants in this gene.
Intellectual disability v9.92 TNR Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: TNR.
Childhood onset dystonia, chorea or related movement disorder v7.4 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Movement disorders
(dystonia (8/14), choreoathetosis (3/14)) were reported in several individuals with biallelic variants in this gene.
Childhood onset hereditary spastic paraplegia v8.10 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Spastic para- or tetraparesis, apparent from infancy or early childhood, was reported in 13/15 individuals with biallelic variants in this gene.
Intellectual disability v9.92 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Impaired intellectual development noted in multiple individuals with biallelic variants in this gene, although the severity was highly variable and no formal neuropsychological testing was done. Nonetheless, cognitive developmental delay was recorded as moderate in at least 5 unrelated cases which supports inclusion on the panel.
Intellectual disability v9.92 TNR Arina Puzriakova Tag Q3_25_promote_green was removed from gene: TNR.
Childhood onset dystonia, chorea or related movement disorder v7.4 TNR Arina Puzriakova Entity copied from Intellectual disability v9.92
Childhood onset dystonia, chorea or related movement disorder v7.4 TNR Arina Puzriakova gene: TNR was added
gene: TNR was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Expert list,Expert Review Amber
Q3_25_promote_green tags were added to gene: TNR.
Mode of inheritance for gene: TNR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNR were set to 28334938; 32099069
Phenotypes for gene: TNR were set to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Childhood onset hereditary spastic paraplegia v8.10 TNR Arina Puzriakova Entity copied from Intellectual disability v9.92
Childhood onset hereditary spastic paraplegia v8.10 TNR Arina Puzriakova gene: TNR was added
gene: TNR was added to Childhood onset hereditary spastic paraplegia. Sources: Expert list,Expert Review Amber
Q3_25_promote_green tags were added to gene: TNR.
Mode of inheritance for gene: TNR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNR were set to 28334938; 32099069
Phenotypes for gene: TNR were set to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Intellectual disability v9.92 TNR Arina Puzriakova Publications for gene: TNR were updated from 22730557; 32099069 to 28334938; 32099069
Intellectual disability v9.91 TNR Arina Puzriakova Publications for gene: TNR were set to 32099069
Intellectual disability v9.91 TNR Arina Puzriakova Phenotypes for gene: TNR were changed from Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653 to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Rare anaemia v3.10 PPOX Sharon Whatley gene: PPOX was added
gene: PPOX was added to Rare anaemia. Sources: Other
Mode of inheritance for gene: PPOX was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: PPOX were set to 38940544; 30828546; 9454777; 7757079; 40296768; 21103937
Phenotypes for gene: PPOX were set to 121300; 618892
Penetrance for gene: PPOX were set to Incomplete
Review for gene: PPOX was set to GREEN
Added comment: Relevant metabolic investigation: Plasma porphyrin fluorescence emission and faecal coproporphyrin isomer (III:I) ratio (for hereditary coproporphyria) and faecal harderoporphyrin (for harderoporphyria)

PMID: 38940544 Aarsand reports that porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes. Defects in the CPOX gene cause hereditary coproporphyria.

PMID: 16159891 Schmitt reports that there are two very rare, homozygous forms of HCP one of which is characterised by the faecal excretion of harderoporphyrin. Harderoporphyria has predominantly haematological manifestations such as neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

PMID: 30828546 Moghe, 9454777 Lamoril, 7757079 Lamoril, 40296768 Kelestemur, 21103937 Hasanoglu report eight patients (from five families) with biallelic pathogenic CPOX variants. They presented with neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

PMID: 16159891 Schmitt reports that during childhood and adulthood, a mild residual anaemia is chronically observed in harderoporphyria patients.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Sources: Other
Intellectual disability v9.90 TNR Arina Puzriakova Phenotypes for gene: TNR were changed from Spastic para- or tetraparesis; Axial muscular hypotonia; Intellectual disability; Transient opisthotonus to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Intellectual disability v9.89 TNR Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: TNR.
Childhood onset dystonia, chorea or related movement disorder v7.3 CPOX Sharon Whatley reviewed gene: CPOX: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v7.8 CPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).; to: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Hereditary neuropathy or pain disorder v7.8 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 23605133, 35584894; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy v1.500 CPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.
PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).; to: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Hereditary neuropathy v1.500 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 35584894; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v8.58 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 23236641, 11074238, 23605133, 16159891, 40296768, 33008663, 30828546, 21103937, 16159891, 10505225, 9454777, 7757079, 8012360, 6886003; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.632 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 37540847, 23236641, 11074238, 23605133, 16159891, 40296768, 33008663, 30828546, 21103937, 16159891, 10505225, 9454777, 7757079, 8012360, 6886003; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Vascular skin disorders v2.1 CPOX Sharon Whatley reviewed gene: CPOX: Rating: RED; Mode of pathogenicity: None; Publications: 23236641; Phenotypes: ; Mode of inheritance: None
Cutaneous photosensitivity with a likely genetic cause v3.9 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 23236641, 11074238, 40296768, 33008663, 30828546, 21103937, 16159891, 10505225, 9454777, 7757079, 8012360, 6886003; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Non-acute porphyrias v1.26 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 11309681, 23236641, 11074238, 16159891, 40296768, 33008663, 30828546, 21103937, 16159891, 10505225, 9454777, 7757079, 8012360, 6886003; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Structural eye disease v4.20 NTN1 Ida Ertmanska commented on gene: NTN1: Comment on list classification: There is one patient reported in literature with structural eye disease (coloboma and microphthalmia), heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had no ocular abnormalities. Gene knockouts in zebrafish and mouse embryos resulted in ocular coloboma phenotype, supporting the gene's role in eye development. Based on the available evidence, NTN1 should be rated Amber for Structural eye disease.
Structural eye disease v4.20 NTN1 Ida Ertmanska reviewed gene: NTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39648562, 31162046; Phenotypes: Associated with Mirror movements 4, OMIM:618264, microphthalmia, isolated, with coloboma, MONDO:0000170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorder with complex IV deficiency v4.9 COX18 Achchuthan Shanmugasundram Classified gene: COX18 as Amber List (moderate evidence)
Mitochondrial disorder with complex IV deficiency v4.9 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the promotion of this gene to green rating in the next GMS update.
Mitochondrial disorder with complex IV deficiency v4.9 COX18 Achchuthan Shanmugasundram Gene: cox18 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex IV deficiency v4.8 COX18 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: COX18.
Mitochondrial disorder with complex IV deficiency v4.8 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from No OMIM phenotype to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Mitochondrial disorder with complex IV deficiency v4.7 COX18 Achchuthan Shanmugasundram Publications for gene: COX18 were set to
Mitochondrial disorder with complex IV deficiency v4.6 COX18 Achchuthan Shanmugasundram Mode of inheritance for gene: COX18 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v4.5 COX18 Achchuthan Shanmugasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 37468577, 40830826; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.31 COX18 Achchuthan Shanmugasundram Classified gene: COX18 as Amber List (moderate evidence)
Mitochondrial disorders v9.31 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the promotion of this gene to green rating in the next GMS update.
Mitochondrial disorders v9.31 COX18 Achchuthan Shanmugasundram Gene: cox18 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.30 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from 37468577; 40830826 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Mitochondrial disorders v9.29 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from No OMIM phenotype to 37468577; 40830826
Mitochondrial disorders v9.28 COX18 Achchuthan Shanmugasundram Publications for gene: COX18 were set to
Mitochondrial disorders v9.27 COX18 Achchuthan Shanmugasundram Mode of inheritance for gene: COX18 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.26 COX18 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: COX18.
Mitochondrial disorders v9.26 COX18 Achchuthan Shanmugasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 37468577, 40830826; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.12 COX18 Achchuthan Shanmugasundram Classified gene: COX18 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v4.12 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the promotion of this gene to green rating in the next GMS update.
Possible mitochondrial disorder - nuclear genes v4.12 COX18 Achchuthan Shanmugasundram Gene: cox18 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v4.11 COX18 Achchuthan Shanmugasundram Publications for gene: COX18 were set to
Possible mitochondrial disorder - nuclear genes v4.10 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from No OMIM phenotype to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Possible mitochondrial disorder - nuclear genes v4.9 COX18 Achchuthan Shanmugasundram Mode of inheritance for gene: COX18 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.8 COX18 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: COX18.
Possible mitochondrial disorder - nuclear genes v4.8 COX18 Achchuthan Shanmugasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 37468577, 40830826; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.8 COX18 Achchuthan Shanmugasundram Classified gene: COX18 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.8 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the association of biallelic COX18 variants with Charcot-Marie-Tooth disease. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.8 COX18 Achchuthan Shanmugasundram Gene: cox18 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.7 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from peripheral neuropathy to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Hereditary neuropathy or pain disorder v7.6 COX18 Achchuthan Shanmugasundram Publications for gene: COX18 were set to 40830826
Hereditary neuropathy or pain disorder v7.5 COX18 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: COX18.
Tag Q3_25_NHS_review tag was added to gene: COX18.
Hereditary neuropathy or pain disorder v7.5 COX18 Achchuthan Shanmugasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 37468577, 40830826; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v6.5 LBX1 Ian Berry gene: LBX1 was added
gene: LBX1 was added to DDG2P. Sources: Expert Review
Mode of inheritance for gene: LBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LBX1 were set to PMID: 30487221
Penetrance for gene: LBX1 were set to Complete
Review for gene: LBX1 was set to GREEN
gene: LBX1 was marked as current diagnostic
Added comment: Single sib-pair in PMID: 30487221 with congenital central hypoventilation syndrome, 1bp resulting in a frameshift in the terminal exon. Mouse model of the same variant expressed a protein with an altered C-terminal and replicated the human phenotype.

Subsequent unpublished studies (in process of publication): 2 further cases in CVA/GEL dataset with comparable phenotypes, 2 further probands (with segregation) in other families via multinational collaboration.

All cases appear to have the same variant NM_006562.5: c.707del p.(Val236Alafs*59) which may be a Roma founder.
Sources: Expert Review
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Classified gene: UPF1 as Amber List (moderate evidence)
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic UPF1 variants with intellectual disability and/or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.88 UPF1 Achchuthan Shanmugasundram Classified gene: UPF1 as Amber List (moderate evidence)
Intellectual disability v9.88 UPF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic UPF1 variants with intellectual disability and/or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.88 UPF1 Achchuthan Shanmugasundram Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.87 UPF1 Achchuthan Shanmugasundram changed review comment from: PMID:28135719 (2017) reported four unrelated patients with de novo heterozygous missense variants in UPF1 gene from the Deciphering Developmental Disorders Study cohort, for which no detailed phenotypic information was available in the publication. Three patients were reported with global developmental delay (mild in one) and the fourth patient was reported with neurodevelopmental delay as one of the presenting phenotypes in the Decipher database (https://www.deciphergenomics.org/gene/UPF1/patient-overlap/snvs).

PMID:28539120 (2017) reported a patient with significant intellectual disability (ID) and gross motor delay and with a heterozygous likely pathogenic variant in UPF1 gene (c.1576_1577delinsAA/ p.Ala526Asn). However, this patient also harboured a heterozygous likely pathogenic variant in SQSTM1 gene. As reviewed below by Ivone Leong, the authors suggested that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

PMID:39571789 (2024) reported two unrelated paediatric patients with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. They both had language and motor delays and were identified with de novo heterozygous variants in UPF1 gene (c.949_951del/ p.Asp317del & c.1984G>A/ p.Asp662Asn). The p.Asp662Asn variant has also been previously reported in a patient from PMID:28135719.

PMID:39993774 (2025) reported a 17‐year‐old male patient with moderate intellectual disability, atypical autism, ADHD, and aggressivity. He was identified with a de novo missense variant in UPF1 gene - c.1576G>A/ p.Ala526Thr.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.; to: PMID:28135719 (2017) reported four unrelated patients with de novo heterozygous missense variants in UPF1 gene from the Deciphering Developmental Disorders Study cohort, for which no detailed phenotypic information was available in the publication. Three patients were reported with global developmental delay (mild in one) and the fourth patient was reported with neurodevelopmental delay as one of the presenting phenotypes in the Decipher database (https://www.deciphergenomics.org/gene/UPF1/patient-overlap/snvs).

PMID:28539120 (2017) reported a patient with significant intellectual disability (ID) and gross motor delay and with a heterozygous likely pathogenic variant in UPF1 gene (c.1576_1577delinsAA/ p.Ala526Asn). However, this patient also harboured a heterozygous likely pathogenic variant in SQSTM1 gene. As reviewed below by Ivone Leong, the authors suggested that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

PMID:39571789 (2024) reported two unrelated paediatric patients with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. They both had language and motor delays and were identified with de novo heterozygous variants in UPF1 gene (c.949_951del/ p.Asp317del & c.1984G>A/ p.Asp662Asn). The p.Asp662Asn variant has also been previously reported in a patient from PMID:28135719.

PMID:39993774 (2025) reported a 17‐year‐old male patient with moderate intellectual disability, atypical autism, ADHD, and aggressivity. He was identified with a de novo missense variant in UPF1 gene - c.1576G>A/ p.Ala526Thr.

As reviewed by Karen Stals, there is an additional patient identified with UPF1 variant in Exeter Genomics Laboratory.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.
Intellectual disability v9.87 UPF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UPF1.
Tag Q3_25_NHS_review tag was added to gene: UPF1.
Intellectual disability v9.87 UPF1 Achchuthan Shanmugasundram Phenotypes for gene: UPF1 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.86 UPF1 Achchuthan Shanmugasundram Publications for gene: UPF1 were set to 33057194; 28539120
Intellectual disability v9.85 UPF1 Achchuthan Shanmugasundram edited their review of gene: UPF1: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v9.85 UPF1 Achchuthan Shanmugasundram reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 28539120, 39571789, 39993774; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v7.3 PPOX Sharon Whatley reviewed gene: PPOX: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v7.5 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 35584894, 37879139, 11286631, 10870850, 8290408; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mitochondrial disorders v9.26 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 33159949, 38940544, 10486317, 8290408, 38940544, 37879139, 40114189; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v6.82 FLII Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: FLII.
Tag Q3_25_expert_review tag was added to gene: FLII.
Tag Q3_25_NHS_review tag was added to gene: FLII.
Fetal anomalies v6.82 FLII Arina Puzriakova changed review comment from: New gene added to this panel with an Amber rating, inline with the recent review by the R21 Clinical Oversight Group.; to: New gene added to this panel with an Amber rating, inline with the recent review by the R21 Clinical Oversight Group. However, tagging for additional review as this rating contradicts the review comment "Sufficient evidence for gene-disease association and may present prenatally with structural heart defects in some cases" and this gene is tagged for promotion to Green on the R135 Paediatric or syndromic cardiomyopathy panel.
Fetal anomalies v6.82 SIRT6 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SIRT6.
Tag Q2_25_expert_review was removed from gene: SIRT6.
Fetal anomalies v6.82 C14orf80 Arina Puzriakova commented on gene: C14orf80: Added new-gene-name tag as the latest HGNC symbol for C14orf80 is TEDC1
Fetal anomalies v6.82 C14orf80 Arina Puzriakova Tag new-gene-name tag was added to gene: C14orf80.
Fetal anomalies v6.82 PDE12 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: PDE12.
Fetal anomalies v6.82 PDE12 Arina Puzriakova changed review comment from: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group.; to: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group. However, tagging for additional expert review to resolve conflicting reviews - first reviewed as Green by Achchuthan Shanmugasundram but then as Amber by Alice Gardham based on the same evidence.
Fetal anomalies v6.82 NDUFB7 Arina Puzriakova edited their review of gene: NDUFB7: Changed rating: GREEN
Fetal anomalies v6.82 NDUFB7 Arina Puzriakova changed review comment from: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group.; to: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group. However, tagging for additional expert review to resolve conflicting reviews - first reviewed as Green by me but then as Amber by Vicki Harrison based on the same evidence.
Fetal anomalies v6.82 ITGAV Arina Puzriakova changed review comment from: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; to: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.

Previously curated as Amber as only one family had fetal cases reported on; however as noted in Natalie Canham review, all affected individuals have brain anomalies which could be detected prenatally. Therefore this gene can be rated Green.
Fetal anomalies v6.82 FAAP100 Arina Puzriakova Phenotypes for gene: FAAP100 were changed from Fanconi anemia to Fanconi anemia, complementation group X, OMIM:621258
Fetal anomalies v6.81 FAAP100 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: FAAP100.
Tag Q3_25_NHS_review tag was added to gene: FAAP100.
Fetal anomalies v6.81 BORCS5 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: BORCS5.
Tag Q3_25_NHS_review tag was added to gene: BORCS5.
Renal tubulopathies v5.6 MAGED2 Arina Puzriakova Phenotypes for gene: MAGED2 were changed from Bartter syndrome, type 5, antenatal, transient, 300971 to Bartter syndrome, type 5, antenatal, transient, OMIM:300971
Fetal anomalies v6.81 MAGED2 Arina Puzriakova Phenotypes for gene: MAGED2 were changed from Bartter syndrome, type 5, antenatal, transient to Bartter syndrome, type 5, antenatal, transient, OMIM:300971
Fetal anomalies v6.80 MAGED2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MAGED2.
Tag Q3_25_NHS_review tag was added to gene: MAGED2.
Fetal anomalies v6.80 ZEB1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ZEB1.
Tag Q3_25_NHS_review tag was added to gene: ZEB1.
Fetal anomalies v6.80 WDR47 Arina Puzriakova Phenotypes for gene: WDR47 were changed from Complex neurodevelopmental disorder to neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.79 WDR47 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: WDR47.
Tag Q3_25_NHS_review tag was added to gene: WDR47.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.42 UNC13D Arina Puzriakova Phenotypes for gene: UNC13D were changed from Hemophagocytic lymphohistiocytosis, familial 3, 608898; FHL3; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); HPLH3; HLH3; Fever, HSM, HLH, cytopenias,; Diseases of Immune Dysregulation to Hemophagocytic lymphohistiocytosis, familial, 3, OMIM:608898
Fetal anomalies v6.79 UNC13D Arina Puzriakova Phenotypes for gene: UNC13D were changed from Hemophagocytic lymphohistiocytosis, familial, 3, OMIM:608898; Hemophagocytic lymphohistiocytosis, familial, 3 to Hemophagocytic lymphohistiocytosis, familial, 3, OMIM:608898
Fetal anomalies v6.78 UNC13D Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: UNC13D.
Tag Q3_25_NHS_review tag was added to gene: UNC13D.
Fetal anomalies v6.78 TCP1 Arina Puzriakova Phenotypes for gene: TCP1 were changed from Intellectual developmental disorder with polymicrogyria and seizures to Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021
Fetal anomalies v6.77 TCP1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: TCP1.
Tag Q3_25_NHS_review tag was added to gene: TCP1.
Fetal anomalies v6.77 STX5 Arina Puzriakova Phenotypes for gene: STX5 were changed from ?Congenital disorder of glycosylation, type IIaa, OMIM:620454; Congenital disorder of glycosylation, type IIaa to Congenital disorder of glycosylation, type IIaa, OMIM:620454
Fetal anomalies v6.76 STX5 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: STX5.
Tag Q3_25_NHS_review tag was added to gene: STX5.
Fetal anomalies v6.76 SRPK3 Arina Puzriakova Phenotypes for gene: SRPK3 were changed from X-linked intellectual developmental disorder-114 to Intellectual developmental disorder, X-linked 114, OMIM:301134
Fetal anomalies v6.75 SRPK3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SRPK3.
Tag Q3_25_NHS_review tag was added to gene: SRPK3.
Fetal anomalies v6.75 SPTA1 Arina Puzriakova Tag watchlist was removed from gene: SPTA1.
Tag Q3_25_promote_green tag was added to gene: SPTA1.
Tag Q3_25_NHS_review tag was added to gene: SPTA1.
Intellectual disability v9.85 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Monogenic short stature v1.23 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Early onset or syndromic epilepsy v8.31 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Severe microcephaly v8.12 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Fetal anomalies v6.75 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Fetal anomalies v6.74 SPOUT1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SPOUT1.
Tag Q3_25_NHS_review tag was added to gene: SPOUT1.
Intellectual disability v9.84 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Early onset or syndromic epilepsy v8.30 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Intellectual disability v9.84 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from ?Arthrogryposis, mental retardation, and seizures (MIM 615553) to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Early onset or syndromic epilepsy v8.29 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from ?Arthrogryposis, mental retardation, and seizures (MIM 615553); Early onset epileptic encephalopathy with skeletal defects to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Likely inborn error of metabolism v8.58 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Congenital disorders of glycosylation v7.5 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures 615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Fetal anomalies v6.74 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Fetal anomalies v6.73 SLC35A3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SLC35A3.
Tag Q3_25_NHS_review tag was added to gene: SLC35A3.
Fetal anomalies v6.73 SLC12A9 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SLC12A9.
Tag Q3_25_NHS_review tag was added to gene: SLC12A9.
Fetal anomalies v6.73 SENP7 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SENP7.
Tag Q3_25_NHS_review tag was added to gene: SENP7.
Fetal anomalies v6.73 RPL26 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RPL26.
Tag Q3_25_NHS_review tag was added to gene: RPL26.
Fetal anomalies v6.73 RNU5B-1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RNU5B-1.
Tag Q3_25_NHS_review tag was added to gene: RNU5B-1.
Fetal anomalies v6.73 RIPPLY2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RIPPLY2.
Tag Q3_25_NHS_review tag was added to gene: RIPPLY2.
Fetal anomalies v6.73 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter; Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
Fetal anomalies v6.72 RAB11B Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RAB11B.
Tag Q3_25_NHS_review tag was added to gene: RAB11B.
Intellectual disability v9.83 PUS3 Arina Puzriakova Phenotypes for gene: PUS3 were changed from Global developmental delay; Microcephaly; Mental retardation, autosomal recessive 55, 617051; Intellectual disability to Neurodevelopmental disorder with microcephaly and gray sclerae, OMIM:617051
Fetal anomalies v6.72 PUS3 Arina Puzriakova Phenotypes for gene: PUS3 were changed from Neurodevelopmental disorder with microcephaly and gray sclerae to Neurodevelopmental disorder with microcephaly and gray sclerae, OMIM:617051
Fetal anomalies v6.71 PUS3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PUS3.
Tag Q3_25_NHS_review tag was added to gene: PUS3.
Fetal anomalies v6.71 PTEN Arina Puzriakova Phenotypes for gene: PTEN were changed from COWDEN DISEASE; Cowden syndrome 1; LHERMITTE-DUCLOS DISEASE; PROTEUS SYNDROME; MACROCEPHALY/AUTISM SYNDROME; BANNAYAN-ZONANA SYNDROME; VACTERL ASSOCIATION WITH HYDROCEPHALUS to Cowden syndrome 1, OMIM:158350
Fetal anomalies v6.70 PTEN Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PTEN.
Tag Q3_25_NHS_review tag was added to gene: PTEN.
Renal ciliopathies v4.3 PSKH1 Arina Puzriakova Phenotypes for gene: PSKH1 were changed from hepatorenal syndrome, MONDO:0001382 to Cholestasis, progressive familial intrahepatic, 13, OMIM:620962
Cholestasis v3.8 PSKH1 Arina Puzriakova Phenotypes for gene: PSKH1 were changed from hepatorenal syndrome, MONDO:0001382 to Cholestasis, progressive familial intrahepatic, 13, OMIM:620962
Fetal anomalies v6.70 PSKH1 Arina Puzriakova Phenotypes for gene: PSKH1 were changed from hepatorenal syndrome, MONDO:0001382 to Cholestasis, progressive familial intrahepatic, 13, OMIM:620962
Fetal anomalies v6.69 PSKH1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PSKH1.
Tag Q3_25_NHS_review tag was added to gene: PSKH1.
Fetal anomalies v6.69 PPFIBP1 Arina Puzriakova Phenotypes for gene: PPFIBP1 were changed from Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024
Fetal anomalies v6.68 PPFIBP1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PPFIBP1.
Tag Q3_25_NHS_review tag was added to gene: PPFIBP1.
Fetal anomalies v6.68 PPFIA3 Arina Puzriakova Phenotypes for gene: PPFIA3 were changed from Paul-Chao neurodevelopmental syndrome to Paul-Chao neurodevelopmental syndrome, OMIM:621122
Fetal anomalies v6.67 PPFIA3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PPFIA3.
Tag Q3_25_NHS_review tag was added to gene: PPFIA3.
Fetal anomalies v6.67 PLAA Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PLAA.
Tag Q3_25_NHS_review tag was added to gene: PLAA.
Fetal anomalies v6.67 PIGW Arina Puzriakova Phenotypes for gene: PIGW were changed from Glycosylphosphatidylinositol biosynthesis defect 11 to Glycosylphosphatidylinositol biosynthesis defect 11, OMIM:616025
Fetal anomalies v6.66 PIGW Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PIGW.
Tag Q3_25_NHS_review tag was added to gene: PIGW.
Fetal anomalies v6.66 PIGP Arina Puzriakova Phenotypes for gene: PIGP were changed from Developmental and epileptic encephalopathy 55 to Developmental and epileptic encephalopathy 55, OMIM:617599
Fetal anomalies v6.65 PIGP Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PIGP.
Tag Q3_25_NHS_review tag was added to gene: PIGP.
Intellectual disability v9.82 PIGG Arina Puzriakova Phenotypes for gene: PIGG were changed from MRT53; Mental retardation, autosomal recessive 53, 616917; # 616917 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 53 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917
Early onset or syndromic epilepsy v8.28 PIGG Arina Puzriakova Phenotypes for gene: PIGG were changed from Mental retardation, autosomal recessive 53 616917 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917
Fetal anomalies v6.65 PIGG Arina Puzriakova Phenotypes for gene: PIGG were changed from Intellectual Disability with Seizures and Hypotonia; Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917; Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917
Fetal anomalies v6.64 PIGG Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PIGG.
Tag Q3_25_NHS_review tag was added to gene: PIGG.
Fetal anomalies v6.64 PI4KA Arina Puzriakova Phenotypes for gene: PI4KA were changed from Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531; Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis MONDO:0014679; Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Fetal anomalies v6.63 PI4KA Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PI4KA.
Tag Q3_25_NHS_review tag was added to gene: PI4KA.
Fetal anomalies v6.63 PHF5A Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PHF5A.
Tag Q3_25_NHS_review tag was added to gene: PHF5A.
Fetal anomalies v6.63 PAK2 Arina Puzriakova Phenotypes for gene: PAK2 were changed from Knobloch syndrome 2 to Knobloch syndrome 2, OMIM:618458
Fetal anomalies v6.62 PAK2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PAK2.
Tag Q3_25_NHS_review tag was added to gene: PAK2.
Fetal anomalies v6.62 PAICS Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PAICS.
Tag Q3_25_NHS_review tag was added to gene: PAICS.
Intellectual disability v9.81 ODC1 Arina Puzriakova Phenotypes for gene: ODC1 were changed from Global developmental delay; Intellectual disability; Macrocephaly; Alopecia; Ectodermal dysplasia to Bachmann-Bupp syndrome, OMIM:619075
Fetal anomalies v6.62 ODC1 Arina Puzriakova Phenotypes for gene: ODC1 were changed from Bachmann-Bupp syndrome to Bachmann-Bupp syndrome, OMIM:619075
Fetal anomalies v6.61 ODC1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ODC1.
Tag Q3_25_NHS_review tag was added to gene: ODC1.
Intellectual disability v9.80 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from BOSCH-BOONSTRA OPTIC ATROPHY SYNDROME to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
Retinal disorders v8.25 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from Bosch-Boonstra-Schaaf optic atrophy syndrome, 615722 to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
Optic neuropathy v5.24 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from Bosch-Boonstra-Schaaf optic atrophy syndrome, 615722 to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
Fetal anomalies v6.61 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from BOSCH-BOONSTRA OPTIC ATROPHY SYNDROME; Bosch-Boonstra-Schaaf optic atrophy syndrome to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
Fetal anomalies v6.60 NR2F1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: NR2F1.
Tag Q3_25_NHS_review tag was added to gene: NR2F1.
Fetal anomalies v6.60 NEXN Arina Puzriakova Tag watchlist was removed from gene: NEXN.
Tag Q3_25_promote_green tag was added to gene: NEXN.
Tag Q3_25_NHS_review tag was added to gene: NEXN.
Fetal anomalies v6.60 NEPRO Arina Puzriakova commented on gene: NEPRO: The 'new-gene-name' tag has been added to this gene as the latest HGNC gene symbol for NEPRO is RMP64.
Fetal anomalies v6.60 NEPRO Arina Puzriakova Tag new-gene-name tag was added to gene: NEPRO.
Tag Q3_25_promote_green tag was added to gene: NEPRO.
Tag Q3_25_NHS_review tag was added to gene: NEPRO.
Fetal anomalies v6.60 MSL2 Arina Puzriakova Phenotypes for gene: MSL2 were changed from Karayol-Borroto-Haghshenas neurodevelopmental syndrome to Karayol-Borroto-Haghshenas neurodevelopmental syndrome, OMIM:620985
Fetal anomalies v6.59 MIA3 Arina Puzriakova Tag Q3_25_NHS_review tag was added to gene: MIA3.
Fetal anomalies v6.59 MSL2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MSL2.
Tag Q3_25_NHS_review tag was added to gene: MSL2.
Skeletal dysplasia v8.9 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from short stature; skeletal dysplasia; amelogenesis; dentinogenesis imperfecta; short stature; brachydactyly; Platyspondyly; insulin-dependent diabetes mellitus; sensorineural hearing loss; mild intellectual disability to Ondontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.59 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Odontochondrodysplasia-2 with hearing loss and diabetes to Ondontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.58 MIA3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MIA3.
Fetal anomalies v6.58 MED11 Arina Puzriakova Phenotypes for gene: MED11 were changed from Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, OMIM:620327
Fetal anomalies v6.57 MED11 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MED11.
Tag Q3_25_NHS_review tag was added to gene: MED11.
Intellectual disability v9.79 MAPK1 Arina Puzriakova Phenotypes for gene: MAPK1 were changed from Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin to Noonan syndrome 13, OMIM:619087
Fetal anomalies v6.57 MAPK1 Arina Puzriakova Phenotypes for gene: MAPK1 were changed from Noonan syndrome 13; Noonan syndrome 13, OMIM:619087 to Noonan syndrome 13, OMIM:619087
Fetal anomalies v6.56 MAPK1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MAPK1.
Tag Q3_25_NHS_review tag was added to gene: MAPK1.
Fetal anomalies v6.56 LSS Arina Puzriakova Phenotypes for gene: LSS were changed from Cataract 44; Alopecia-intellectual disability syndrome 4 to Alopecia-intellectual disability syndrome 4, OMIM:618840; Cataract 44, OMIM:616509
Fetal anomalies v6.55 LSS Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: LSS.
Tag Q3_25_NHS_review tag was added to gene: LSS.
Fetal anomalies v6.55 LGI3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: LGI3.
Tag Q3_25_NHS_review tag was added to gene: LGI3.
Fetal anomalies v6.55 LDB1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: LDB1.
Tag Q3_25_NHS_review tag was added to gene: LDB1.
Proteinuric renal disease v5.2 LAGE3 Arina Puzriakova Phenotypes for gene: LAGE3 were changed from Galloway-Mowat syndrome 2, X-linked #301006 to Galloway-Mowat syndrome 2, X-linked, OMIM:301006
Fetal anomalies v6.55 LAGE3 Arina Puzriakova Phenotypes for gene: LAGE3 were changed from Galloway-Mowat syndrome 2, X-linked; Galloway-Mowat syndrome 2, X-linked, OMIM:301006 to Galloway-Mowat syndrome 2, X-linked, OMIM:301006
Fetal anomalies v6.54 LAGE3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: LAGE3.
Tag Q3_25_NHS_review tag was added to gene: LAGE3.
Fetal anomalies v6.54 C12orf66 Arina Puzriakova commented on gene: C12orf66: Added new-gene-name tag, new approved HGNC gene symbol for C12orf66 is KICS2
Fetal anomalies v6.54 C12orf66 Arina Puzriakova Tag new-gene-name tag was added to gene: C12orf66.
Tag Q3_25_promote_green tag was added to gene: C12orf66.
Tag Q3_25_NHS_review tag was added to gene: C12orf66.
Fetal anomalies v6.54 C12orf66 Arina Puzriakova Phenotypes for gene: C12orf66 were changed from Intellectual developmental disorder, autosomal recessive 83 to Intellectual developmental disorder, autosomal recessive 83, OMIM:621100
Fetal anomalies v6.53 ITGAV Arina Puzriakova Phenotypes for gene: ITGAV were changed from syndromic disease, MONDO:0002254; Syndromic disease, MONDO:0002254 to Syndromic disease, MONDO:0002254
Fetal anomalies v6.52 ITGAV Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ITGAV.
Tag Q3_25_NHS_review tag was added to gene: ITGAV.
Renal ciliopathies v4.2 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, OMIM:615996 to Bardet-Biedl syndrome 19, OMIM:615996
Ophthalmological ciliopathies v5.4 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, 615996 to Bardet-Biedl syndrome 19, OMIM:615996
Fetal anomalies v6.52 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from Bardet-Biedl syndrome 19, OMIM:615996; Bardet-Biedl syndrome 19 to Bardet-Biedl syndrome 19, OMIM:615996
Intellectual disability v9.78 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from Bardet-Biedl syndrome 19, MIM#615996 to Bardet-Biedl syndrome 19, OMIM:615996
Rare multisystem ciliopathy disorders v1.175 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, 615996 to Bardet-Biedl syndrome 19, OMIM:615996
Retinal disorders v8.24 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, OMIM:615996 to Bardet-Biedl syndrome 19, OMIM:615996
Bardet Biedl syndrome v2.8 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, 615996 to Bardet-Biedl syndrome 19, OMIM:615996
Fetal anomalies v6.51 IFT27 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: IFT27.
Tag Q3_25_NHS_review tag was added to gene: IFT27.
Fetal anomalies v6.51 HNRNPU Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: HNRNPU.
Tag Q3_25_NHS_review tag was added to gene: HNRNPU.
Intellectual disability v9.77 HNRNPU Arina Puzriakova Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy, early infantile, 54, 617391; intellectual disability to Developmental and epileptic encephalopathy 54, OMIM:617391
Early onset or syndromic epilepsy v8.27 HNRNPU Arina Puzriakova Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy; Epileptic encephalopathy, early infantile, 54, 617391 to Developmental and epileptic encephalopathy 54, OMIM:617391
Fetal anomalies v6.51 HNRNPU Arina Puzriakova Phenotypes for gene: HNRNPU were changed from EPILEPTIC ENCEPHALOPATHY; Developmental and epileptic encephalopathy 54 to Developmental and epileptic encephalopathy 54, OMIM:617391
Fetal anomalies v6.50 HDAC3 Arina Puzriakova Phenotypes for gene: HDAC3 were changed from HDAC3-related neurodevelopmental disorder to neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.49 HDAC3 Arina Puzriakova Tag gene-checked tag was added to gene: HDAC3.
Fetal anomalies v6.49 HDAC3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: HDAC3.
Tag Q3_25_NHS_review tag was added to gene: HDAC3.
Fetal anomalies v6.49 GNAI2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: GNAI2.
Tag Q3_25_NHS_review tag was added to gene: GNAI2.
Intellectual disability v9.76 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Galactosemia, 230400; GALACTOSEMIA (GALCT) to Galactosemia, OMIM:230400
Fetal anomalies v6.49 GEMIN4 Arina Puzriakova Phenotypes for gene: GEMIN4 were changed from Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, OMIM:617913
Fetal anomalies v6.48 GEMIN4 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: GEMIN4.
Tag Q3_25_NHS_review tag was added to gene: GEMIN4.
Likely inborn error of metabolism v8.57 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Intellectual disability; Classical galactosaemia (Disorders of galactose metabolism); Galactosemia; Cataracts to Galactosemia, OMIM:230400
Undiagnosed metabolic disorders v1.632 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Classical galactosaemia (Disorders of galactose metabolism); Cataracts; Intellectual disability; Galactosemia 230400 to Galactosemia, OMIM:230400
Bilateral congenital or childhood onset cataracts v7.2 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Confirmed DD gene for galactosemia to Galactosemia, OMIM:230400
Fetal anomalies v6.48 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Galactosemia; GALACTOSEMIA to Galactosemia, OMIM:230400
Fetal anomalies v6.47 GALT Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: GALT.
Tag Q3_25_NHS_review tag was added to gene: GALT.
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova changed review comment from: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the complex infantile-onset disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Red to Amber but this gene should be promoted to Green at the next GMS panel update on the basis that cerebellar hypoplasia is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported.; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v8.21
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova gene: EXOSC8 was added
gene: EXOSC8 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review Amber
Q3_25_promote_green tags were added to gene: EXOSC8.
Mode of inheritance for gene: EXOSC8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC8 were set to 24989451; 38017281; 34210538
Phenotypes for gene: EXOSC8 were set to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Cerebellar hypoplasia v1.78 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Green List (high evidence)
Cerebellar hypoplasia v1.78 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green on the basis that cerebellar hypoplasia is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported.
Cerebellar hypoplasia v1.78 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.77 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to
Cerebellar hypoplasia v1.76 EXOSC8 Arina Puzriakova Mode of inheritance for gene: EXOSC8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.75 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24989451, 38017281, 34210538; Phenotypes: Pontocerebellar hypoplasia, type 1C, OMIM:616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v8.10 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Green List (high evidence)
Hereditary ataxia with onset in adulthood v8.10 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red on this panel.

There are currently five reported families with biallelic variants in this gene, all presenting with an infantile-onset disorder (latest reported age of onset is 6 months) (PMIDs: 24989451; 38017281; 34210538). Motor dysfunction is a prominent feature, although it does not overtly manifest as ataxia. Nevertheless, this gene has been added to the 'Ataxia and cerebellar anomalies - narrow panel' due to the presence of cerebellar hypoplasia in affected individuals, and because the early age of onset aligns more closely with that panel.
Hereditary ataxia with onset in adulthood v8.10 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Green List (High Evidence).
Hereditary ataxia with onset in adulthood v8.9 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to
Hereditary ataxia with onset in adulthood v8.8 EXOSC8 Arina Puzriakova Tag Q3_25_demote_red tag was added to gene: EXOSC8.
Ataxia and cerebellar anomalies - narrow panel v8.21 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.21 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but this gene should be promoted to Green at the next GMS panel update on the basis that cerebellar hypoplasia is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported.
Ataxia and cerebellar anomalies - narrow panel v8.21 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.20 EXOSC8 Arina Puzriakova Mode of inheritance for gene: EXOSC8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.19 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to
Ataxia and cerebellar anomalies - narrow panel v8.18 EXOSC8 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EXOSC8.
Ataxia and cerebellar anomalies - narrow panel v8.18 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24989451, 38017281, 34210538; Phenotypes: Pontocerebellar hypoplasia, type 1C, OMIM:616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.75 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to 24989451; 38017281; 34210538
Intellectual disability v9.74 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to 24989451; 29656927
Intellectual disability v9.73 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Amber List (moderate evidence)
Intellectual disability v9.73 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update - 5 unrelated families with pontocerebellar hypoplasia due to biallelic variants in this gene. Almost all described patients exhibited psychomotor retardation (PMIDs: 24989451; 38017281; 34210538)
Intellectual disability v9.73 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Tag founder-effect tag was added to gene: EXOSC8.
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Tag watchlist was removed from gene: EXOSC8.
Tag founder-effect was removed from gene: EXOSC8.
Tag Q3_25_promote_green tag was added to gene: EXOSC8.
Intellectual disability v9.72 EXOSC8 Arina Puzriakova edited their review of gene: EXOSC8: Added comment: PMID: 34210538 (2021) - 16-year-old Spanish boy with cerebellar and spinal muscular atrophy, spasticity, psychomotor retardation, nystagmus, ophthalmoparesis, epilepsy, and mitochondrial respiratory chain (MRC) deficiency. The phenotype was described as milder compared to previous cases. WES revealed three variants in the EXOSC8 gene (c.[390+1delG];[628C>T;815G>C]) which lead to reduced mRNA expression and protein levels.

PMID: 38017281 (2024) - Homozygous missense variant c.238G>A;p.Val80Ile causing exon skipping in a patient with psychomotor retardation, spasticity, spinal muscle atrophy, respiratory problems, diaphragmatic hernia, dilated lateral ventricles, hypoplastic temporal lobes, thinning of the brain stem, dysmorphic facies, nystagmus, congenital esotropia and contractures.; Changed rating: GREEN; Changed publications to: 24989451, 38017281, 34210538
Intellectual disability v9.72 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 37879139,40114189, 33159949, 35164799, 9811936, 8290408, 2004012, 6143163; Phenotypes: 620483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Intellectual disability v9.71 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Hereditary neuropathy v1.500 PPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP).
PMID: 38940544 Aarsand reports that variegate porphyria (VP) is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy.
PMID:11286631 Kauppinen reports a patient who following birth presented with severe bullous skin disease followed by increased fragility and keloid-like scarring. His fingers were shortened. Mental status, EEG, and CT of the head were normal, but sensory polyneuropathy was shown in especially in the upper extremities. Fine motor coordination disturbances were accompanied by minor verbal and visuospatial deficiencies. DNA from the patient showed that he is compound heterozygous for PPOX: c.35T>C, p.(Ile12Thr) and c.767C>G, p.(Pro256Arg).
PMID:10870850 Corrigall reports a 10-month-old child with fragile skin with blisters, scars, and milia most marked in sun-exposed areas. She had brachydactyly, photo-onycholysis, myopia, nystagmus, a sensory neuropathy and problems with concentration. She never had a typical acute attack. Genetic analysis showed that this patient was compound heterozygous for PPOX c.175C>T, p.(Arg59Trp) and c.1043A>G, p.(Tyr348Cys).
PMID: 8290408 Hift reports child who within days of birth developed severe blistering of the face and hands. She had brachydactyly, severe myopia and a pendular nystagmus. Neurological development was delayed with normal intelligence. She had gross sensory neuropathy of the hands and feet but no acute attacks.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP).
PMID: 38940544 Aarsand reports that variegate porphyria (VP) is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy, as reported by the previous reviewer.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
Hereditary neuropathy v1.500 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 35584894, 37879139, 11286631, 10870850, 8290408; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.8 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 33159949, 38940544, 10486317, 8290408, 37879139, 40114189; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v9.70 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, MIM#616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Hereditary ataxia with onset in adulthood v8.8 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia type 1C to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Cerebellar hypoplasia v1.75 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia,type 1C, 616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Ataxia and cerebellar anomalies - narrow panel v8.18 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia,type 1C, 616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Fetal anomalies v6.47 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081; Pontocerebellar hypoplasia type 1C to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Fetal anomalies v6.46 EXOSC8 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EXOSC8.
Tag Q3_25_NHS_review tag was added to gene: EXOSC8.
Fetal anomalies v6.46 EXOC6B Arina Puzriakova Phenotypes for gene: EXOC6B were changed from Spondyloepimetaphyseal dysplasia with joint laxity, type 3 to Spondyloepimetaphyseal dysplasia with joint laxity, type 3, OMIM:618395
Fetal anomalies v6.45 EXOC6B Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EXOC6B.
Tag Q3_25_NHS_review tag was added to gene: EXOC6B.
Fetal anomalies v6.45 EFL1 Arina Puzriakova Phenotypes for gene: EFL1 were changed from Shwachman-Diamond syndrome 2 to Shwachman-Diamond syndrome 2, OMIM:617941
Fetal anomalies v6.44 EFL1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EFL1.
Tag Q3_25_NHS_review tag was added to gene: EFL1.
Intellectual disability v9.69 EEFSEC Arina Puzriakova Phenotypes for gene: EEFSEC were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
Fetal anomalies v6.44 EEFSEC Arina Puzriakova Phenotypes for gene: EEFSEC were changed from Neurodevelopmental disorder with progressive spasticity and brain abnormalities to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
Early onset or syndromic epilepsy v8.26 EEFSEC Arina Puzriakova Phenotypes for gene: EEFSEC were changed from neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027 to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
Ataxia and cerebellar anomalies - narrow panel v8.17 EEFSEC Arina Puzriakova Phenotypes for gene: EEFSEC were changed from neurodevelopmental disorder, MONDO:0700092; hereditary cerebellar ataxia, MONDO:0100310 to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
Fetal anomalies v6.43 EEFSEC Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EEFSEC.
Tag Q3_25_NHS_review tag was added to gene: EEFSEC.
Fetal anomalies v6.43 DST Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DST.
Tag Q3_25_NHS_review tag was added to gene: DST.
Fetal anomalies v6.43 DSE Arina Puzriakova Phenotypes for gene: DSE were changed from Ehlers-Danlos syndrome, musculocontractural type 2 to Ehlers-Danlos syndrome, musculocontractural type 2, OMIM:615539
Undiagnosed metabolic disorders v1.631 PPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen and plasma porphyrin fluorescence emission
PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.
PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks.
PMID: 8290408 Hift reports that the cutaneous VP presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma porphyrin fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence emission) as the penetrance of variegate porphyria is so low
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen and plasma porphyrin fluorescence emission
PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.
PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks.
PMID: 8290408 Hift reports that the cutaneous VP presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma porphyrin fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence emission) as the penetrance of VP is so low
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
Fetal anomalies v6.42 DSE Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DSE.
Tag Q3_25_NHS_review tag was added to gene: DSE.
Fetal anomalies v6.42 DHX9 Arina Puzriakova Phenotypes for gene: DHX9 were changed from Intellectual developmental disorder, autosomal dominant 75 to Intellectual developmental disorder, autosomal dominant 75, OMIM:620988
Fetal anomalies v6.41 DHX9 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DHX9.
Tag Q3_25_NHS_review tag was added to gene: DHX9.
Undiagnosed metabolic disorders v1.631 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 10486317, 8290408, 38940544, 37879139, 40114189, 33159949; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v6.41 DHRSX Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DHRSX.
Tag Q3_25_NHS_review tag was added to gene: DHRSX.
Fetal anomalies v6.41 COQ2 Arina Puzriakova Phenotypes for gene: COQ2 were changed from COENZYME Q10 DEFICIENCY; Coenzyme Q10 deficiency, primary, 1 to Coenzyme Q10 deficiency, primary, 1, OMIM:607426
Fetal anomalies v6.40 COQ2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: COQ2.
Tag Q3_25_NHS_review tag was added to gene: COQ2.
Skeletal dysplasia v8.8 COMP Arina Puzriakova Phenotypes for gene: COMP were changed from Epiphyseal dysplasia, multiple, 1 132400; Pseudoachondroplasia 177170 to Epiphyseal dysplasia, multiple, 1, OMIM:132400; Pseudoachondroplasia, OMIM:177170
Fetal anomalies v6.40 COMP Arina Puzriakova Phenotypes for gene: COMP were changed from Pseudoachondroplasia; MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 1; Epiphyseal dysplasia, multiple, 1; ARE THE CAUSE OF PSEUDOACHONDROPLASIA to Epiphyseal dysplasia, multiple, 1, OMIM:132400; Pseudoachondroplasia, OMIM:177170
Fetal anomalies v6.39 COMP Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: COMP.
Tag Q3_25_NHS_review tag was added to gene: COMP.
Fetal anomalies v6.39 COL25A1 Arina Puzriakova Phenotypes for gene: COL25A1 were changed from Arthrogryposis multiplex congenita, MONDO:0015168; Arthrogryposis multiplex congenita to Arthrogryposis multiplex congenita, MONDO:0015168
Ehlers Danlos syndrome with a likely monogenic cause v4.2 FLNA Neeti Ghali edited their review of gene: FLNA: Added comment: Currently on R125 panel as well as other panels but I would argue that there is a connective tissue phenotype for a number of patients with missense variants in FLNA. A patient recently had R101 for connective tissue features, but went on to have R125 because of valvular disease and a FLNA pathogenic variant was identified. This is reasonable given the function of the protein Filamin A. Therefore, it would be beneficial for it to also be on R101 panel; Changed publications to: 34863227, 30089473, 40883083, 23032111; Changed phenotypes to: connective tissue phenotype eg. hypermobility, skin hyperextensibility, perforated ear drum, retinal detachment, arterial fragility, aortic dilatation, arterial tortuosity, valvular disease, PVL, lung
Fetal anomalies v6.38 COL25A1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: COL25A1.
Tag Q3_25_NHS_review tag was added to gene: COL25A1.
Fetal anomalies v6.38 C1orf127 Arina Puzriakova Phenotypes for gene: C1orf127 were changed from Heterotaxy, visceral, 14, autosomal; Heterotaxy, visceral, 14, autosomal, OMIM:621080 to Heterotaxy, visceral, 14, autosomal, OMIM:621080
Fetal anomalies v6.37 CELSR1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: CELSR1.
Tag Q3_25_NHS_review tag was added to gene: CELSR1.
Fetal anomalies v6.37 CELSR1 Arina Puzriakova Phenotypes for gene: CELSR1 were changed from Lymphatic malformation 9, OMIM:619319; Lymphatic malformation-9 to Lymphatic malformation 9, OMIM:619319
Variegate porphyria v1.1 PPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyria attack), plasma porphyrin fluorescence emission (cutaneous symptoms)
PMID: 35584894 Schulenburg-Brand reports that patients with variegate porphyria (VP) may develop acute attacks often characterised by abdominal pain, nausea, vomiting and other neurological symptoms. They may also present with photosensitive skin lesions. Affected skin is excessively fragile, leading to blisters, milia, and scarring.
PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks.
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (when in acute attacks urine porphobilinogen, followed by analysis of plasma fluorescence emission and when cutaneous symptoms alone, plasma porphyrin fluorescence emission s) as the penetrance of variegate porphyria is so low. Genetic testing of the PPOX gene should only be used for family testing so that the genetically predisposed individuals can be advised against precipitating factors such as alcohol and certain drugs.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyria attack), plasma porphyrin fluorescence emission (cutaneous symptoms)
PMID: 35584894 Schulenburg-Brand reports that patients with variegate porphyria (VP) may develop acute attacks often characterised by abdominal pain, nausea, vomiting and other neurological symptoms. They may also present with photosensitive skin lesions. Affected skin is excessively fragile, leading to blisters, milia, and scarring.
PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks.
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma porphyrin fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence emission) as the penetrance of variegate porphyria is so low. Genetic testing of the PPOX gene should only be used for family testing so that the genetically predisposed individuals can be advised against precipitating factors such as alcohol and certain drugs.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
Hereditary ataxia with onset in adulthood v8.7 CDK5 Arina Puzriakova Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, 616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Cerebellar hypoplasia v1.74 CDK5 Arina Puzriakova Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia 616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Ataxia and cerebellar anomalies - narrow panel v8.16 CDK5 Arina Puzriakova Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia 616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Fetal anomalies v6.36 CDK5 Arina Puzriakova Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Fetal anomalies v6.35 CDK5 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: CDK5.
Tag Q3_25_NHS_review tag was added to gene: CDK5.
Fetal anomalies v6.35 CTGF Arina Puzriakova Phenotypes for gene: CTGF were changed from Kyphomelic dysplasia to kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
Fetal anomalies v6.34 CTGF Arina Puzriakova Tag new-gene-name tag was added to gene: CTGF.
Tag Q3_25_promote_green tag was added to gene: CTGF.
Tag Q3_25_NHS_review tag was added to gene: CTGF.
Fetal anomalies v6.34 BHLHE22 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: BHLHE22.
Tag Q3_25_NHS_review tag was added to gene: BHLHE22.
Fetal anomalies v6.34 ARL6IP1 Arina Puzriakova Tag Q3_24_NHS_review tag was added to gene: ARL6IP1.
Tag Q3_25_promote_green tag was added to gene: ARL6IP1.
Vascular skin disorders v2.1 PPOX Sharon Whatley reviewed gene: PPOX: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.9 PPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: plasma porphyrin fluorescence emission
PMID: 10486317 Whatley reports that vVariegate porphyria (VP) is usually classified as an acute porphyria but in 59% of cases skin lesions may be the only manifestation.
PMID: 8290408 Hift reports that tThe cutaneous disease presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes.
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using a biochemical test for plasma porphyrin fluorescence emission as the penetrance is so low.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (21 families) reported with homozygous VP (PMID: 40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: plasma porphyrin fluorescence emission
PMID: 10486317 Whatley reports that variegate porphyria (VP) is usually classified as an acute porphyria but in 59% of cases skin lesions may be the only manifestation.
PMID: 8290408 Hift reports that the cutaneous disease presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes.
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using a biochemical test for plasma porphyrin fluorescence emission as the penetrance is so low.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (21 families) reported with homozygous VP (PMID: 40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
Cutaneous photosensitivity with a likely genetic cause v3.9 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 8290408, 38940544, 37879139, 40114189, 33159949; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Variegate porphyria v1.1 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 35584894, 10486317, 38940544, 37879139; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Non-acute porphyrias v1.26 PPOX Sharon Whatley commented on gene: PPOX: Relevant metabolic investigation: plasma porphyrin fluorescence emission
PMID: 10486317 Whatley reports that variegate porphyria (VP) is usually classified as an acute porphyria but in 59% of cases skin lesions may be the only manifestation.
PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed based on biochemical testing including analysis of plasma porphyrin fluorescence emission as the clinical penetrance is so low.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
Non-acute porphyrias v1.26 PPOX Sharon Whatley Deleted their comment
Non-acute porphyrias v1.26 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 35584894, 10486317, 38940544, 37879139; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v7.86 PKD2 Achchuthan Shanmugasundram Classified gene: PKD2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.86 PKD2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are patients from five unrelated families reported with five different heterozygous PKD2 variants and with cardiomyopathy. Of these, four families were from APKD2 database at Mayo Clinic and one was from the UK 100,000 genomes cohort. There is also functional evidence available from zebrafish and mice model. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.86 PKD2 Achchuthan Shanmugasundram Gene: pkd2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.85 PKD2 Achchuthan Shanmugasundram changed review comment from: Autosomal dominant variants in PKD2 gene are associated with Polycystic kidney disease 2 (MIM #613095, OMIM phenotype accessed on 07 September 2025).

Reports on human patients:
PMID:23376035 (2014) examined ADPKD database at Mayo clinic with 2,620 ADPKD patients seen between 1984 and 2010, where 374 patients were genotyped and 67 of them were identified with PKD2 variants. Of these 67, six patients from four different families had a diagnosis of idiopathic dilated cardiomyopathy (IDCM). The identified variants were p.Arg361Ter, p.Arg807Ter, c.423_430del8 and c.1095-5A>G.

PMID:29270497 (2017) reported 3,885 ADPKD patients seen in the period between 1984 and 2015 in the same database as PMID:23376035, of which seven patients from four families had the same PKD2 variants.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with hypertrophic cardiomyopathy was identified with a heterozygous stop-gain variant in PKD2 gene via analysis of data from singleton genome sequencing.

Functional studies:

PMID:23376035 (2014) studied Pkd2 mutant zebrafish, which showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants.

PMID:27081851 (2016) reported that 9-month-old Pkd2+/- mice showed several anatomical features consistent with a dilated cardiac phenotype. However, Pkd2+/- 5-month-old mice did not present with a cardiac phenotype that paralleled either dilated cardiomyopathy or left ventricular hypertrophy, suggesting that PKD2 caused late-onset progressive cardiomyopathy.
Sources: Literature; to: Autosomal dominant variants in PKD2 gene are associated with Polycystic kidney disease 2 (MIM #613095, OMIM phenotype accessed on 07 September 2025).

Reports on human patients:
PMID:23376035 (2014) examined ADPKD database at Mayo clinic with 2,620 ADPKD patients seen between 1984 and 2010, where 374 patients were genotyped and 67 of them were identified with PKD2 variants. Of these 67, six patients from four different families had a diagnosis of idiopathic dilated cardiomyopathy (IDCM). The identified variants were p.Arg361Ter, p.Arg807Ter, c.423_430del8 and c.1095-5A>G.

PMID:29270497 (2017) reported 3,885 ADPKD patients seen in the period between 1984 and 2015 in the same database as PMID:23376035, of which seven patients from four families had the same PKD2 variants.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with hypertrophic cardiomyopathy was identified with a heterozygous stop-gain variant in PKD2 gene (p.Arg213Ter) via analysis of data from singleton genome sequencing.

Functional studies:

PMID:23376035 (2014) studied Pkd2 mutant zebrafish, which showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants.

PMID:27081851 (2016) reported that 9-month-old Pkd2+/- mice showed several anatomical features consistent with a dilated cardiac phenotype. However, Pkd2+/- 5-month-old mice did not present with a cardiac phenotype that paralleled either dilated cardiomyopathy or left ventricular hypertrophy, suggesting that PKD2 caused late-onset progressive cardiomyopathy.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.85 PKD2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PKD2.
Paediatric or syndromic cardiomyopathy v7.85 PKD2 Achchuthan Shanmugasundram gene: PKD2 was added
gene: PKD2 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: PKD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PKD2 were set to 23376035; 27081851; 29270497; 39472908
Phenotypes for gene: PKD2 were set to Polycystic kidney disease 2, OMIM:613095; polycystic kidney disease 2, MONDO:0013131; dilated cardiomyopathy, MONDO:0005021
Review for gene: PKD2 was set to GREEN
Added comment: Autosomal dominant variants in PKD2 gene are associated with Polycystic kidney disease 2 (MIM #613095, OMIM phenotype accessed on 07 September 2025).

Reports on human patients:
PMID:23376035 (2014) examined ADPKD database at Mayo clinic with 2,620 ADPKD patients seen between 1984 and 2010, where 374 patients were genotyped and 67 of them were identified with PKD2 variants. Of these 67, six patients from four different families had a diagnosis of idiopathic dilated cardiomyopathy (IDCM). The identified variants were p.Arg361Ter, p.Arg807Ter, c.423_430del8 and c.1095-5A>G.

PMID:29270497 (2017) reported 3,885 ADPKD patients seen in the period between 1984 and 2015 in the same database as PMID:23376035, of which seven patients from four families had the same PKD2 variants.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with hypertrophic cardiomyopathy was identified with a heterozygous stop-gain variant in PKD2 gene via analysis of data from singleton genome sequencing.

Functional studies:

PMID:23376035 (2014) studied Pkd2 mutant zebrafish, which showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants.

PMID:27081851 (2016) reported that 9-month-old Pkd2+/- mice showed several anatomical features consistent with a dilated cardiac phenotype. However, Pkd2+/- 5-month-old mice did not present with a cardiac phenotype that paralleled either dilated cardiomyopathy or left ventricular hypertrophy, suggesting that PKD2 caused late-onset progressive cardiomyopathy.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.84 SELENON Achchuthan Shanmugasundram Classified gene: SELENON as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v7.84 SELENON Achchuthan Shanmugasundram Added comment: Comment on list classification: Biallelic SELENON variants cause an early-onset congenital muscular dystrophy characterised by spinal rigidity and respiratory failure, with no significant cardiomyopathy reported. Any observed cardiac abnormalities are secondary to respiratory failure in most of the reported cases. Hence, this gene should be rated red with the current evidence.
Paediatric or syndromic cardiomyopathy v7.84 SELENON Achchuthan Shanmugasundram Gene: selenon has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v7.83 SELENON Achchuthan Shanmugasundram Publications for gene: SELENON were set to 35868898
Paediatric or syndromic cardiomyopathy v7.82 SELENON Achchuthan Shanmugasundram edited their review of gene: SELENON: Changed publications to: 35868898, 39472908
Paediatric or syndromic cardiomyopathy v7.82 SELENON Achchuthan Shanmugasundram Phenotypes for gene: SELENON were changed from to Congenital myopathy 3 with rigid spine, OMIM:602771; rigid spine muscular dystrophy 1, MONDO:0011271
Paediatric or syndromic cardiomyopathy v7.81 SELENON Achchuthan Shanmugasundram changed review comment from: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing.
Sources: Literature; to: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing.

This gene has been associated with Congenital myopathy 3 with rigid spine in OMIM (MIM #602771, OMIM accessed on 06 September 2025) and with SELENON-related myopathy in Gene2Phenotype (with 'definitive' rating).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.81 SELENON Achchuthan Shanmugasundram edited their review of gene: SELENON: Changed phenotypes to: Congenital myopathy 3 with rigid spine, OMIM:602771, rigid spine muscular dystrophy 1, MONDO:0011271
Paediatric or syndromic cardiomyopathy v7.81 SELENON Achchuthan Shanmugasundram gene: SELENON was added
gene: SELENON was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: SELENON was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SELENON were set to 35868898
Review for gene: SELENON was set to RED
Added comment: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.80 ADSSL1 Achchuthan Shanmugasundram Classified gene: ADSSL1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.80 ADSSL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Hypertrophic cardiomyopathy has been reported in a significant proportion of patients with biallelic ADSSL1 variants - 12 patients (25%) in PMID:32646962 and two additional unrelated families. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.80 ADSSL1 Achchuthan Shanmugasundram Gene: adssl1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.79 ADSSL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ADSSL1.
Paediatric or syndromic cardiomyopathy v7.79 ADSSL1 Achchuthan Shanmugasundram commented on gene: ADSSL1: The 'new-gene-name' tag has been added as the official HGNC gene symbol of ADSSL1 is ADSS1.
Paediatric or syndromic cardiomyopathy v7.79 ADSSL1 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: ADSSL1.
Paediatric or syndromic cardiomyopathy v7.79 ADSSL1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 06 September 2025.
Paediatric or syndromic cardiomyopathy v7.79 ADSSL1 Achchuthan Shanmugasundram Phenotypes for gene: ADSSL1 were changed from Myopathy, distal, 5, OMIM:617030; myopathy, distal, 5, MONDO:0014877; hypertrophic cardiomyopathy, MONDO:0005045 to Myopathy, distal, 5, OMIM:617030; myopathy, distal, 5, MONDO:0014877; hypertrophic cardiomyopathy, MONDO:0005045
Paediatric or syndromic cardiomyopathy v7.78 ADSSL1 Achchuthan Shanmugasundram gene: ADSSL1 was added
gene: ADSSL1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: ADSSL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADSSL1 were set to 32646962; 39472908; 40302423
Phenotypes for gene: ADSSL1 were set to Myopathy, distal, 5, OMIM:617030; myopathy, distal, 5, MONDO:0014877; hypertrophic cardiomyopathy, MONDO:0005045
Review for gene: ADSSL1 was set to GREEN
Added comment: PMID:32646962 (2020) reported the identification of 63 patients from 59 families with biallelic variants of ADSSL1. Seven distinct variants were identified in total, of which c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other five were novel. Most of the reported patients presented with variable myopathy with distal and proximal limb muscle weakness (often childhood onset of exercise intolerance) and facial and bulbar involvement were common in them. Left ventricular hypertrophy (LVH) was noted in 12 (25.0%) of 48 patients on EKG or echocardiography. ADSSL1 variants in nine of these patients were identified by WES and 3 were identified by Sanger sequencing. Patient 12 developed progressive heart failure with LVH before the onset of apparent muscle weakness at age 20, and he died due to multiple organ failure at age 25.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Asp261Asn) in ADSSL1 gene via analysis of data from trio genome sequencing.

PMID:40302423 (2025) reported the identification of compound heterozygous pathogenic variants (c.781G>A/c.919delA) in ADSSL1 gene in two siblings with ADSSL1-myopathy. LVH was observed in both siblings and pathologically confirmed in the case where autopsy was done.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.77 GLA Achchuthan Shanmugasundram Classified gene: GLA as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.77 GLA Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of GLA variants with hypertrophic cardiomyopathy as part of the Fabry disease phenotype, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.77 GLA Achchuthan Shanmugasundram Gene: gla has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.76 GLA Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: GLA.
Paediatric or syndromic cardiomyopathy v7.76 GLA Achchuthan Shanmugasundram Phenotypes for gene: GLA were changed from Fabry disease, 301500; HCM is a late complication in adults, also found in female carriers; Limb pain, angiokeratom; syndromic HCM; Fabry disease, cardiac variant, 301500; Fabry disease (Sphingolipidoses); Fabry Disease; Fabry disease; HCM to Fabry disease, OMIM:301500; Fabry disease, cardiac variant, OMIM:301500; Fabry disease, MONDO:0010526
Paediatric or syndromic cardiomyopathy v7.75 GLA Achchuthan Shanmugasundram Publications for gene: GLA were set to 27604308
Paediatric or syndromic cardiomyopathy v7.74 GLA Achchuthan Shanmugasundram reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 39472908, 39620496, 39995634; Phenotypes: Fabry disease, OMIM:301500, Fabry disease, cardiac variant, OMIM:301500, Fabry disease, MONDO:0010526; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v6.34 ARL2BP Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ARL2BP.
Tag Q3_25_NHS_review tag was added to gene: ARL2BP.
Fetal anomalies v6.34 ARL2BP Arina Puzriakova Phenotypes for gene: ARL2BP were changed from Situs Inversus to Retinitis pigmentosa 82 with or without situs inversus, OMIM:615434; Situs Inversus
Fetal anomalies v6.33 AGT Arina Puzriakova Phenotypes for gene: AGT were changed from Renal tubular dysgenesis, OMIM:267430; Renal tubular dysgenesis to Renal tubular dysgenesis, OMIM:267430
Fetal anomalies v6.32 AGT Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: AGT.
Tag Q3_25_NHS_review tag was added to gene: AGT.
Fetal anomalies v6.32 AGRN Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: AGRN.
Tag Q3_25_NHS_review tag was added to gene: AGRN.
Fetal anomalies v6.32 AGRN Arina Puzriakova Phenotypes for gene: AGRN were changed from Fetal akinesia deformation sequence, MONDO:0008824; Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects to Fetal akinesia deformation sequence, MONDO:0008824; Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects, OMIM:615120
Fetal anomalies v6.31 NODAL Arina Puzriakova Phenotypes for gene: NODAL were changed from Heterotaxy, visceral, 5; HETEROTAXY SYNDROME to Heterotaxy, visceral, 5, OMIM:270100
Fetal anomalies v6.30 NODAL Arina Puzriakova Tag Q3_25_NHS_review tag was added to gene: NODAL.
Tag Q3_25_demote_red tag was added to gene: NODAL.
Fetal anomalies v6.30 MYH9 Arina Puzriakova Phenotypes for gene: MYH9 were changed from DEAFNESS AUTOSOMAL DOMINANT TYPE 17; MAY-HEGGLIN ANOMALY; SEBASTIAN SYNDROME; FECHTNER SYNDROME; EPSTEIN SYNDROME; Deafness, autosomal dominant 17; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss; MACROTHROMBOCYTOPENIA WITH PROGRESSIVE SENSORINEURAL DEAFNESS to Deafness, autosomal dominant 17; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
Fetal anomalies v6.29 MYH9 Arina Puzriakova Tag Q3_25_NHS_review tag was added to gene: MYH9.
Tag Q3_25_demote_red tag was added to gene: MYH9.
Fetal anomalies v6.29 GNS Arina Puzriakova Tag Q3_25_NHS_review tag was added to gene: GNS.
Tag Q3_25_demote_amber tag was added to gene: GNS.
Fetal anomalies v6.29 CDH11 Arina Puzriakova reviewed gene: CDH11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 FAAP100 Arina Puzriakova reviewed gene: FAAP100: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 BORCS5 Arina Puzriakova reviewed gene: BORCS5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MAGED2 Arina Puzriakova reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ZNRF3 Arina Puzriakova reviewed gene: ZNRF3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ZNHIT3 Arina Puzriakova reviewed gene: ZNHIT3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ZNF808 Arina Puzriakova reviewed gene: ZNF808: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ZMYND11 Arina Puzriakova reviewed gene: ZMYND11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ZEB1 Arina Puzriakova reviewed gene: ZEB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 WDR47 Arina Puzriakova reviewed gene: WDR47: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 UNC50 Arina Puzriakova reviewed gene: UNC50: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 UNC13D Arina Puzriakova edited their review of gene: UNC13D: Added comment: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: GREEN
Fetal anomalies v6.29 TPM1 Arina Puzriakova reviewed gene: TPM1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 C14orf80 Arina Puzriakova reviewed gene: C14orf80: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 TCP1 Arina Puzriakova reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 TCF20 Arina Puzriakova reviewed gene: TCF20: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 TAAR1 Arina Puzriakova reviewed gene: TAAR1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SUPT7L Arina Puzriakova reviewed gene: SUPT7L: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 STXBP2 Arina Puzriakova reviewed gene: STXBP2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 STX5 Arina Puzriakova reviewed gene: STX5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 STX11 Arina Puzriakova reviewed gene: STX11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SRPK3 Arina Puzriakova reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SRP54 Arina Puzriakova reviewed gene: SRP54: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SPTA1 Arina Puzriakova edited their review of gene: SPTA1: Added comment: Upgraded from Red to Amber but there is sufficient evidence to make Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group. MOI has also been updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as per the review.; Changed rating: GREEN
Fetal anomalies v6.29 SPOUT1 Arina Puzriakova reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SNAPC4 Arina Puzriakova reviewed gene: SNAPC4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SLC35A3 Arina Puzriakova reviewed gene: SLC35A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SLC30A5 Arina Puzriakova reviewed gene: SLC30A5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SLC19A1 Arina Puzriakova reviewed gene: SLC19A1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SLC12A9 Arina Puzriakova reviewed gene: SLC12A9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SIRT6 Arina Puzriakova reviewed gene: SIRT6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SENP7 Arina Puzriakova reviewed gene: SENP7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 SEL1L Arina Puzriakova reviewed gene: SEL1L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 RPL26 Arina Puzriakova reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 RNU5B-1 Arina Puzriakova reviewed gene: RNU5B-1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 RNU5A-1 Arina Puzriakova reviewed gene: RNU5A-1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 RNF31 Arina Puzriakova reviewed gene: RNF31: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 RIPPLY2 Arina Puzriakova reviewed gene: RIPPLY2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 RBFOX2 Arina Puzriakova reviewed gene: RBFOX2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 RAB11B Arina Puzriakova reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PYGL Arina Puzriakova reviewed gene: PYGL: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PUS3 Arina Puzriakova reviewed gene: PUS3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PURA Arina Puzriakova reviewed gene: PURA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PTEN Arina Puzriakova reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PSKH1 Arina Puzriakova reviewed gene: PSKH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PROC Arina Puzriakova reviewed gene: PROC: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PPFIBP1 Arina Puzriakova reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PPFIA3 Arina Puzriakova reviewed gene: PPFIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 POU3F3 Arina Puzriakova reviewed gene: POU3F3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PLVAP Arina Puzriakova reviewed gene: PLVAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PLAA Arina Puzriakova reviewed gene: PLAA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PIGW Arina Puzriakova reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PIGQ Arina Puzriakova reviewed gene: PIGQ: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PIGP Arina Puzriakova reviewed gene: PIGP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PIGM Arina Puzriakova reviewed gene: PIGM: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PIGG Arina Puzriakova reviewed gene: PIGG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PI4KA Arina Puzriakova reviewed gene: PI4KA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PHF5A Arina Puzriakova reviewed gene: PHF5A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PDE12 Arina Puzriakova reviewed gene: PDE12: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PDCD2 Arina Puzriakova reviewed gene: PDCD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PAK2 Arina Puzriakova reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 PAICS Arina Puzriakova reviewed gene: PAICS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 OSBPL9 Arina Puzriakova reviewed gene: OSBPL9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ODC1 Arina Puzriakova reviewed gene: ODC1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NUP214 Arina Puzriakova reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NT5E Arina Puzriakova reviewed gene: NT5E: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NR2F1 Arina Puzriakova reviewed gene: NR2F1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NODAL Arina Puzriakova reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NMNAT1 Arina Puzriakova reviewed gene: NMNAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NKX2-6 Arina Puzriakova reviewed gene: NKX2-6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NFASC Arina Puzriakova reviewed gene: NFASC: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NEXN Arina Puzriakova edited their review of gene: NEXN: Added comment: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group. MOI has also been updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as per the review.; Changed rating: GREEN
Fetal anomalies v6.29 NEUROD1 Arina Puzriakova reviewed gene: NEUROD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NEPRO Arina Puzriakova reviewed gene: NEPRO: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NDUFB7 Arina Puzriakova edited their review of gene: NDUFB7: Added comment: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: AMBER
Fetal anomalies v6.29 NAGS Arina Puzriakova reviewed gene: NAGS: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 NAGLU Arina Puzriakova reviewed gene: NAGLU: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MYL2 Arina Puzriakova reviewed gene: MYL2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MYH9 Arina Puzriakova reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MSL2 Arina Puzriakova reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MPL Arina Puzriakova reviewed gene: MPL: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MIA3 Arina Puzriakova reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MET Arina Puzriakova reviewed gene: MET: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MED11 Arina Puzriakova reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MAPK1 Arina Puzriakova reviewed gene: MAPK1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MAP3K3 Arina Puzriakova reviewed gene: MAP3K3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MAN2B2 Arina Puzriakova reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 MAL Arina Puzriakova reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 LSS Arina Puzriakova reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 LRRC8C Arina Puzriakova reviewed gene: LRRC8C: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 LIPN Arina Puzriakova reviewed gene: LIPN: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 LGI3 Arina Puzriakova reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 LDB1 Arina Puzriakova reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 LAGE3 Arina Puzriakova reviewed gene: LAGE3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 KMT2E Arina Puzriakova reviewed gene: KMT2E: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 C12orf66 Arina Puzriakova reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 KDM6B Arina Puzriakova reviewed gene: KDM6B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 KDM1A Arina Puzriakova reviewed gene: KDM1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 KCNH2 Arina Puzriakova reviewed gene: KCNH2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 KCNB1 Arina Puzriakova reviewed gene: KCNB1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 KBTBD2 Arina Puzriakova reviewed gene: KBTBD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 KAT7 Arina Puzriakova reviewed gene: KAT7: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 JPH1 Arina Puzriakova reviewed gene: JPH1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ITGAV Arina Puzriakova reviewed gene: ITGAV: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 IRF4 Arina Puzriakova reviewed gene: IRF4: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 HNRNPU Arina Puzriakova reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 HIRA Arina Puzriakova reviewed gene: HIRA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 HECTD1 Arina Puzriakova reviewed gene: HECTD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 HDAC3 Arina Puzriakova reviewed gene: HDAC3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GUK1 Arina Puzriakova reviewed gene: GUK1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GTPBP1 Arina Puzriakova reviewed gene: GTPBP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GNS Arina Puzriakova reviewed gene: GNS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GNPNAT1 Arina Puzriakova reviewed gene: GNPNAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GNAI2 Arina Puzriakova reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GEMIN4 Arina Puzriakova reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GDAP1 Arina Puzriakova reviewed gene: GDAP1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GATA5 Arina Puzriakova reviewed gene: GATA5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 GALT Arina Puzriakova reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 G6PD Arina Puzriakova reviewed gene: G6PD: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 FLVCR1 Arina Puzriakova reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 FLII Arina Puzriakova reviewed gene: FLII: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 FGG Arina Puzriakova reviewed gene: FGG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 FBXW11 Arina Puzriakova reviewed gene: FBXW11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 FBXO22 Arina Puzriakova reviewed gene: FBXO22: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 FAM177A1 Arina Puzriakova reviewed gene: FAM177A1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 EXOC6B Arina Puzriakova reviewed gene: EXOC6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ERG Arina Puzriakova reviewed gene: ERG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 EFL1 Arina Puzriakova reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 EEFSEC Arina Puzriakova reviewed gene: EEFSEC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DVL2 Arina Puzriakova reviewed gene: DVL2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DTNA Arina Puzriakova reviewed gene: DTNA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DST Arina Puzriakova reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DSE Arina Puzriakova reviewed gene: DSE: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DSC2 Arina Puzriakova reviewed gene: DSC2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DOHH Arina Puzriakova reviewed gene: DOHH: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DNAJC21 Arina Puzriakova reviewed gene: DNAJC21: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DHX9 Arina Puzriakova reviewed gene: DHX9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DHRSX Arina Puzriakova reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DDX17 Arina Puzriakova reviewed gene: DDX17: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 DAND5 Arina Puzriakova reviewed gene: DAND5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 CYP24A1 Arina Puzriakova reviewed gene: CYP24A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 COQ2 Arina Puzriakova reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 COMP Arina Puzriakova reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 COL25A1 Arina Puzriakova reviewed gene: COL25A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 C1orf127 Arina Puzriakova commented on gene: C1orf127: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.
Fetal anomalies v6.29 CHAF1A Arina Puzriakova reviewed gene: CHAF1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 CFI Arina Puzriakova reviewed gene: CFI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 CELSR1 Arina Puzriakova edited their review of gene: CELSR1: Added comment: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: GREEN
Fetal anomalies v6.29 CDK5 Arina Puzriakova reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 CCT8 Arina Puzriakova reviewed gene: CCT8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 CCT6A Arina Puzriakova reviewed gene: CCT6A: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 CCT3 Arina Puzriakova reviewed gene: CCT3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 CTGF Arina Puzriakova reviewed gene: CTGF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 BRD2 Arina Puzriakova reviewed gene: BRD2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 BORCS8 Arina Puzriakova reviewed gene: BORCS8: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 BICRA Arina Puzriakova reviewed gene: BICRA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 BHLHE22 Arina Puzriakova reviewed gene: BHLHE22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 BAIAP2 Arina Puzriakova reviewed gene: BAIAP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ASCC3 Arina Puzriakova reviewed gene: ASCC3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ARPC5 Arina Puzriakova reviewed gene: ARPC5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ARL6IP1 Arina Puzriakova reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ARL2BP Arina Puzriakova reviewed gene: ARL2BP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 AGT Arina Puzriakova edited their review of gene: AGT: Added comment: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: GREEN
Fetal anomalies v6.29 AGRN Arina Puzriakova edited their review of gene: AGRN: Added comment: Upgraded from Red to Amber but there is sufficient evidence to make Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: GREEN
Fetal anomalies v6.29 ACTN2 Arina Puzriakova reviewed gene: ACTN2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.29 ACO2 Arina Puzriakova edited their review of gene: ACO2: Added comment: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: AMBER
Fetal anomalies v6.28 CDH11 Natalie Chandler commented on gene: CDH11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 FAAP100 Sarah Graham commented on gene: FAAP100: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 BORCS5 Sarah Graham commented on gene: BORCS5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MAGED2 Sarah Graham commented on gene: MAGED2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ZNRF3 Sarah Graham commented on gene: ZNRF3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ZNHIT3 Sarah Graham commented on gene: ZNHIT3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ZNF808 Elizabeth Wall commented on gene: ZNF808: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ZMYND11 Natalie Bibb commented on gene: ZMYND11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ZEB1 Sarah Graham commented on gene: ZEB1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 WDR47 Sarah Graham commented on gene: WDR47: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 UNC50 Sarah Graham commented on gene: UNC50: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 UNC13D Anna de Burca commented on gene: UNC13D: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 TPM1 Alice Gardham commented on gene: TPM1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 C14orf80 Sunayna Best commented on gene: C14orf80: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 TCP1 Natalie Bibb commented on gene: TCP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 TCF20 Stephanie Allen commented on gene: TCF20: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 TAAR1 Sarah Graham commented on gene: TAAR1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SUPT7L Soo-Mi Park commented on gene: SUPT7L: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 STXBP2 Alice Gardham commented on gene: STXBP2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 STX5 Sahar Mansour commented on gene: STX5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 STX11 Vicki Harrison commented on gene: STX11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SRPK3 Sarah Graham commented on gene: SRPK3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SRP54 Stephanie Allen commented on gene: SRP54: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SPTA1 Sarah Graham commented on gene: SPTA1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SPOUT1 Sunayna Best commented on gene: SPOUT1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SNAPC4 Esther Kinning commented on gene: SNAPC4: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SLC35A3 Sunayna Best commented on gene: SLC35A3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SLC30A5 Natalie Chandler commented on gene: SLC30A5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SLC19A1 Soo-Mi Park commented on gene: SLC19A1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SLC12A9 Sarah Graham commented on gene: SLC12A9: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SIRT6 Natalie Canham commented on gene: SIRT6: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SENP7 Natalie Bibb commented on gene: SENP7: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 SEL1L Anna de Burca commented on gene: SEL1L: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 RPL26 Elizabeth Wall commented on gene: RPL26: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 RNU5B-1 Natalie Chandler commented on gene: RNU5B-1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 RNU5A-1 Natalie Chandler commented on gene: RNU5A-1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 RNF31 Natalie Chandler commented on gene: RNF31: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 RIPPLY2 Sahar Mansour commented on gene: RIPPLY2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 RBFOX2 Anna de Burca commented on gene: RBFOX2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 RAB11B Sahar Mansour commented on gene: RAB11B: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PYGL Soo-Mi Park commented on gene: PYGL: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PUS3 Elizabeth Scotchman commented on gene: PUS3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PURA Natalie Canham commented on gene: PURA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PTEN Sunayna Best commented on gene: PTEN: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PSKH1 Sarah Graham commented on gene: PSKH1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PROC Elizabeth Wall commented on gene: PROC: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PPFIBP1 Stephanie Allen commented on gene: PPFIBP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PPFIA3 Stephanie Allen commented on gene: PPFIA3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 POU3F3 Natalie Chandler commented on gene: POU3F3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PLVAP Alice Gardham commented on gene: PLVAP: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PLAA Stephanie Allen commented on gene: PLAA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PIGW Sahar Mansour commented on gene: PIGW: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PIGQ Esther Kinning commented on gene: PIGQ: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PIGP Elizabeth Wall commented on gene: PIGP: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PIGM Elizabeth Scotchman commented on gene: PIGM: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PIGG Anna de Burca commented on gene: PIGG: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PIGC Alice Gardham commented on gene: PIGC: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PI4KA Anna de Burca commented on gene: PI4KA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PHF5A Vicki Harrison commented on gene: PHF5A: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PDE12 Alice Gardham commented on gene: PDE12: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PDCD2 Soo-Mi Park commented on gene: PDCD2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PAK2 Sarah Graham commented on gene: PAK2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 PAICS Sunayna Best commented on gene: PAICS: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 OSBPL9 Natalie Chandler commented on gene: OSBPL9: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ODC1 Anna de Burca commented on gene: ODC1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NUP214 Stephanie Allen commented on gene: NUP214: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NT5E Natalie Chandler commented on gene: NT5E: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NR2F1 Soo-Mi Park commented on gene: NR2F1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NODAL Natalie Chandler commented on gene: NODAL: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NMNAT1 Natalie Chandler commented on gene: NMNAT1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NKX2-6 Sunayna Best commented on gene: NKX2-6: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NFASC Natalie Bibb commented on gene: NFASC: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NEXN Sarah Graham commented on gene: NEXN: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NEUROD1 Soo-Mi Park commented on gene: NEUROD1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NEPRO Natalie Canham commented on gene: NEPRO: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NDUFB7 Vicki Harrison commented on gene: NDUFB7: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NAGS Elizabeth Wall commented on gene: NAGS: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 NAGLU Sarah Graham commented on gene: NAGLU: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MYL2 Vicki Harrison commented on gene: MYL2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MYH9 Natalie Chandler commented on gene: MYH9: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MSL2 Natalie Chandler commented on gene: MSL2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MPL Elizabeth Scotchman commented on gene: MPL: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MIA3 Sarah Graham commented on gene: MIA3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MET Stephanie Allen commented on gene: MET: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MED11 Soo-Mi Park commented on gene: MED11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MAPK1 Sarah Graham commented on gene: MAPK1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MAP3K3 Alice Gardham commented on gene: MAP3K3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MAN2B2 Sarah Graham commented on gene: MAN2B2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 MAL Sahar Mansour commented on gene: MAL: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 LSS Natalie Chandler commented on gene: LSS: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 LRRC8C Vicki Harrison commented on gene: LRRC8C: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 LIPN Stephanie Allen commented on gene: LIPN: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 LGI3 Soo-Mi Park commented on gene: LGI3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 LDB1 Vicki Harrison commented on gene: LDB1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 LAGE3 Natalie Chandler commented on gene: LAGE3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 KMT2E Natalie Bibb commented on gene: KMT2E: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 C12orf66 Sahar Mansour commented on gene: C12orf66: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 KDM6B Sunayna Best commented on gene: KDM6B: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 KDM1A Esther Kinning commented on gene: KDM1A: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 KCNH2 Sahar Mansour commented on gene: KCNH2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 KCNB1 Soo-Mi Park commented on gene: KCNB1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 KBTBD2 Esther Kinning commented on gene: KBTBD2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 KAT7 Natalie Chandler commented on gene: KAT7: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 JPH1 Sarah Graham commented on gene: JPH1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ITGAV Natalie Canham commented on gene: ITGAV: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 IRF4 Natalie Chandler commented on gene: IRF4: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 IFT27 Sahar Mansour commented on gene: IFT27: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 HNRNPU Sarah Graham commented on gene: HNRNPU: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 HIRA Sarah Graham commented on gene: HIRA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 HECTD1 Sarah Graham commented on gene: HECTD1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 HDAC3 Sarah Graham commented on gene: HDAC3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GUK1 Esther Kinning commented on gene: GUK1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GTPBP1 Natalie Chandler commented on gene: GTPBP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GNS Sarah Graham commented on gene: GNS: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GNPNAT1 Vicki Harrison commented on gene: GNPNAT1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GNAI2 Sarah Graham commented on gene: GNAI2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GEMIN4 Sahar Mansour commented on gene: GEMIN4: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GDAP1 Alice Gardham commented on gene: GDAP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GATA5 Natalie Chandler commented on gene: GATA5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 GALT Sarah Graham commented on gene: GALT: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 G6PD Sarah Graham commented on gene: G6PD: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 FLVCR1 Natalie Canham commented on gene: FLVCR1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 FLII Sarah Graham commented on gene: FLII: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 FGG Natalie Canham commented on gene: FGG: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 FBXW11 Elizabeth Scotchman commented on gene: FBXW11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 FBXO22 Natalie Bibb commented on gene: FBXO22: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 FAM177A1 Vicki Harrison commented on gene: FAM177A1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 EXOSC8 Sarah Graham commented on gene: EXOSC8: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 EXOC6B Natalie Bibb commented on gene: EXOC6B: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ERG Sunayna Best commented on gene: ERG: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 EFL1 Esther Kinning commented on gene: EFL1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 EEFSEC Natalie Chandler commented on gene: EEFSEC: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DVL2 Natalie Bibb commented on gene: DVL2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DTNA Natalie Bibb commented on gene: DTNA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DST Sarah Graham commented on gene: DST: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DSE Natalie Chandler commented on gene: DSE: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DSC2 Alice Gardham commented on gene: DSC2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DOHH Esther Kinning commented on gene: DOHH: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DNAJC21 Elizabeth Wall commented on gene: DNAJC21: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DHX9 Elizabeth Scotchman commented on gene: DHX9: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DHRSX Elizabeth Scotchman commented on gene: DHRSX: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DDX17 Elizabeth Scotchman commented on gene: DDX17: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 DAND5 Elizabeth Wall commented on gene: DAND5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CYP24A1 Natalie Chandler commented on gene: CYP24A1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 COQ2 Anna de Burca commented on gene: COQ2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 COMP Elizabeth Wall commented on gene: COMP: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 COL25A1 Sarah Graham commented on gene: COL25A1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 C1orf127 Elizabeth Scotchman commented on gene: C1orf127: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CHAF1A Elizabeth Wall commented on gene: CHAF1A: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CFI Esther Kinning commented on gene: CFI: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CELSR1 Sarah Graham commented on gene: CELSR1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CDK5 Sarah Graham commented on gene: CDK5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CCT8 Sarah Graham commented on gene: CCT8: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CCT6A Sarah Graham commented on gene: CCT6A: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CCT3 Natalie Canham commented on gene: CCT3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 CTGF Elizabeth Scotchman commented on gene: CTGF: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 BRD2 Natalie Canham commented on gene: BRD2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 BORCS8 Natalie Canham commented on gene: BORCS8: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 BICRA Natalie Chandler commented on gene: BICRA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 BHLHE22 Sarah Graham commented on gene: BHLHE22: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 BAIAP2 Anna de Burca commented on gene: BAIAP2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ASCC3 Anna de Burca commented on gene: ASCC3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ARPC5 Stephanie Allen commented on gene: ARPC5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ARL6IP1 Alice Gardham commented on gene: ARL6IP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ARL2BP Vicki Harrison commented on gene: ARL2BP: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 AGT Esther Kinning commented on gene: AGT: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 AGRN Alice Gardham commented on gene: AGRN: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ACTN2 Natalie Chandler commented on gene: ACTN2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.28 ACO2 Natalie Chandler commented on gene: ACO2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.27 DMPK_CTG Arina Puzriakova Tag Q3_25_expert_review was removed from STR: DMPK_CTG.
Fetal anomalies v6.27 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Amber List (moderate evidence)
Fetal anomalies v6.27 DMPK_CTG Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support the association with Myotonic dystrophy. This STR is Green on multiple GMS panels meaning that it has been approved by the NHS STR working group and can be promoted to Green on this panel at the next GMS panel update.
Fetal anomalies v6.27 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.26 DMPK_CTG Arina Puzriakova Tag Q3_25_promote_green tag was added to STR: DMPK_CTG.
Tag Q3_25_expert_review tag was added to STR: DMPK_CTG.
Tag Q3_25_NHS_review tag was added to STR: DMPK_CTG.
Fetal anomalies v6.26 XYLT1_GCC Arina Puzriakova Classified STR: XYLT1_GCC as Red List (low evidence)
Fetal anomalies v6.26 XYLT1_GCC Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support an association with Desbuquois dysplasia, however, this STR is currently not green on any panels as it has not been approved by the NHS STR working group and is not NGS validated. Therefore the Red rating will be maintained for now.
Fetal anomalies v6.26 XYLT1_GCC Arina Puzriakova Str: xylt1_gcc has been classified as Red List (Low Evidence).
Fetal anomalies v6.25 CNBP_CCTG Arina Puzriakova Classified STR: CNBP_CCTG as Red List (low evidence)
Fetal anomalies v6.25 CNBP_CCTG Arina Puzriakova Added comment: Comment on list classification: This STR was downgraded from Amber to Red inline with the Red review by the R21 Clinical Oversight Group.
Fetal anomalies v6.25 CNBP_CCTG Arina Puzriakova Str: cnbp_cctg has been classified as Red List (Low Evidence).
Fetal anomalies v6.24 DMPK_CTG Arina Puzriakova commented on STR: DMPK_CTG: This STR and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.24 XYLT1_GCC Arina Puzriakova commented on STR: XYLT1_GCC: This STR and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.24 CNBP_CCTG Arina Puzriakova commented on STR: CNBP_CCTG: This STR and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
Fetal anomalies v6.24 XYLT1_GCC Arina Puzriakova reviewed STR: XYLT1_GCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 22711505, 30554721; Phenotypes: Desbuquois dysplasia 2, OMIM:615777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 DMPK_CTG Arina Puzriakova edited their review of STR: DMPK_CTG: Added comment: Green expert review added on behalf of Sunayna Best (Leeds Teaching Hospitals NHS Trust), as part of a review of this panel by the R21 Clinical Oversight Group:

"Prenatal presentations of DM1 have been associated with nonspecific ultrasound findings such as clubbed foot, polyhydramnios, ventriculomegaly, and decreased fetal movement. Few published cases include prenatal neuroimaging findings, and ventriculomegaly has been described Shear et al, 2024: report expansion of the prenatal phenotype of DM1 with fetal SVT and frontal bossing with dilated subarachnoid spaces."; Changed rating: GREEN; Changed phenotypes to: Myotonic dystrophy 1; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 CNBP_CCTG Arina Puzriakova changed review comment from: Red expert review added on behalf of Alice Gardham (North West Thames Genetics), as part of a review of this panel by the R21 Clinical Oversight Group:

Myotonic dytrophy 2 - no fetal presentation.; to: Red expert review added on behalf of Alice Gardham (North West Thames Genetics), as part of a review of this panel by the R21 Clinical Oversight Group:

"Myotonic dytrophy 2 - no fetal presentation."
Fetal anomalies v6.24 CNBP_CCTG Arina Puzriakova edited their review of STR: CNBP_CCTG: Added comment: Red expert review added on behalf of Alice Gardham (North West Thames Genetics), as part of a review of this panel by the R21 Clinical Oversight Group:

Myotonic dytrophy 2 - no fetal presentation.; Changed rating: RED
Fetal anomalies v6.24 CDH11 Natalie Chandler reviewed gene: CDH11: Rating: AMBER; Mode of pathogenicity: ; Publications: 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.24 FAAP100 Sarah Graham reviewed gene: FAAP100: Rating: GREEN; Mode of pathogenicity: ; Publications: 40232843, 40244696; Phenotypes: Fanconi anemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 BORCS5 Sarah Graham reviewed gene: BORCS5: Rating: GREEN; Mode of pathogenicity: ; Publications: 40385417; Phenotypes: Arthrogryposis multiplex congenita, brain malformations; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 MAGED2 Sarah Graham reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bartter syndrome, type 5, antenatal, transient; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v6.24 ZNRF3 Sarah Graham reviewed gene: ZNRF3: Rating: AMBER; Mode of pathogenicity: ; Publications: 39168120; Phenotypes: Complex neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 ZNHIT3 Sarah Graham reviewed gene: ZNHIT3: Rating: AMBER; Mode of pathogenicity: ; Publications: 39252897, 28335020; Phenotypes: PEHO syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ZNF808 Elizabeth Wall reviewed gene: ZNF808: Rating: RED; Mode of pathogenicity: ; Publications: 37973953, 37308312; Phenotypes: Pancreatic agenesis 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ZMYND11 Natalie Bibb reviewed gene: ZMYND11: Rating: AMBER; Mode of pathogenicity: ; Publications: 39521787; Phenotypes: Intellectual developmental disorder, autosomal dominant 30; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 ZEB1 Sarah Graham reviewed gene: ZEB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 37857482; Phenotypes: Anomalies of the corpus callosum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 WDR47 Sarah Graham reviewed gene: WDR47: Rating: GREEN; Mode of pathogenicity: ; Publications: 39609633; Phenotypes: Complex neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 UNC50 Sarah Graham reviewed gene: UNC50: Rating: AMBER; Mode of pathogenicity: ; Publications: 33820833, 40219868, 29016857; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 UNC13D Anna de Burca reviewed gene: UNC13D: Rating: GREEN; Mode of pathogenicity: ; Publications: 33082562, 29262924, 21646258; Phenotypes: Hemophagocytic lymphohistiocytosis, familial, 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 TPM1 Alice Gardham reviewed gene: TPM1: Rating: AMBER; Mode of pathogenicity: ; Publications: 33553264; Phenotypes: Left ventricular noncompaction 9; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 C14orf80 Sunayna Best reviewed gene: C14orf80: Rating: AMBER; Mode of pathogenicity: ; Publications: 39979680; Phenotypes: severe growth impairment and endocrine complications; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 TCP1 Natalie Bibb reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39480921; Phenotypes: Intellectual developmental disorder with polymicrogyria and seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 TCF20 Stephanie Allen reviewed gene: TCF20: Rating: AMBER; Mode of pathogenicity: ; Publications: 30819258, 40066675; Phenotypes: Developmental delay with variable intellectual impairment and behavioral abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 TAAR1 Sarah Graham reviewed gene: TAAR1: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Cerebellar vermis hypoplasia, cystic kidneys, polydactyly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SUPT7L Soo-Mi Park reviewed gene: SUPT7L: Rating: RED; Mode of pathogenicity: ; Publications: 38592547; Phenotypes: Fischer-Zirnsak progeroid syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 STXBP2 Alice Gardham reviewed gene: STXBP2: Rating: RED; Mode of pathogenicity: ; Publications: 38084697, 33593331; Phenotypes: Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 STX5 Sahar Mansour reviewed gene: STX5: Rating: GREEN; Mode of pathogenicity: ; Publications: 34711829; Phenotypes: Congenital disorder of glycosylation, type IIaa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 STX11 Vicki Harrison reviewed gene: STX11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Haemophagocytic lymphohistiocytosis, familial, 4, OMIM:603552; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SRPK3 Sarah Graham reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: 39073169; Phenotypes: X-linked intellectual developmental disorder-114; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v6.24 SRP54 Stephanie Allen reviewed gene: SRP54: Rating: AMBER; Mode of pathogenicity: ; Publications: 28972538, 29914977; Phenotypes: Neutropenia, severe congenital, 8, autosomal dominant; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 SPTA1 Sarah Graham reviewed gene: SPTA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31333484, 34132406, 30198572, 38031483; Phenotypes: Hereditary pyropoikilocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SPOUT1 Sunayna Best reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39962046; Phenotypes: Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SNAPC4 Esther Kinning reviewed gene: SNAPC4: Rating: AMBER; Mode of pathogenicity: ; Publications: 40186013; Phenotypes: Neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SLC35A3 Sunayna Best reviewed gene: SLC35A3: Rating: GREEN; Mode of pathogenicity: ; Publications: 28777481, 24031089, 28328131, 33416188; Phenotypes: Arthrogryposis, mental retardation, and seizures, OMIM:615553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SLC30A5 Natalie Chandler reviewed gene: SLC30A5: Rating: AMBER; Mode of pathogenicity: ; Publications: 39790720, 12095919, 33547425; Phenotypes: Cardiomyopathy, hydrops fetalis, or cystic hygroma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SLC19A1 Soo-Mi Park reviewed gene: SLC19A1: Rating: AMBER; Mode of pathogenicity: ; Publications: 32276275, 11266438, 36745868, 36517554; Phenotypes: Immunodeficiency 114, folate-responsive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SLC12A9 Sarah Graham reviewed gene: SLC12A9: Rating: GREEN; Mode of pathogenicity: ; Publications: 38334070; Phenotypes: SLC12A9-related syndromic neurodevelopmental disorder with lysosome defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SIRT6 Natalie Canham reviewed gene: SIRT6: Rating: AMBER; Mode of pathogenicity: ; Publications: 29555651, 30135584; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SENP7 Natalie Bibb reviewed gene: SENP7: Rating: GREEN; Mode of pathogenicity: ; Publications: 37460201, 39763084; Phenotypes: Fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 SEL1L Anna de Burca reviewed gene: SEL1L: Rating: AMBER; Mode of pathogenicity: ; Publications: 37943610, 37943617; Phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 RPL26 Elizabeth Wall reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: ; Publications: 22431104, 39268718; Phenotypes: Diamond-Blackfan anaemia 11, OMIM:614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 RNU5B-1 Natalie Chandler reviewed gene: RNU5B-1: Rating: GREEN; Mode of pathogenicity: ; Publications: 40379786; Phenotypes: Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 RNU5A-1 Natalie Chandler reviewed gene: RNU5A-1: Rating: AMBER; Mode of pathogenicity: ; Publications: 40379786; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 RNF31 Natalie Chandler reviewed gene: RNF31: Rating: RED; Mode of pathogenicity: ; Publications: 30936877, 26008899; Phenotypes: Immunodeficiency 115 with autoinflammation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 RIPPLY2 Sahar Mansour reviewed gene: RIPPLY2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32212228, 33410135, 25343988, 26238661; Phenotypes: Spondylocostal dysostosis 6, OMIM:616566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 RBFOX2 Anna de Burca reviewed gene: RBFOX2: Rating: AMBER; Mode of pathogenicity: ; Publications: 35137168, 27485310, 27670201, 26785492, 25205790, 37165897; Phenotypes: Congenital heart disease, MONDO:0005453; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 RAB11B Sahar Mansour reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: ; Publications: 39502218; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 PYGL Soo-Mi Park reviewed gene: PYGL: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Glycogen storage disease VI; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v6.24 PUS3 Elizabeth Scotchman reviewed gene: PUS3: Rating: GREEN; Mode of pathogenicity: ; Publications: 27055666, 30697592, 31444731, 39891418, 30308082; Phenotypes: Neurodevelopmental disorder with microcephaly and gray sclerae; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PURA Natalie Canham reviewed gene: PURA: Rating: RED; Mode of pathogenicity: ; Publications: 39521787; Phenotypes: Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 PTEN Sunayna Best reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: ; Publications: 40261085; Phenotypes: Cowden syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 PSKH1 Sarah Graham reviewed gene: PSKH1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39132680; Phenotypes: hepatorenal syndrome, MONDO:0001382; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PROC Elizabeth Wall reviewed gene: PROC: Rating: AMBER; Mode of pathogenicity: ; Publications: 39763161; Phenotypes: Thrombophilia 3 due to protein C deficiency, autosomal recessive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PPFIBP1 Stephanie Allen reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 35830857, 37229200; Phenotypes: Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PPFIA3 Stephanie Allen reviewed gene: PPFIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: 38508193, 38181735, 37034625, 38723631; Phenotypes: Paul-Chao neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 POU3F3 Natalie Chandler reviewed gene: POU3F3: Rating: AMBER; Mode of pathogenicity: ; Publications: 37593446, 31303265; Phenotypes: Snijders Blok-Fisher syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 PLVAP Alice Gardham reviewed gene: PLVAP: Rating: AMBER; Mode of pathogenicity: ; Publications: 26207260, 29875123, 29661969, 31215290; Phenotypes: Diarrhoea 10, protein-losing enteropathy type, OMIM:618183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PLAA Stephanie Allen reviewed gene: PLAA: Rating: GREEN; Mode of pathogenicity: ; Publications: 38650658, 28413018, 28007986, 31322726; Phenotypes: Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, OMIM:617527; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PIGW Sahar Mansour reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: ; Publications: 40180615; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 11; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PIGQ Esther Kinning reviewed gene: PIGQ: Rating: AMBER; Mode of pathogenicity: ; Publications: 24463883, 31148362, 25558065, 32588908; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 4; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PIGP Elizabeth Wall reviewed gene: PIGP: Rating: GREEN; Mode of pathogenicity: ; Publications: 32042915, 28334793, 31139695; Phenotypes: Developmental and epileptic encephalopathy 55; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PIGM Elizabeth Scotchman reviewed gene: PIGM: Rating: AMBER; Mode of pathogenicity: ; Publications: 25293775, 16767100; Phenotypes: Glycosylphosphatidylinositol deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PIGG Anna de Burca reviewed gene: PIGG: Rating: GREEN; Mode of pathogenicity: ; Publications: 34113002, 26996948; Phenotypes: Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PIGC Alice Gardham reviewed gene: PIGC: Rating: AMBER; Mode of pathogenicity: ; Publications: 32707268, 27694521; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PI4KA Anna de Burca reviewed gene: PI4KA: Rating: GREEN; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PHF5A Vicki Harrison reviewed gene: PHF5A: Rating: GREEN; Mode of pathogenicity: ; Publications: 37422718, 33811463; Phenotypes: PHF5A-related neurodevelopmental disorder with congenital malformations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 PDE12 Alice Gardham reviewed gene: PDE12: Rating: AMBER; Mode of pathogenicity: ; Publications: 39567835; Phenotypes: Mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PDCD2 Soo-Mi Park reviewed gene: PDCD2: Rating: AMBER; Mode of pathogenicity: ; Publications: 40208938; Phenotypes: hydrops fetalis and early pregnancy loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 PAK2 Sarah Graham reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: ; Publications: 40262506, 37808560, 39876536, 33693784, 38894571, 39994693; Phenotypes: Knobloch syndrome 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 PAICS Sunayna Best reviewed gene: PAICS: Rating: GREEN; Mode of pathogenicity: ; Publications: 31178128, 38179855, 3965093, 30758658; Phenotypes: Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 OSBPL9 Natalie Chandler reviewed gene: OSBPL9: Rating: RED; Mode of pathogenicity: ; Publications: 40182349; Phenotypes: Fetal Cerebral Ventriculomegaly, Cerebellar Hypoplasia, and Arthrogryposis Multiplex; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ODC1 Anna de Burca reviewed gene: ODC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 40188065; Phenotypes: Bachmann-Bupp syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 NUP214 Stephanie Allen reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: ; Publications: 31178128, 39650934, 30758658; Phenotypes: Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NT5E Natalie Chandler reviewed gene: NT5E: Rating: RED; Mode of pathogenicity: ; Publications: 26010187, 34999808, 26178434, 21288095, 32522903, 28825389, 27045881; Phenotypes: arterial calcification, joint calcification; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NR2F1 Soo-Mi Park reviewed gene: NR2F1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31318166, 32712214, 36221391, 32484994, 40066675; Phenotypes: Bosch-Boonstra-Schaaf optic atrophy syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v6.24 NODAL Natalie Chandler reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: ; Publications: 19064609, 9354794; Phenotypes: Heterotaxy, visceral, 5; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 NMNAT1 Natalie Chandler reviewed gene: NMNAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NKX2-6 Sunayna Best reviewed gene: NKX2-6: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Conotruncal heart malformations, Persistent truncus arteriosus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NFASC Natalie Bibb reviewed gene: NFASC: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Neurodevelopmental disorder with central and peripheral motor dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NEXN Sarah Graham reviewed gene: NEXN: Rating: GREEN; Mode of pathogenicity: ; Publications: 33949776, 39183344, 35166435, 32058062; Phenotypes: Cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NEUROD1 Soo-Mi Park reviewed gene: NEUROD1: Rating: AMBER; Mode of pathogenicity: ; Publications: 26669242, 20573748, 10545951, 29521454, 26773576, 19609565; Phenotypes: Maturity-onset diabetes of the young 6; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v6.24 NEPRO Natalie Canham reviewed gene: NEPRO: Rating: GREEN; Mode of pathogenicity: ; Publications: 31250547, 29620724, 26633546, 37294112; Phenotypes: Anauxetic dysplasia 3, OMIM:618853; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NDUFB7 Vicki Harrison reviewed gene: NDUFB7: Rating: AMBER; Mode of pathogenicity: ; Publications: 33502047, 40025060; Phenotypes: Mitochondrial complex I deficiency, nuclear type 39; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NAGS Elizabeth Wall reviewed gene: NAGS: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: N-acetylglutamate synthase deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 NAGLU Sarah Graham reviewed gene: NAGLU: Rating: AMBER; Mode of pathogenicity: ; Publications: 40066675; Phenotypes: Mucopolysaccharidosis type IIIB (Sanfilippo B); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 MYL2 Vicki Harrison reviewed gene: MYL2: Rating: AMBER; Mode of pathogenicity: ; Publications: 39831482; Phenotypes: Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, Cardiomyopathy, hypertrophic, 10; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.24 MYH9 Natalie Chandler reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: ; Publications: 16969870, 31384440; Phenotypes: Deafness, autosomal dominant 17, Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 MSL2 Natalie Chandler reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: ; Publications: 33057194, 38815585, 31332282; Phenotypes: Karayol-Borroto-Haghshenas neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 MPL Elizabeth Scotchman reviewed gene: MPL: Rating: AMBER; Mode of pathogenicity: ; Publications: 39763161; Phenotypes: Amegakaryocytic thrombocytopenia, congenital, 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 MIA3 Sarah Graham reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: 32101163, 33778321, 40119123; Phenotypes: Odontochondrodysplasia-2 with hearing loss and diabetes; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 MET Stephanie Allen reviewed gene: MET: Rating: RED; Mode of pathogenicity: ; Publications: 30777867, 38429387; Phenotypes: ?Arthrogryposis, distal, type 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 MED11 Soo-Mi Park reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: ; Publications: 39578696, 36001086; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v6.24 MAPK1 Sarah Graham reviewed gene: MAPK1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 40257485, 32721402; Phenotypes: Noonan syndrome 13; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 MAP3K3 Alice Gardham reviewed gene: MAP3K3: Rating: RED; Mode of pathogenicity: ; Publications: 25728774; Phenotypes: Cerebral cavernous malformations 5; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 MAN2B2 Sarah Graham reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: ; Publications: 38622837, 35637269, 31775018; Phenotypes: Congenital disorder of glycosylation type 1EE with or without immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 MAL Sahar Mansour reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: Other; Publications: 35217805; Phenotypes: ?Leukodystrophy, hypomyelinating, 28; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 LSS Natalie Chandler reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: ; Publications: 39359128; Phenotypes: Alopecia-intellectual disability syndrome 4, Cataract 44; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 LRRC8C Vicki Harrison reviewed gene: LRRC8C: Rating: AMBER; Mode of pathogenicity: ; Publications: 39623139; Phenotypes: TIMES syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 LIPN Stephanie Allen reviewed gene: LIPN: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Ichthyosis, congenital, autosomal recessive 8; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 LGI3 Soo-Mi Park reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: ; Publications: 35948005; Phenotypes: Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v6.24 LDB1 Vicki Harrison reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39680505; Phenotypes: Congenital hydrocephalus, MONDO:0016349; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 LAGE3 Natalie Chandler reviewed gene: LAGE3: Rating: GREEN; Mode of pathogenicity: ; Publications: 28805828, 31069511, 36682911; Phenotypes: Galloway-Mowat syndrome 2, X-linked; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v6.24 KMT2E Natalie Bibb reviewed gene: KMT2E: Rating: AMBER; Mode of pathogenicity: ; Publications: 40186013; Phenotypes: O'Donnell-Luria-Rodan syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 C12orf66 Sahar Mansour reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: ; Publications: 39824192; Phenotypes: Intellectual developmental disorder, autosomal recessive 83; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 KDM6B Sunayna Best reviewed gene: KDM6B: Rating: AMBER; Mode of pathogenicity: ; Publications: 31124270, 37196654; Phenotypes: Stolerman neurodevelopmental syndrome, OMIM:618505; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 KDM1A Esther Kinning reviewed gene: KDM1A: Rating: AMBER; Mode of pathogenicity: ; Publications: 26656649, 24838796, 27094131; Phenotypes: Cleft palate, psychomotor retardation, and distinctive facial features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 KCNH2 Sahar Mansour reviewed gene: KCNH2: Rating: AMBER; Mode of pathogenicity: ; Publications: 36973673, 39698424, 38094730; Phenotypes: Short QT syndrome 1, OMIM:609620, Long QT syndrome 2, OMIM:613688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 KCNB1 Soo-Mi Park reviewed gene: KCNB1: Rating: AMBER; Mode of pathogenicity: ; Publications: 36257979, 31513310, 39237446; Phenotypes: Developmental and epileptic encephalopathy 26; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v6.24 KBTBD2 Esther Kinning reviewed gene: KBTBD2: Rating: AMBER; Mode of pathogenicity: ; Publications: 39313616; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 KAT7 Natalie Chandler reviewed gene: KAT7: Rating: RED; Mode of pathogenicity: ; Publications: 40186013; Phenotypes: Abnormal male external genitalia morphology, Tetralogy of Fallot; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 JPH1 Sarah Graham reviewed gene: JPH1: Rating: AMBER; Mode of pathogenicity: ; Publications: 39209426; Phenotypes: Congenital myopathy-25; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ITGAV Natalie Canham reviewed gene: ITGAV: Rating: GREEN; Mode of pathogenicity: ; Publications: 39526957; Phenotypes: Syndromic disease, MONDO:0002254; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 IRF4 Natalie Chandler reviewed gene: IRF4: Rating: RED; Mode of pathogenicity: ; Publications: 29537367, 36917008, 29408330, 36662884; Phenotypes: Immunodeficiency 131; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.24 IFT27 Sahar Mansour reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: ; Publications: 25443296, 2970430, 24488770, 30761183, 37239474, 26763875; Phenotypes: Bardet-Biedl syndrome 19; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 HNRNPU Sarah Graham reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: ; Publications: 39976380, 39965881, 39237446, 35138025; Phenotypes: Developmental and epileptic encephalopathy 54; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 HIRA Sarah Graham reviewed gene: HIRA: Rating: AMBER; Mode of pathogenicity: ; Publications: 38511226, 33417013; Phenotypes: Complex neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 HECTD1 Sarah Graham reviewed gene: HECTD1: Rating: AMBER; Mode of pathogenicity: ; Publications: 37165897, 38451291, 39879987; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.24 HDAC3 Sarah Graham reviewed gene: HDAC3: Rating: GREEN; Mode of pathogenicity: ; Publications: 39047730; Phenotypes: HDAC3-related neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 GUK1 Esther Kinning reviewed gene: GUK1: Rating: RED; Mode of pathogenicity: ; Publications: 39230499; Phenotypes: Mitochondrial DNA depletion syndrome 21; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 GTPBP1 Natalie Chandler reviewed gene: GTPBP1: Rating: AMBER; Mode of pathogenicity: ; Publications: 38118446; Phenotypes: Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 GNS Sarah Graham reviewed gene: GNS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Mucopolysaccharidosis type IIID, OMIM:252940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 GNPNAT1 Vicki Harrison reviewed gene: GNPNAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: 39945447; Phenotypes: Rhizomelic dysplasia, Ain-Naz type; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 GNAI2 Sarah Graham reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: ; Publications: 39298586; Phenotypes: Syndromic developmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 GEMIN4 Sahar Mansour reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 GDAP1 Alice Gardham reviewed gene: GDAP1: Rating: RED; Mode of pathogenicity: ; Publications: 39945447; Phenotypes: Charcot-Marie-Tooth disease, type 4A; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 GATA5 Natalie Chandler reviewed gene: GATA5: Rating: AMBER; Mode of pathogenicity: ; Publications: 40076735; Phenotypes: Congenital heart defects, multiple types, 5; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.24 GALT Sarah Graham reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Galactosemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 G6PD Sarah Graham reviewed gene: G6PD: Rating: AMBER; Mode of pathogenicity: ; Publications: 39041728; Phenotypes: Glucose-6-phosphate dehydrogenase deficiency; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v6.24 FLVCR1 Natalie Canham reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39306721; Phenotypes: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 FLII Sarah Graham reviewed gene: FLII: Rating: AMBER; Mode of pathogenicity: ; Publications: 37561591, 32870709; Phenotypes: Cardiomyopathy, dilated, 2J; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 FGG Natalie Canham reviewed gene: FGG: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Hypofibrinogenemia, congenital, Afibrinogenemia, congenital; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 FBXW11 Elizabeth Scotchman reviewed gene: FBXW11: Rating: AMBER; Mode of pathogenicity: ; Publications: 40188065, 31402090; Phenotypes: Neurodevelopmental, jaw, eye, and digital syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 FBXO22 Natalie Bibb reviewed gene: FBXO22: Rating: AMBER; Mode of pathogenicity: ; Publications: 40215970; Phenotypes: Tayoun-Maawali syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 FAM177A1 Vicki Harrison reviewed gene: FAM177A1: Rating: AMBER; Mode of pathogenicity: ; Publications: 38767059, 25558065; Phenotypes: Neurodevelopmental disorder with white matter abnormalities and gait disturbance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 EXOSC8 Sarah Graham reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: ; Publications: 34210538, 38017281, 24989451; Phenotypes: Pontocerebellar hypoplasia type 1C; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 EXOC6B Natalie Bibb reviewed gene: EXOC6B: Rating: GREEN; Mode of pathogenicity: ; Publications: 30284759, 26669664, 36150098; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ERG Sunayna Best reviewed gene: ERG: Rating: AMBER; Mode of pathogenicity: ; Publications: 36928819; Phenotypes: Lymphatic malformation 14; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 EFL1 Esther Kinning reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31151987, 29970384, 34115847, 28331068; Phenotypes: Shwachman-Diamond syndrome 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 EEFSEC Natalie Chandler reviewed gene: EEFSEC: Rating: GREEN; Mode of pathogenicity: ; Publications: 39753114; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 DVL2 Natalie Bibb reviewed gene: DVL2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 35047859, 30521570, 33599851; Phenotypes: Robinow syndrome, MONDO:0019978; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 DTNA Natalie Bibb reviewed gene: DTNA: Rating: RED; Mode of pathogenicity: ; Publications: 36799992; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 DST Sarah Graham reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: ; Publications: 37431644; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 DSE Natalie Chandler reviewed gene: DSE: Rating: GREEN; Mode of pathogenicity: ; Publications: 31655143, 32130795, 25703627, 23704329; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 DSC2 Alice Gardham reviewed gene: DSC2: Rating: RED; Mode of pathogenicity: ; Publications: 40188065; Phenotypes: Arrhythmogenic right ventricular dysplasia, familial, 11; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.24 DOHH Esther Kinning reviewed gene: DOHH: Rating: AMBER; Mode of pathogenicity: ; Publications: 35858628; Phenotypes: Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, OMIM:620066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 DNAJC21 Elizabeth Wall reviewed gene: DNAJC21: Rating: AMBER; Mode of pathogenicity: ; Publications: 27346687, 28062395, 29700810; Phenotypes: Bone marrow failure syndrome 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 DHX9 Elizabeth Scotchman reviewed gene: DHX9: Rating: GREEN; Mode of pathogenicity: ; Publications: 37467750, 37369308; Phenotypes: Intellectual developmental disorder, autosomal dominant 75; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 DHRSX Elizabeth Scotchman reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: ; Publications: 38821050; Phenotypes: Congenital disorder of glycosylation, type 1DD, OMIM:301133; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 DDX17 Elizabeth Scotchman reviewed gene: DDX17: Rating: RED; Mode of pathogenicity: ; Publications: 39405200; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 DAND5 Elizabeth Wall reviewed gene: DAND5: Rating: AMBER; Mode of pathogenicity: ; Publications: 34215651, 36316122; Phenotypes: Heterotaxy, visceral, 13, autosomal; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 CYP24A1 Natalie Chandler reviewed gene: CYP24A1: Rating: RED; Mode of pathogenicity: ; Publications: 22337913, 28324001, 27105398, 34307984; Phenotypes: hypercalcaemia, nephrocalcinosis, cystic kidney disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 COQ2 Anna de Burca reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: ; Publications: 39763161; Phenotypes: Coenzyme Q10 deficiency, primary, 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 COMP Elizabeth Wall reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 40188065, 39521787; Phenotypes: Epiphyseal dysplasia, multiple, 1, Pseudoachondroplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 COL25A1 Sarah Graham reviewed gene: COL25A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 40158061; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 C1orf127 Elizabeth Scotchman reviewed gene: C1orf127: Rating: GREEN; Mode of pathogenicity: ; Publications: 39753129; Phenotypes: Heterotaxy, visceral, 14, autosomal; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 CHAF1A Elizabeth Wall reviewed gene: CHAF1A: Rating: AMBER; Mode of pathogenicity: ; Publications: 39333427; Phenotypes: Oculo-auriculo-vertebral spectrum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 CFI Esther Kinning reviewed gene: CFI: Rating: AMBER; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Complement factor I deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 CELSR1 Sarah Graham reviewed gene: CELSR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 38272662; Phenotypes: Lymphatic malformation-9; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 CDK5 Sarah Graham reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: ; Publications: 25560765, 40186457; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 CCT8 Sarah Graham reviewed gene: CCT8: Rating: AMBER; Mode of pathogenicity: ; Publications: 39480921; Phenotypes: CCT8-related neurodevelopmental disorder with brain abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 CCT6A Sarah Graham reviewed gene: CCT6A: Rating: RED; Mode of pathogenicity: ; Publications: 39480921; Phenotypes: CCT6A-related neurodevelopmental disorder with or without brain abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.24 CCT3 Natalie Canham reviewed gene: CCT3: Rating: AMBER; Mode of pathogenicity: ; Publications: 39480921; Phenotypes: Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 CTGF Elizabeth Scotchman reviewed gene: CTGF: Rating: GREEN; Mode of pathogenicity: ; Publications: 39506047, 39414788, 12736220; Phenotypes: Kyphomelic dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 BRD2 Natalie Canham reviewed gene: BRD2: Rating: RED; Mode of pathogenicity: ; Publications: 40186013; Phenotypes: Agenesis of corpus callosum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 BORCS8 Natalie Canham reviewed gene: BORCS8: Rating: RED; Mode of pathogenicity: ; Publications: 38128568; Phenotypes: Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 BICRA Natalie Chandler reviewed gene: BICRA: Rating: AMBER; Mode of pathogenicity: ; Publications: 33232675; Phenotypes: Coffin-Siris syndrome 12; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 BHLHE22 Sarah Graham reviewed gene: BHLHE22: Rating: GREEN; Mode of pathogenicity: ; Publications: 39502664; Phenotypes: Complex neurodevelopmental disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.24 BAIAP2 Anna de Burca reviewed gene: BAIAP2: Rating: AMBER; Mode of pathogenicity: ; Publications: 38149472; Phenotypes: Lissencephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 ASCC3 Anna de Burca reviewed gene: ASCC3: Rating: AMBER; Mode of pathogenicity: ; Publications: 21937992, 35047834; Phenotypes: Intellectual developmental disorder, autosomal recessive 81, OMIM:620700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ARPC5 Stephanie Allen reviewed gene: ARPC5: Rating: RED; Mode of pathogenicity: ; Publications: 37382373, 37349293; Phenotypes: Immunodeficiency 113 with autoimmunity and autoinflammation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ARL6IP1 Alice Gardham reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39954331; Phenotypes: Spastic paraplegia 61, autosomal recessive, OMIM:615685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ARL2BP Vicki Harrison reviewed gene: ARL2BP: Rating: GREEN; Mode of pathogenicity: ; Publications: 36507858, 40384762, 38649918, 23849777, 27790702; Phenotypes: Situs Inversus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 AGT Esther Kinning reviewed gene: AGT: Rating: GREEN; Mode of pathogenicity: ; Publications: 39641285; Phenotypes: Renal tubular dysgenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 AGRN Alice Gardham reviewed gene: AGRN: Rating: GREEN; Mode of pathogenicity: ; Publications: 39807604; Phenotypes: Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.24 ACTN2 Natalie Chandler reviewed gene: ACTN2: Rating: RED; Mode of pathogenicity: ; Publications: 39521787; Phenotypes: Congenital myopathy 8, Cardiomyopathy, hypertrophic, 23, with or without LVNC, Cardiomyopathy, dilated, 1AA, with or without LVNC; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.24 ACO2 Natalie Chandler reviewed gene: ACO2: Rating: AMBER; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Infantile cerebellar-retinal degeneration; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.23 CNBP_CCTG Arina Puzriakova Classified STR: CNBP_CCTG as Red List (low evidence)
Fetal anomalies v6.23 CNBP_CCTG Arina Puzriakova Str: cnbp_cctg has been classified as Red List (Low Evidence).
Fetal anomalies v6.22 XYLT1_GCC Arina Puzriakova Entity copied from Skeletal dysplasia v8.7
Fetal anomalies v6.22 XYLT1_GCC Arina Puzriakova STR: XYLT1_GCC was added
STR: XYLT1_GCC was added to Fetal anomalies. Sources: Literature
STR, NGS Not Validated tags were added to STR: XYLT1_GCC.
Mode of inheritance for STR: XYLT1_GCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: XYLT1_GCC were set to 22711505; 30554721
Phenotypes for STR: XYLT1_GCC were set to Desbuquois dysplasia 2, OMIM:615777; Desbuquois dysplasia 2, MONDO:0014343
Fetal anomalies v6.21 CDH11 Arina Puzriakova gene: CDH11 was added
gene: CDH11 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: CDH11 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CDH11 were set to 33811546; 29271567
Phenotypes for gene: CDH11 were set to Elsahy-Waters syndrome
Fetal anomalies v6.21 FAAP100 Arina Puzriakova gene: FAAP100 was added
gene: FAAP100 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: FAAP100 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAAP100 were set to 40244696; 40232843
Phenotypes for gene: FAAP100 were set to Fanconi anemia
Fetal anomalies v6.21 BORCS5 Arina Puzriakova gene: BORCS5 was added
gene: BORCS5 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Arthrogryposis multiplex congenita, brain malformations
Fetal anomalies v6.21 MAGED2 Arina Puzriakova gene: MAGED2 was added
gene: MAGED2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: MAGED2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: MAGED2 were set to Bartter syndrome, type 5, antenatal, transient
Fetal anomalies v6.21 ZNRF3 Arina Puzriakova gene: ZNRF3 was added
gene: ZNRF3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to Complex neurodevelopmental disorder
Fetal anomalies v6.21 ZNHIT3 Arina Puzriakova Source Expert Review Amber was added to ZNHIT3.
Added phenotypes PEHO syndrome for gene: ZNHIT3
Publications for gene: ZNHIT3 were updated from 28335020; 31048081 to 39252897; 28335020; 31048081
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 ZNF808 Arina Puzriakova gene: ZNF808 was added
gene: ZNF808 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: ZNF808 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF808 were set to 37308312; 37973953
Phenotypes for gene: ZNF808 were set to Pancreatic agenesis 3
Fetal anomalies v6.21 ZMYND11 Arina Puzriakova Mode of inheritance for gene ZMYND11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Intellectual developmental disorder, autosomal dominant 30 for gene: ZMYND11
Publications for gene: ZMYND11 were updated from to 39521787
Fetal anomalies v6.21 ZEB1 Arina Puzriakova gene: ZEB1 was added
gene: ZEB1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: ZEB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZEB1 were set to 37857482
Phenotypes for gene: ZEB1 were set to Anomalies of the corpus callosum
Fetal anomalies v6.21 WDR47 Arina Puzriakova gene: WDR47 was added
gene: WDR47 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: WDR47 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR47 were set to 39609633
Phenotypes for gene: WDR47 were set to Complex neurodevelopmental disorder
Fetal anomalies v6.21 UNC50 Arina Puzriakova gene: UNC50 was added
gene: UNC50 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: UNC50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC50 were set to 29016857; 40219868; 33820833
Phenotypes for gene: UNC50 were set to Arthrogryposis multiplex congenita
Fetal anomalies v6.21 UNC13D Arina Puzriakova Added phenotypes Hemophagocytic lymphohistiocytosis, familial, 3 for gene: UNC13D
Publications for gene: UNC13D were updated from 33082562; 33249554 to 21646258; 33249554; 29262924; 33082562
Fetal anomalies v6.21 TPM1 Arina Puzriakova gene: TPM1 was added
gene: TPM1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: TPM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TPM1 were set to 33553264
Phenotypes for gene: TPM1 were set to Left ventricular noncompaction 9
Fetal anomalies v6.21 C14orf80 Arina Puzriakova gene: C14orf80 was added
gene: C14orf80 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: C14orf80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C14orf80 were set to 39979680
Phenotypes for gene: C14orf80 were set to severe growth impairment and endocrine complications
Fetal anomalies v6.21 TCP1 Arina Puzriakova gene: TCP1 was added
gene: TCP1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: TCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCP1 were set to 39480921
Phenotypes for gene: TCP1 were set to Intellectual developmental disorder with polymicrogyria and seizures
Fetal anomalies v6.21 TCF20 Arina Puzriakova Mode of inheritance for gene TCF20 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Developmental delay with variable intellectual impairment and behavioral abnormalities for gene: TCF20
Publications for gene: TCF20 were updated from to 30819258; 40066675
Fetal anomalies v6.21 TAAR1 Arina Puzriakova gene: TAAR1 was added
gene: TAAR1 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: TAAR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAAR1 were set to 39891418
Phenotypes for gene: TAAR1 were set to Cerebellar vermis hypoplasia, cystic kidneys, polydactyly
Fetal anomalies v6.21 SUPT7L Arina Puzriakova gene: SUPT7L was added
gene: SUPT7L was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: SUPT7L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUPT7L were set to 38592547
Phenotypes for gene: SUPT7L were set to Fischer-Zirnsak progeroid syndrome
Fetal anomalies v6.21 STXBP2 Arina Puzriakova gene: STXBP2 was added
gene: STXBP2 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: STXBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STXBP2 were set to 33593331; 38084697
Phenotypes for gene: STXBP2 were set to Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease
Fetal anomalies v6.21 STX5 Arina Puzriakova Added phenotypes Congenital disorder of glycosylation, type IIaa for gene: STX5
Fetal anomalies v6.21 STX11 Arina Puzriakova gene: STX11 was added
gene: STX11 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: STX11 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STX11 were set to Haemophagocytic lymphohistiocytosis, familial, 4, OMIM:603552
Fetal anomalies v6.21 SRPK3 Arina Puzriakova gene: SRPK3 was added
gene: SRPK3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SRPK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SRPK3 were set to 39073169
Phenotypes for gene: SRPK3 were set to X-linked intellectual developmental disorder-114
Fetal anomalies v6.21 SRP54 Arina Puzriakova Mode of inheritance for gene SRP54 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Neutropenia, severe congenital, 8, autosomal dominant for gene: SRP54
Publications for gene: SRP54 were updated from to 28972538; 29914977
Fetal anomalies v6.21 SPTA1 Arina Puzriakova Source Expert Review Amber was added to SPTA1.
Mode of inheritance for gene SPTA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Hereditary pyropoikilocytosis for gene: SPTA1
Publications for gene: SPTA1 were updated from 31333484; 33082562; 34132406 to 34132406; 30198572; 38031483; 33082562; 31333484
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 SPOUT1 Arina Puzriakova gene: SPOUT1 was added
gene: SPOUT1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities
Fetal anomalies v6.21 SNAPC4 Arina Puzriakova gene: SNAPC4 was added
gene: SNAPC4 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 40186013
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction
Fetal anomalies v6.21 SLC35A3 Arina Puzriakova gene: SLC35A3 was added
gene: SLC35A3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35A3 were set to 28328131; 28777481; 24031089; 33416188
Phenotypes for gene: SLC35A3 were set to Arthrogryposis, mental retardation, and seizures, OMIM:615553
Fetal anomalies v6.21 SLC30A5 Arina Puzriakova gene: SLC30A5 was added
gene: SLC30A5 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SLC30A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A5 were set to 33547425; 12095919; 39790720
Phenotypes for gene: SLC30A5 were set to Cardiomyopathy, hydrops fetalis, or cystic hygroma
Fetal anomalies v6.21 SLC19A1 Arina Puzriakova gene: SLC19A1 was added
gene: SLC19A1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SLC19A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC19A1 were set to 32276275; 36745868; 11266438; 36517554
Phenotypes for gene: SLC19A1 were set to Immunodeficiency 114, folate-responsive
Fetal anomalies v6.21 SLC12A9 Arina Puzriakova gene: SLC12A9 was added
gene: SLC12A9 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SLC12A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC12A9 were set to 38334070
Phenotypes for gene: SLC12A9 were set to SLC12A9-related syndromic neurodevelopmental disorder with lysosome defects
Fetal anomalies v6.21 SIRT6 Arina Puzriakova Added phenotypes Neurodevelopmental disorder, MONDO:0700092 for gene: SIRT6
Publications for gene: SIRT6 were updated from 29555651; 30135584 to 30135584; 29555651
Fetal anomalies v6.21 SENP7 Arina Puzriakova gene: SENP7 was added
gene: SENP7 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SENP7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SENP7 were set to 37460201; 39763084
Phenotypes for gene: SENP7 were set to Fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia
Fetal anomalies v6.21 SEL1L Arina Puzriakova gene: SEL1L was added
gene: SEL1L was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEL1L were set to 37943617; 37943610
Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia
Fetal anomalies v6.21 RPL26 Arina Puzriakova gene: RPL26 was added
gene: RPL26 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: RPL26 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL26 were set to 22431104; 39268718
Phenotypes for gene: RPL26 were set to Diamond-Blackfan anaemia 11, OMIM:614900
Fetal anomalies v6.21 RNU5B-1 Arina Puzriakova gene: RNU5B-1 was added
gene: RNU5B-1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5B-1 were set to 40379786
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302
Fetal anomalies v6.21 RNU5A-1 Arina Puzriakova gene: RNU5A-1 was added
gene: RNU5A-1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.21 RNF31 Arina Puzriakova gene: RNF31 was added
gene: RNF31 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: RNF31 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF31 were set to 26008899; 30936877
Phenotypes for gene: RNF31 were set to Immunodeficiency 115 with autoinflammation
Fetal anomalies v6.21 RIPPLY2 Arina Puzriakova gene: RIPPLY2 was added
gene: RIPPLY2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: RIPPLY2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIPPLY2 were set to 26238661; 25343988; 32212228; 33410135
Phenotypes for gene: RIPPLY2 were set to Spondylocostal dysostosis 6, OMIM:616566
Fetal anomalies v6.21 RBFOX2 Arina Puzriakova gene: RBFOX2 was added
gene: RBFOX2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBFOX2 were set to 27670201; 25205790; 37165897; 26785492; 27485310; 35137168
Phenotypes for gene: RBFOX2 were set to Congenital heart disease, MONDO:0005453
Fetal anomalies v6.21 RAB11B Arina Puzriakova Added phenotypes Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter for gene: RAB11B
Publications for gene: RAB11B were updated from 29106825 to 39502218; 29106825
Fetal anomalies v6.21 PYGL Arina Puzriakova Added phenotypes Glycogen storage disease VI for gene: PYGL
Publications for gene: PYGL were updated from to 39891418
Fetal anomalies v6.21 PUS3 Arina Puzriakova gene: PUS3 was added
gene: PUS3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PUS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PUS3 were set to 31444731; 39891418; 30308082; 30697592; 27055666
Phenotypes for gene: PUS3 were set to Neurodevelopmental disorder with microcephaly and gray sclerae
Fetal anomalies v6.21 PURA Arina Puzriakova Mode of inheritance for gene PURA was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties for gene: PURA
Publications for gene: PURA were updated from to 39521787
Fetal anomalies v6.21 PTEN Arina Puzriakova Source Expert Review Amber was added to PTEN.
Mode of inheritance for gene PTEN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Cowden syndrome 1 for gene: PTEN
Publications for gene: PTEN were updated from to 40261085
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 PSKH1 Arina Puzriakova gene: PSKH1 was added
gene: PSKH1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSKH1 were set to 39132680
Phenotypes for gene: PSKH1 were set to hepatorenal syndrome, MONDO:0001382
Fetal anomalies v6.21 PROC Arina Puzriakova gene: PROC was added
gene: PROC was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PROC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PROC were set to 39763161
Phenotypes for gene: PROC were set to Thrombophilia 3 due to protein C deficiency, autosomal recessive
Fetal anomalies v6.21 PPFIBP1 Arina Puzriakova gene: PPFIBP1 was added
gene: PPFIBP1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to 35830857; 37229200
Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities
Fetal anomalies v6.21 PPFIA3 Arina Puzriakova gene: PPFIA3 was added
gene: PPFIA3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PPFIA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPFIA3 were set to 37034625; 38508193; 38723631; 38181735
Phenotypes for gene: PPFIA3 were set to Paul-Chao neurodevelopmental syndrome
Fetal anomalies v6.21 POU3F3 Arina Puzriakova gene: POU3F3 was added
gene: POU3F3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU3F3 were set to 37593446; 31303265
Phenotypes for gene: POU3F3 were set to Snijders Blok-Fisher syndrome
Fetal anomalies v6.21 PLVAP Arina Puzriakova gene: PLVAP was added
gene: PLVAP was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 31215290; 29875123; 29661969; 26207260
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Fetal anomalies v6.21 PLAA Arina Puzriakova Added phenotypes Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, OMIM:617527 for gene: PLAA
Publications for gene: PLAA were updated from 28007986; 28413018; 31322726 to 31322726; 38650658; 28413018; 28007986
Fetal anomalies v6.21 PIGW Arina Puzriakova gene: PIGW was added
gene: PIGW was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PIGW was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGW were set to 40180615
Phenotypes for gene: PIGW were set to Glycosylphosphatidylinositol biosynthesis defect 11
Fetal anomalies v6.21 PIGQ Arina Puzriakova gene: PIGQ was added
gene: PIGQ was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PIGQ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGQ were set to 24463883; 25558065; 31148362; 32588908
Phenotypes for gene: PIGQ were set to Multiple congenital anomalies-hypotonia-seizures syndrome 4
Fetal anomalies v6.21 PIGP Arina Puzriakova gene: PIGP was added
gene: PIGP was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PIGP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGP were set to 28334793; 32042915; 31139695
Phenotypes for gene: PIGP were set to Developmental and epileptic encephalopathy 55
Fetal anomalies v6.21 PIGM Arina Puzriakova gene: PIGM was added
gene: PIGM was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PIGM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGM were set to 25293775; 16767100
Phenotypes for gene: PIGM were set to Glycosylphosphatidylinositol deficiency
Fetal anomalies v6.21 PIGG Arina Puzriakova Added phenotypes Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy for gene: PIGG
Fetal anomalies v6.21 PIGC Arina Puzriakova gene: PIGC was added
gene: PIGC was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PIGC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGC were set to 32707268; 27694521
Phenotypes for gene: PIGC were set to Glycosylphosphatidylinositol biosynthesis defect 16
Fetal anomalies v6.21 PI4KA Arina Puzriakova Added phenotypes Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis for gene: PI4KA
Publications for gene: PI4KA were updated from 34415310 to 34415310; 39891418
Fetal anomalies v6.21 PHF5A Arina Puzriakova gene: PHF5A was added
gene: PHF5A was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PHF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHF5A were set to 33811463; 37422718
Phenotypes for gene: PHF5A were set to PHF5A-related neurodevelopmental disorder with congenital malformations
Fetal anomalies v6.21 PDE12 Arina Puzriakova Added phenotypes Mitochondrial disease, MONDO:0044970 for gene: PDE12
Fetal anomalies v6.21 PDCD2 Arina Puzriakova gene: PDCD2 was added
gene: PDCD2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD2 were set to 40208938
Phenotypes for gene: PDCD2 were set to hydrops fetalis and early pregnancy loss
Fetal anomalies v6.21 PAK2 Arina Puzriakova gene: PAK2 was added
gene: PAK2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAK2 were set to 39994693; 40262506; 33693784; 38894571; 37808560; 39876536
Phenotypes for gene: PAK2 were set to Knobloch syndrome 2
Fetal anomalies v6.21 PAICS Arina Puzriakova Added phenotypes Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426 for gene: PAICS
Publications for gene: PAICS were updated from 31600779 to 31178128; 31600779; 3965093; 38179855; 30758658
Fetal anomalies v6.21 OSBPL9 Arina Puzriakova gene: OSBPL9 was added
gene: OSBPL9 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: OSBPL9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSBPL9 were set to 40182349
Phenotypes for gene: OSBPL9 were set to Fetal Cerebral Ventriculomegaly, Cerebellar Hypoplasia, and Arthrogryposis Multiplex
Fetal anomalies v6.21 ODC1 Arina Puzriakova gene: ODC1 was added
gene: ODC1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: ODC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ODC1 were set to 40188065
Phenotypes for gene: ODC1 were set to Bachmann-Bupp syndrome
Fetal anomalies v6.21 NUP214 Arina Puzriakova Added phenotypes Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426 for gene: NUP214
Publications for gene: NUP214 were updated from 31178128; 38179855; 30758658; 3965093 to 31178128; 3965093; 38179855; 39650934; 30758658
Fetal anomalies v6.21 NT5E Arina Puzriakova gene: NT5E was added
gene: NT5E was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: NT5E was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NT5E were set to 21288095; 32522903; 28825389; 26178434; 34999808; 27045881; 26010187
Phenotypes for gene: NT5E were set to arterial calcification; joint calcification
Fetal anomalies v6.21 NR2F1 Arina Puzriakova Source Expert Review Amber was added to NR2F1.
Mode of inheritance for gene NR2F1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Bosch-Boonstra-Schaaf optic atrophy syndrome for gene: NR2F1
Publications for gene: NR2F1 were updated from to 40066675; 32712214; 31318166; 36221391; 32484994
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 NODAL Arina Puzriakova Mode of inheritance for gene NODAL was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Heterotaxy, visceral, 5 for gene: NODAL
Publications for gene: NODAL were updated from to 9354794; 19064609
Fetal anomalies v6.21 NMNAT1 Arina Puzriakova Source Expert Review Amber was added to NMNAT1.
Added phenotypes Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis for gene: NMNAT1
Publications for gene: NMNAT1 were updated from to 39891418
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 NKX2-6 Arina Puzriakova Added phenotypes Conotruncal heart malformations; Persistent truncus arteriosus for gene: NKX2-6
Publications for gene: NKX2-6 were updated from 32198970; 15649947; 24421281; 25319568; 25380965 to 25319568; 15649947; 32198970; 39891418; 25380965; 24421281
Fetal anomalies v6.21 NFASC Arina Puzriakova gene: NFASC was added
gene: NFASC was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: NFASC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFASC were set to 39891418
Phenotypes for gene: NFASC were set to Neurodevelopmental disorder with central and peripheral motor dysfunction
Fetal anomalies v6.21 NEXN Arina Puzriakova Mode of inheritance for gene NEXN was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Cardiomyopathy for gene: NEXN
Publications for gene: NEXN were updated from 33947203; 32058062; 35166435; 33027564; 33949776 to 39183344; 33947203; 33949776; 33027564; 35166435; 32058062
Fetal anomalies v6.21 NEUROD1 Arina Puzriakova gene: NEUROD1 was added
gene: NEUROD1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: NEUROD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROD1 were set to 26773576; 10545951; 29521454; 26669242; 19609565; 20573748
Phenotypes for gene: NEUROD1 were set to Maturity-onset diabetes of the young 6
Fetal anomalies v6.21 NEPRO Arina Puzriakova gene: NEPRO was added
gene: NEPRO was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEPRO were set to 29620724; 31250547; 37294112; 26633546
Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, OMIM:618853
Fetal anomalies v6.21 NDUFB7 Arina Puzriakova Added phenotypes Mitochondrial complex I deficiency, nuclear type 39 for gene: NDUFB7
Publications for gene: NDUFB7 were updated from 33502047; 27626371; 40025060 to 27626371; 40025060; 33502047
Fetal anomalies v6.21 NAGS Arina Puzriakova Added phenotypes N-acetylglutamate synthase deficiency for gene: NAGS
Publications for gene: NAGS were updated from to 39891418
Fetal anomalies v6.21 NAGLU Arina Puzriakova Added phenotypes Mucopolysaccharidosis type IIIB (Sanfilippo B) for gene: NAGLU
Publications for gene: NAGLU were updated from to 40066675
Fetal anomalies v6.21 MYL2 Arina Puzriakova gene: MYL2 was added
gene: MYL2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: MYL2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYL2 were set to 39831482
Phenotypes for gene: MYL2 were set to Cardiomyopathy, hypertrophic, 10; Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy
Fetal anomalies v6.21 MYH9 Arina Puzriakova Added phenotypes Deafness, autosomal dominant 17; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss for gene: MYH9
Publications for gene: MYH9 were updated from to 16969870; 31384440
Fetal anomalies v6.21 MSL2 Arina Puzriakova gene: MSL2 was added
gene: MSL2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MSL2 were set to 38815585; 33057194; 31332282
Phenotypes for gene: MSL2 were set to Karayol-Borroto-Haghshenas neurodevelopmental syndrome
Fetal anomalies v6.21 MPL Arina Puzriakova gene: MPL was added
gene: MPL was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: MPL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPL were set to 39763161
Phenotypes for gene: MPL were set to Amegakaryocytic thrombocytopenia, congenital, 1
Fetal anomalies v6.21 MIA3 Arina Puzriakova gene: MIA3 was added
gene: MIA3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIA3 were set to 32101163; 40119123; 33778321
Phenotypes for gene: MIA3 were set to Odontochondrodysplasia-2 with hearing loss and diabetes
Fetal anomalies v6.21 MET Arina Puzriakova gene: MET was added
gene: MET was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: MET was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MET were set to 30777867; 38429387
Phenotypes for gene: MET were set to ?Arthrogryposis, distal, type 1
Fetal anomalies v6.21 MED11 Arina Puzriakova gene: MED11 was added
gene: MED11 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086; 39578696
Phenotypes for gene: MED11 were set to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities
Fetal anomalies v6.21 MAPK1 Arina Puzriakova Mode of pathogenicity for gene MAPK1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added phenotypes Noonan syndrome 13 for gene: MAPK1
Publications for gene: MAPK1 were updated from 32721402 to 32721402; 40257485
Fetal anomalies v6.21 MAP3K3 Arina Puzriakova gene: MAP3K3 was added
gene: MAP3K3 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: MAP3K3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K3 were set to 25728774
Phenotypes for gene: MAP3K3 were set to Cerebral cavernous malformations 5
Fetal anomalies v6.21 MAN2B2 Arina Puzriakova gene: MAN2B2 was added
gene: MAN2B2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: MAN2B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B2 were set to 35637269; 31775018; 38622837
Phenotypes for gene: MAN2B2 were set to Congenital disorder of glycosylation type 1EE with or without immunodeficiency
Fetal anomalies v6.21 MAL Arina Puzriakova gene: MAL was added
gene: MAL was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to ?Leukodystrophy, hypomyelinating, 28
Mode of pathogenicity for gene: MAL was set to Other
Fetal anomalies v6.21 LSS Arina Puzriakova gene: LSS was added
gene: LSS was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 39359128
Phenotypes for gene: LSS were set to Cataract 44; Alopecia-intellectual disability syndrome 4
Fetal anomalies v6.21 LRRC8C Arina Puzriakova gene: LRRC8C was added
gene: LRRC8C was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome
Fetal anomalies v6.21 LIPN Arina Puzriakova Added phenotypes Ichthyosis, congenital, autosomal recessive 8 for gene: LIPN
Publications for gene: LIPN were updated from 21439540 to 21439540; 39891418
Fetal anomalies v6.21 LGI3 Arina Puzriakova gene: LGI3 was added
gene: LGI3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to 35948005
Phenotypes for gene: LGI3 were set to Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007
Fetal anomalies v6.21 LDB1 Arina Puzriakova gene: LDB1 was added
gene: LDB1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349
Fetal anomalies v6.21 LAGE3 Arina Puzriakova Added phenotypes Galloway-Mowat syndrome 2, X-linked for gene: LAGE3
Publications for gene: LAGE3 were updated from 31069511; 28805828 to 31069511; 28805828; 36682911
Fetal anomalies v6.21 KMT2E Arina Puzriakova Source Expert Review Amber was added to KMT2E.
Mode of inheritance for gene KMT2E was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes O'Donnell-Luria-Rodan syndrome for gene: KMT2E
Publications for gene: KMT2E were updated from to 40186013
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 C12orf66 Arina Puzriakova gene: C12orf66 was added
gene: C12orf66 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C12orf66 were set to 39824192
Phenotypes for gene: C12orf66 were set to Intellectual developmental disorder, autosomal recessive 83
Fetal anomalies v6.21 KDM6B Arina Puzriakova gene: KDM6B was added
gene: KDM6B was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: KDM6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM6B were set to 31124270; 37196654
Phenotypes for gene: KDM6B were set to Stolerman neurodevelopmental syndrome, OMIM:618505
Fetal anomalies v6.21 KDM1A Arina Puzriakova Added phenotypes Cleft palate, psychomotor retardation, and distinctive facial features for gene: KDM1A
Publications for gene: KDM1A were updated from 27094131; 24838796; 26656649 to 27094131; 24838796; 26656649
Fetal anomalies v6.21 KCNH2 Arina Puzriakova gene: KCNH2 was added
gene: KCNH2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: KCNH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNH2 were set to 36973673; 38094730; 39698424
Phenotypes for gene: KCNH2 were set to Short QT syndrome 1, OMIM:609620; Long QT syndrome 2, OMIM:613688
Fetal anomalies v6.21 KCNB1 Arina Puzriakova Source Expert Review Amber was added to KCNB1.
Mode of inheritance for gene KCNB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Developmental and epileptic encephalopathy 26 for gene: KCNB1
Publications for gene: KCNB1 were updated from to 36257979; 39237446; 31513310
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 KBTBD2 Arina Puzriakova gene: KBTBD2 was added
gene: KBTBD2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KBTBD2 were set to 39313616
Phenotypes for gene: KBTBD2 were set to Neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.21 KAT7 Arina Puzriakova gene: KAT7 was added
gene: KAT7 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: KAT7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KAT7 were set to 40186013
Phenotypes for gene: KAT7 were set to Abnormal male external genitalia morphology; Tetralogy of Fallot
Fetal anomalies v6.21 JPH1 Arina Puzriakova gene: JPH1 was added
gene: JPH1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy-25
Fetal anomalies v6.21 ITGAV Arina Puzriakova Added phenotypes Syndromic disease, MONDO:0002254 for gene: ITGAV
Fetal anomalies v6.21 IRF4 Arina Puzriakova gene: IRF4 was added
gene: IRF4 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: IRF4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: IRF4 were set to 36917008; 36662884; 29537367; 29408330
Phenotypes for gene: IRF4 were set to Immunodeficiency 131
Fetal anomalies v6.21 IFT27 Arina Puzriakova Added phenotypes Bardet-Biedl syndrome 19 for gene: IFT27
Publications for gene: IFT27 were updated from 25443296; 24488770; 26763875; 30761183 to 25443296; 37239474; 24488770; 30761183; 26763875; 2970430
Fetal anomalies v6.21 HNRNPU Arina Puzriakova Source Expert Review Amber was added to HNRNPU.
Mode of inheritance for gene HNRNPU was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Developmental and epileptic encephalopathy 54 for gene: HNRNPU
Publications for gene: HNRNPU were updated from to 39237446; 39965881; 35138025; 39976380
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 HIRA Arina Puzriakova gene: HIRA was added
gene: HIRA was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIRA were set to 33417013; 38511226
Phenotypes for gene: HIRA were set to Complex neurodevelopmental disorder
Fetal anomalies v6.21 HECTD1 Arina Puzriakova gene: HECTD1 was added
gene: HECTD1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: HECTD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: HECTD1 were set to 39879987; 38451291; 37165897
Phenotypes for gene: HECTD1 were set to Neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.21 HDAC3 Arina Puzriakova gene: HDAC3 was added
gene: HDAC3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: HDAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HDAC3 were set to 39047730
Phenotypes for gene: HDAC3 were set to HDAC3-related neurodevelopmental disorder
Fetal anomalies v6.21 GUK1 Arina Puzriakova gene: GUK1 was added
gene: GUK1 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GUK1 were set to 39230499
Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome 21
Fetal anomalies v6.21 GTPBP1 Arina Puzriakova Added phenotypes Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888 for gene: GTPBP1
Fetal anomalies v6.21 GNS Arina Puzriakova Added phenotypes Mucopolysaccharidosis type IIID, OMIM:252940 for gene: GNS
Fetal anomalies v6.21 GNPNAT1 Arina Puzriakova gene: GNPNAT1 was added
gene: GNPNAT1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNPNAT1 were set to 39945447
Phenotypes for gene: GNPNAT1 were set to Rhizomelic dysplasia, Ain-Naz type
Fetal anomalies v6.21 GNAI2 Arina Puzriakova gene: GNAI2 was added
gene: GNAI2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNAI2 were set to 39298586
Phenotypes for gene: GNAI2 were set to Syndromic developmental disorder
Fetal anomalies v6.21 GEMIN4 Arina Puzriakova gene: GEMIN4 was added
gene: GEMIN4 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: GEMIN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN4 were set to 39891418
Phenotypes for gene: GEMIN4 were set to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities
Fetal anomalies v6.21 GDAP1 Arina Puzriakova gene: GDAP1 was added
gene: GDAP1 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: GDAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GDAP1 were set to 39945447
Phenotypes for gene: GDAP1 were set to Charcot-Marie-Tooth disease, type 4A
Fetal anomalies v6.21 GATA5 Arina Puzriakova Mode of inheritance for gene GATA5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes Congenital heart defects, multiple types, 5 for gene: GATA5
Publications for gene: GATA5 were updated from 33082562 to 40076735; 33082562
Fetal anomalies v6.21 GALT Arina Puzriakova Source Expert Review Amber was added to GALT.
Added phenotypes Galactosemia for gene: GALT
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 G6PD Arina Puzriakova Source Expert Review Amber was added to G6PD.
Added phenotypes Glucose-6-phosphate dehydrogenase deficiency for gene: G6PD
Publications for gene: G6PD were updated from 33082562 to 39041728; 33082562
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 FLVCR1 Arina Puzriakova Added phenotypes Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060 for gene: FLVCR1
Fetal anomalies v6.21 FLII Arina Puzriakova gene: FLII was added
gene: FLII was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: FLII was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLII were set to 37561591; 32870709
Phenotypes for gene: FLII were set to Cardiomyopathy, dilated, 2J
Fetal anomalies v6.21 FGG Arina Puzriakova gene: FGG was added
gene: FGG was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: FGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGG were set to 39891418
Phenotypes for gene: FGG were set to Afibrinogenemia, congenital; Hypofibrinogenemia, congenital
Fetal anomalies v6.21 FBXW11 Arina Puzriakova Added phenotypes Neurodevelopmental, jaw, eye, and digital syndrome for gene: FBXW11
Publications for gene: FBXW11 were updated from 31402090 to 31402090; 40188065
Fetal anomalies v6.21 FBXO22 Arina Puzriakova gene: FBXO22 was added
gene: FBXO22 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: FBXO22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO22 were set to 40215970
Phenotypes for gene: FBXO22 were set to Tayoun-Maawali syndrome
Fetal anomalies v6.21 FAM177A1 Arina Puzriakova gene: FAM177A1 was added
gene: FAM177A1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: FAM177A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM177A1 were set to 38767059; 25558065
Phenotypes for gene: FAM177A1 were set to Neurodevelopmental disorder with white matter abnormalities and gait disturbance
Fetal anomalies v6.21 EXOSC8 Arina Puzriakova Added phenotypes Pontocerebellar hypoplasia type 1C for gene: EXOSC8
Publications for gene: EXOSC8 were updated from 24989451; 34210538 to 38017281; 34210538; 24989451
Fetal anomalies v6.21 EXOC6B Arina Puzriakova gene: EXOC6B was added
gene: EXOC6B was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: EXOC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC6B were set to 30284759; 36150098; 26669664
Phenotypes for gene: EXOC6B were set to Spondyloepimetaphyseal dysplasia with joint laxity, type 3
Fetal anomalies v6.21 ERG Arina Puzriakova gene: ERG was added
gene: ERG was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: ERG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERG were set to 36928819
Phenotypes for gene: ERG were set to Lymphatic malformation 14
Fetal anomalies v6.21 EFL1 Arina Puzriakova gene: EFL1 was added
gene: EFL1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: EFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFL1 were set to 28331068; 31151987; 34115847; 29970384
Phenotypes for gene: EFL1 were set to Shwachman-Diamond syndrome 2
Fetal anomalies v6.21 EEFSEC Arina Puzriakova gene: EEFSEC was added
gene: EEFSEC was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEFSEC were set to 39753114
Phenotypes for gene: EEFSEC were set to Neurodevelopmental disorder with progressive spasticity and brain abnormalities
Fetal anomalies v6.21 DVL2 Arina Puzriakova Mode of pathogenicity for gene DVL2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added phenotypes Robinow syndrome, MONDO:0019978 for gene: DVL2
Publications for gene: DVL2 were updated from 35047859; 33599851; 30521570 to 33599851; 30521570; 35047859
Fetal anomalies v6.21 DTNA Arina Puzriakova gene: DTNA was added
gene: DTNA was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: DTNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DTNA were set to 36799992
Phenotypes for gene: DTNA were set to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2
Fetal anomalies v6.21 DST Arina Puzriakova gene: DST was added
gene: DST was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to 37431644
Phenotypes for gene: DST were set to Arthrogryposis multiplex congenita
Fetal anomalies v6.21 DSE Arina Puzriakova gene: DSE was added
gene: DSE was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: DSE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DSE were set to 31655143; 25703627; 23704329; 32130795
Phenotypes for gene: DSE were set to Ehlers-Danlos syndrome, musculocontractural type 2
Fetal anomalies v6.21 DSC2 Arina Puzriakova gene: DSC2 was added
gene: DSC2 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: DSC2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DSC2 were set to 40188065
Phenotypes for gene: DSC2 were set to Arrhythmogenic right ventricular dysplasia, familial, 11
Fetal anomalies v6.21 DOHH Arina Puzriakova Added phenotypes Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, OMIM:620066 for gene: DOHH
Fetal anomalies v6.21 DNAJC21 Arina Puzriakova gene: DNAJC21 was added
gene: DNAJC21 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: DNAJC21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC21 were set to 29700810; 28062395; 27346687
Phenotypes for gene: DNAJC21 were set to Bone marrow failure syndrome 3
Fetal anomalies v6.21 DHX9 Arina Puzriakova gene: DHX9 was added
gene: DHX9 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX9 were set to 37369308; 37467750
Phenotypes for gene: DHX9 were set to Intellectual developmental disorder, autosomal dominant 75
Fetal anomalies v6.21 DHRSX Arina Puzriakova gene: DHRSX was added
gene: DHRSX was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: DHRSX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRSX were set to 38821050
Phenotypes for gene: DHRSX were set to Congenital disorder of glycosylation, type 1DD, OMIM:301133
Fetal anomalies v6.21 DDX17 Arina Puzriakova gene: DDX17 was added
gene: DDX17 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: DDX17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX17 were set to 39405200
Phenotypes for gene: DDX17 were set to Neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.21 DAND5 Arina Puzriakova gene: DAND5 was added
gene: DAND5 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: DAND5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAND5 were set to 36316122; 34215651
Phenotypes for gene: DAND5 were set to Heterotaxy, visceral, 13, autosomal
Fetal anomalies v6.21 CYP24A1 Arina Puzriakova gene: CYP24A1 was added
gene: CYP24A1 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: CYP24A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP24A1 were set to 28324001; 34307984; 22337913; 27105398
Phenotypes for gene: CYP24A1 were set to cystic kidney disease; hypercalcaemia; nephrocalcinosis
Fetal anomalies v6.21 COQ2 Arina Puzriakova Source Expert Review Amber was added to COQ2.
Added phenotypes Coenzyme Q10 deficiency, primary, 1 for gene: COQ2
Publications for gene: COQ2 were updated from to 39763161
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 COMP Arina Puzriakova Source Expert Review Amber was added to COMP.
Mode of inheritance for gene COMP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of pathogenicity for gene COMP was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added phenotypes Pseudoachondroplasia; Epiphyseal dysplasia, multiple, 1 for gene: COMP
Publications for gene: COMP were updated from to 39521787; 40188065
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 COL25A1 Arina Puzriakova Source Expert Review Amber was added to COL25A1.
Added phenotypes Arthrogryposis multiplex congenita for gene: COL25A1
Publications for gene: COL25A1 were updated from 26437029; 35077597 to 26437029; 40158061; 35077597
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 C1orf127 Arina Puzriakova Added phenotypes Heterotaxy, visceral, 14, autosomal for gene: C1orf127
Fetal anomalies v6.21 CHAF1A Arina Puzriakova gene: CHAF1A was added
gene: CHAF1A was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: CHAF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHAF1A were set to 39333427
Phenotypes for gene: CHAF1A were set to Oculo-auriculo-vertebral spectrum
Fetal anomalies v6.21 CFI Arina Puzriakova gene: CFI was added
gene: CFI was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: CFI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFI were set to 39891418
Phenotypes for gene: CFI were set to Complement factor I deficiency
Fetal anomalies v6.21 CELSR1 Arina Puzriakova Added phenotypes Lymphatic malformation-9 for gene: CELSR1
Publications for gene: CELSR1 were updated from 26855770; 31215153; 31403174 to 38272662; 31403174; 26855770; 31215153
Fetal anomalies v6.21 CDK5 Arina Puzriakova gene: CDK5 was added
gene: CDK5 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK5 were set to 25560765; 40186457
Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia
Fetal anomalies v6.21 CCT8 Arina Puzriakova gene: CCT8 was added
gene: CCT8 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: CCT8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCT8 were set to 39480921
Phenotypes for gene: CCT8 were set to CCT8-related neurodevelopmental disorder with brain abnormalities
Fetal anomalies v6.21 CCT6A Arina Puzriakova gene: CCT6A was added
gene: CCT6A was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: CCT6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCT6A were set to 39480921
Phenotypes for gene: CCT6A were set to CCT6A-related neurodevelopmental disorder with or without brain abnormalities
Fetal anomalies v6.21 CCT3 Arina Puzriakova gene: CCT3 was added
gene: CCT3 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: CCT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT3 were set to 39480921
Phenotypes for gene: CCT3 were set to Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination
Fetal anomalies v6.21 CTGF Arina Puzriakova gene: CTGF was added
gene: CTGF was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTGF were set to 39506047; 12736220; 39414788
Phenotypes for gene: CTGF were set to Kyphomelic dysplasia
Fetal anomalies v6.21 BRD2 Arina Puzriakova gene: BRD2 was added
gene: BRD2 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: BRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRD2 were set to 40186013
Phenotypes for gene: BRD2 were set to Agenesis of corpus callosum
Fetal anomalies v6.21 BORCS8 Arina Puzriakova gene: BORCS8 was added
gene: BORCS8 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS8 were set to 38128568
Phenotypes for gene: BORCS8 were set to Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities
Fetal anomalies v6.21 BICRA Arina Puzriakova gene: BICRA was added
gene: BICRA was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BICRA were set to 33232675
Phenotypes for gene: BICRA were set to Coffin-Siris syndrome 12
Fetal anomalies v6.21 BHLHE22 Arina Puzriakova gene: BHLHE22 was added
gene: BHLHE22 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Complex neurodevelopmental disorder
Fetal anomalies v6.21 BAIAP2 Arina Puzriakova gene: BAIAP2 was added
gene: BAIAP2 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAIAP2 were set to 38149472
Phenotypes for gene: BAIAP2 were set to Lissencephaly
Fetal anomalies v6.21 ASCC3 Arina Puzriakova Added phenotypes Intellectual developmental disorder, autosomal recessive 81, OMIM:620700 for gene: ASCC3
Fetal anomalies v6.21 ARPC5 Arina Puzriakova gene: ARPC5 was added
gene: ARPC5 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARPC5 were set to 37349293; 37382373
Phenotypes for gene: ARPC5 were set to Immunodeficiency 113 with autoimmunity and autoinflammation
Fetal anomalies v6.21 ARL6IP1 Arina Puzriakova gene: ARL6IP1 was added
gene: ARL6IP1 was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: ARL6IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL6IP1 were set to 39954331
Phenotypes for gene: ARL6IP1 were set to Spastic paraplegia 61, autosomal recessive, OMIM:615685
Fetal anomalies v6.21 ARL2BP Arina Puzriakova gene: ARL2BP was added
gene: ARL2BP was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: ARL2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL2BP were set to 27790702; 36507858; 23849777; 38649918; 40384762
Phenotypes for gene: ARL2BP were set to Situs Inversus
Fetal anomalies v6.21 AGT Arina Puzriakova Added phenotypes Renal tubular dysgenesis for gene: AGT
Publications for gene: AGT were updated from 16116425; 28976722; 33163725; 34234805 to 34234805; 28976722; 16116425; 39641285; 33163725
Fetal anomalies v6.21 AGRN Arina Puzriakova Source Expert Review Amber was added to AGRN.
Added phenotypes Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects for gene: AGRN
Publications for gene: AGRN were updated from 31730230; 39807604 to 31730230; 39807604
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Fetal anomalies v6.21 ACTN2 Arina Puzriakova gene: ACTN2 was added
gene: ACTN2 was added to Fetal anomalies. Sources: Expert Review Red
Mode of inheritance for gene: ACTN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTN2 were set to 39521787
Phenotypes for gene: ACTN2 were set to Cardiomyopathy, hypertrophic, 23, with or without LVNC; Cardiomyopathy, dilated, 1AA, with or without LVNC; Congenital myopathy 8
Fetal anomalies v6.21 ACO2 Arina Puzriakova Added phenotypes Infantile cerebellar-retinal degeneration for gene: ACO2
Publications for gene: ACO2 were updated from 34056600 to 34056600; 39891418
Paediatric or syndromic cardiomyopathy v7.74 TANGO2 Achchuthan Shanmugasundram Publications for gene: TANGO2 were set to 26805781; 30245509; 31339582; 32527145; 35568137; 40156300
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram edited their review of gene: TANGO2: Changed publications to: 26805781, 30245509, 31339582, 32527145, 35568137, 39472908, 40156300
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram changed review comment from: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature; to: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult patient with unspecified cardiomyopathy was identified with an intragenic homozygous deletion in TANGO2 gene via analysis of data from trio genome sequencing.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram changed review comment from: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature; to: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: TANGO2.
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram Classified gene: TANGO2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although cardiomyopathy was reported only in a very small proportion of patients with biallelic TANGO2 variants from earlier studies, 19 patients (70%) from the multi-centre study from PMID:35568137 and both unrelated patients from PMID:4015630 were reported with cardiomyopathy.

As there are over 20 patients reported with cardiomyopathy, this gene can be promoted to green rating on this panel in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram Gene: tango2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.72 TANGO2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM (MIM #616878, accessed on 05 September 2025) and Gene2Phenotype (TANGO2-related infancy-onset recurrent metabolic crises with encephalocardiomyopathy with 'definitive' rating on the DD panel).
Paediatric or syndromic cardiomyopathy v7.72 TANGO2 Achchuthan Shanmugasundram Phenotypes for gene: TANGO2 were changed from Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820 to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820
Cardiac arrhythmias - additional genes v3.7 TANGO2 Achchuthan Shanmugasundram Publications for gene: TANGO2 were set to 26805781; 26805782; 30245509; 31339582; 32929747
Cardiac arrhythmias - additional genes v3.6 TANGO2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are over 20 unrelated patients reported with biallelic TANGO2 variants and with cardiac arrhythmia as one of the clinical presentations of the TANGO2-related disorder.

Expert review is being sought on the promotion of this gene to green rating on this panel. This is due to this gene being not previously approved for promotion to green rating on this panel by the NHS Genomic Medicine Service.; to: Comment on list classification: There are over 30 unrelated patients reported with biallelic TANGO2 variants and with cardiac arrhythmia as one of the clinical presentations of the TANGO2-related disorder.

Expert review is being sought on the promotion of this gene to green rating on this panel. This is due to this gene being not previously approved for promotion to green rating on this panel by the NHS Genomic Medicine Service.
Cardiac arrhythmias - additional genes v3.6 TANGO2 Achchuthan Shanmugasundram edited their review of gene: TANGO2: Changed publications to: 26805781, 26805782, 30245509, 31339582, 32929747, 35568137, 40156300
Cardiac arrhythmias - additional genes v3.6 TANGO2 Achchuthan Shanmugasundram changed review comment from: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Life-threatening cardiac tachyarrhythmia presented as torsade de pointes or ventricular tachycardia in 4 of 12 patients.

PMID:26805782 (2016) reported the identification of three different biallelic truncating variants in TANGO2 genes in three unrelated patients with infantile-onset metabolic disorder characterised by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation.

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Arrhythmia was reported in five of 14 patients.

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). All, but one patient showed cardiac arrhythmias.

PMID:32929747 (2021) conducted a retrospective analysis of patients with a diagnosis of TANGO2 disease, where seven single nucleotide variants (five were novel), 2 small deletions and exons 3-9 deletion were identified in 20 patients from 14 families. 12 of these patients had cardiac abnormalities - long QT in ten, Brugada pattern in two, and cardiac arrhythmia in six.; to: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Life-threatening cardiac tachyarrhythmia presented as torsade de pointes or ventricular tachycardia in 4 of 12 patients.

PMID:26805782 (2016) reported the identification of three different biallelic truncating variants in TANGO2 genes in three unrelated patients with infantile-onset metabolic disorder characterised by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation.

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Arrhythmia was reported in five of 14 patients.

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). All, but one patient showed cardiac arrhythmias.

PMID:32929747 (2021) conducted a retrospective analysis of patients with a diagnosis of TANGO2 disease, where seven single nucleotide variants (five were novel), 2 small deletions and exons 3-9 deletion were identified in 20 patients from 14 families. 12 of these patients had cardiac abnormalities - long QT in ten, Brugada pattern in two, and cardiac arrhythmia in six.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Paediatric or syndromic cardiomyopathy v7.71 TANGO2 Achchuthan Shanmugasundram gene: TANGO2 was added
gene: TANGO2 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TANGO2 were set to 26805781; 30245509; 31339582; 32527145; 35568137; 40156300
Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820
Review for gene: TANGO2 was set to GREEN
Added comment: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature
Cardiac arrhythmias - additional genes v3.6 TANGO2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: TANGO2.
Tag Q3_25_expert_review tag was added to gene: TANGO2.
Cardiac arrhythmias - additional genes v3.6 TANGO2 Achchuthan Shanmugasundram Classified gene: TANGO2 as Amber List (moderate evidence)
Cardiac arrhythmias - additional genes v3.6 TANGO2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are over 20 unrelated patients reported with biallelic TANGO2 variants and with cardiac arrhythmia as one of the clinical presentations of the TANGO2-related disorder.

Expert review is being sought on the promotion of this gene to green rating on this panel. This is due to this gene being not previously approved for promotion to green rating on this panel by the NHS Genomic Medicine Service.
Cardiac arrhythmias - additional genes v3.6 TANGO2 Achchuthan Shanmugasundram Gene: tango2 has been classified as Amber List (Moderate Evidence).
Cardiac arrhythmias - additional genes v3.5 TANGO2 Achchuthan Shanmugasundram Publications for gene: TANGO2 were set to 26805782; 30245509
Cardiac arrhythmias - additional genes v3.4 TANGO2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM (MIM #616878, accessed on 05 September 2025) and Gene2Phenotype (TANGO2-related infancy-onset recurrent metabolic crises with encephalocardiomyopathy with 'definitive' rating on the DD panel).
Cardiac arrhythmias - additional genes v3.4 TANGO2 Achchuthan Shanmugasundram Phenotypes for gene: TANGO2 were changed from Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 616878 to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820
Cardiac arrhythmias - additional genes v3.3 TANGO2 Achchuthan Shanmugasundram reviewed gene: TANGO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26805781, 26805782, 30245509, 31339582, 32929747; Phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Acute rhabdomyolysis v2.3 POC5 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and sometimes accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.

This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and sometimes accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.
Acute rhabdomyolysis v2.3 POC5 Arina Puzriakova Entity copied from Rhabdomyolysis and metabolic muscle disorders v5.9
Acute rhabdomyolysis v2.3 POC5 Arina Puzriakova gene: POC5 was added
gene: POC5 was added to Acute rhabdomyolysis. Sources: Literature,Expert Review Amber
dd_review, Q3_25_promote_green tags were added to gene: POC5.
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 29272404; 40590205
Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology; muscle cramps
Rhabdomyolysis and metabolic muscle disorders v5.9 POC5 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.

This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and sometimes accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.

This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.
Rhabdomyolysis and metabolic muscle disorders v5.9 POC5 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (often triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.

This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.

This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.
Rhabdomyolysis and metabolic muscle disorders v5.9 POC5 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (often triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.

This disorder is also relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (often triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.

This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.
Rhabdomyolysis and metabolic muscle disorders v5.9 POC5 Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v5.9 POC5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (often triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.

This disorder is also relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.
Rhabdomyolysis and metabolic muscle disorders v5.9 POC5 Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v5.3 POC5 Arina Puzriakova changed review comment from: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature; to: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature
Lipodystrophy - childhood onset v4.62 POC5 Arina Puzriakova changed review comment from: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature; to: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature
Monogenic diabetes v3.3 POC5 Arina Puzriakova changed review comment from: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature; to: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature
Retinal disorders v8.23 POC5 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Rhabdomyolysis and metabolic muscle disorders v5.8 POC5 Arina Puzriakova gene: POC5 was added
gene: POC5 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
dd_review, Q3_25_promote_green tags were added to gene: POC5.
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 29272404; 40590205
Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology; muscle cramps
Review for gene: POC5 was set to GREEN
Added comment: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and neuromuscular abnormalities (10/12) primarily comprising intermittent, involuntary painful muscle cramps (8/12). Muscle cramps arose in childhood and were often disabling and difficult to treat. Elevated serum CK levels were noted in 4 individuals.

Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature
DDG2P v6.5 TNFRSF13B Arina Puzriakova Classified gene: TNFRSF13B as Green List (high evidence)
DDG2P v6.5 TNFRSF13B Arina Puzriakova Added comment: Comment on list classification: The content of this panel reflects genes and classifications assigned by Gene2Phenotype on their DDG2P panel. 'TNFRSF13B-related immunodeficiency, common variable' is currently classified as 'strong' (https://www.ebi.ac.uk/gene2phenotype/gene/TNFRSF13B) which maps to the PanelApp rating of Green - therefore this rating will be maintained on this panel.
DDG2P v6.5 TNFRSF13B Arina Puzriakova Gene: tnfrsf13b has been classified as Green List (High Evidence).
DDG2P v6.4 PDE1B Arina Puzriakova Classified gene: PDE1B as No list
DDG2P v6.4 PDE1B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support this gene disease association, however, the content of this panel reflects genes and classifications assigned by Gene2Phenotype (G2P) on their DDG2P panel. PDE1B is currently not associated with any disease models in G2P and therefore the grey rating will be maintained on this panel at this time.

PDE1B has already been curated on other GMS panels with a green recommendation (Childhood onset dystonia, chorea or related movement disorder and Ataxia and cerebellar anomalies) to capture the evidence and ensure inclusion of this gene in the NHS GMS.
DDG2P v6.4 PDE1B Arina Puzriakova Gene: pde1b has been removed from the panel.
Paediatric or syndromic cardiomyopathy v7.70 ATAD3A Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ATAD3A.
Paediatric or syndromic cardiomyopathy v7.70 ATAD3A Achchuthan Shanmugasundram Classified gene: ATAD3A as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.70 ATAD3A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in ATAD3A gene with syndromic cardiomyopathy.

Although the majority of the cases are reported with CNVs involving deletions or duplications of ATAD3 gene cluster (ATAD3A, ATAD3B & ATAD3C genes), there are also patients reported with small variants in monoallelic or biallelic states (as homozygous or as compound heterozygous with the CNV).

Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.70 ATAD3A Achchuthan Shanmugasundram Gene: atad3a has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.69 ATAD3A Achchuthan Shanmugasundram Tag cnv tag was added to gene: ATAD3A.
Paediatric or syndromic cardiomyopathy v7.69 ATAD3A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 02 September 2025.
Paediatric or syndromic cardiomyopathy v7.69 ATAD3A Achchuthan Shanmugasundram Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, OMIM:617183; Harel-Yoon syndrome, MONDO:0014958; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, MONDO:0032931 to Harel-Yoon syndrome, OMIM:617183; Harel-Yoon syndrome, MONDO:0014958; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, MONDO:0032931
Paediatric or syndromic cardiomyopathy v7.68 ATAD3A Achchuthan Shanmugasundram gene: ATAD3A was added
gene: ATAD3A was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307; 28549128; 31727539; 32004445; 33575671; 37095554
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, OMIM:617183; Harel-Yoon syndrome, MONDO:0014958; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, MONDO:0032931
Review for gene: ATAD3A was set to GREEN
Added comment: PMID:27640307 (2016) reported the identification of the same recurrent de novo ATAD3A variant (c.1582C>T/ p.Arg528Trp) in five unrelated individuals. Their clinical presentations included global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy (HCM). HCM was identified in two of five patients. This study also reported two additional families with biallelic ATAD3A variants - one family with homozygous c.158C>T/ p.Thr53Ile variant and the unrelated newborn with biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. The newborn with the deletion variants had mild RVH with septal hypertrophy.

PMID:28549128 (2017) reported five patients from four unrelated families with fatal congenital pontocerebellar hypoplasia and with large biallelic deletions that generate chimeric ATAD3B/ATAD3A fusion genes. Progressive cardiac hypertrophy was reported in one of five patients.

PMID:31727539 (2019) reported the identification of a novel homozygous missense variant in ATAD3A gene (c.1217 T > G/ p.Leu406Arg) in four siblings from a consanguineous family presenting with fatal neonatal cerebellar hypoplasia, seizures, axial hypotonia, HCM, hepatomegaly, congenital cataract, and dysmorphic facies. HCM was reported in all four patients.

PMID:32004445 (2020) reported five unrelated neonates with a heterozygous 67-kb duplication at 1p36.33 creating an in-frame ATAD3A–ATAD3C fusion gene. They presented with a disorder characterised by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures. HCM and DCM were reported in three and two patients respectively.

PMID:33575671 (2021) reported the investigation of 17 patients from 16 unrelated families, where six different de novo duplications in the ATAD3 gene locus (ATAD3A–ATAD3C fusion duplications) were reported. They presented with lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently corneal clouding or cataracts and encephalopathy.

PMID:37095554 (2023) reported four patients from two families with compound heterozygous c.229C>G (p.Leu77Val) variant and 3-4 exon deletion in ATAD3A gene. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. Two patients from one of these two families were reported with mild HCM.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which two paediatric patients with unspecified cardiomyopathy were identified with de novo heterozygous duplication in ATAD3 gene cluster via reanalysis of data from trio genome sequencing.

Both monoallelic and biallelic variants in ATAD3A gene have been reported with relevant phenotypes in both OMIM (MIM #617183) and Gene2Phenotype (definitive rating for monoallelic and strong rating for biallelic on the DD panel). Records from both resources include hypertrophic cardiomyopathy as part of the phenotype. This gene is also green on the 'Cardiomyopathy_Paediatric' panel on PanelApp Australia.
Sources: Literature
DDG2P v6.3 ELFN1 Arina Puzriakova Publications for gene: ELFN1 were set to 34509675
DDG2P v6.2 ELFN1 Arina Puzriakova Classified gene: ELFN1 as Red List (low evidence)
DDG2P v6.2 ELFN1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support this gene disease association, however, the content of this panel reflects genes and classifications assigned by Gene2Phenotype on their DDG2P panel. 'ELFN1-related intellectual disability and epilepsy' is currently classified as 'limited' (https://www.ebi.ac.uk/gene2phenotype/gene/ELFN1) which maps to the PanelApp rating of Red - therefore this rating will be maintained on this panel. This gene has been added to other GMS panels with a green recommendation (ID and epilepsy) to capture the evidence and ensure inclusion of ELFN1 in the NHS GMS.
DDG2P v6.2 ELFN1 Arina Puzriakova Gene: elfn1 has been classified as Red List (Low Evidence).
Intellectual disability v9.68 ELFN1 Arina Puzriakova Classified gene: ELFN1 as Amber List (moderate evidence)
Intellectual disability v9.68 ELFN1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v9.68 ELFN1 Arina Puzriakova Gene: elfn1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.25 ELFN1 Arina Puzriakova Classified gene: ELFN1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.25 ELFN1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Early onset or syndromic epilepsy v8.25 ELFN1 Arina Puzriakova Gene: elfn1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.24 ELFN1 Arina Puzriakova gene: ELFN1 was added
gene: ELFN1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: ELFN1.
Mode of inheritance for gene: ELFN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ELFN1 were set to 40576023; 34509675; 34452636
Phenotypes for gene: ELFN1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: ELFN1 was set to GREEN
Added comment: Total of 14 individuals from 7 unrelated families with biallelic loss of function variants in ELFN1 and a neurodevelopmental disorder comprising DD/ID ranging from moderate to severe (13/13) and epilepsy (12/13). Other features included dysmorphic features, behavioural disturbances, ADHD, ASD, hypotonia, muscle weakness, ataxia. Knockout and haploinsufficiency studies in mice resulted in detectable phenotypes compatible with ELFN1 deficiency disorder.
Sources: Literature
Intellectual disability v9.67 ELFN1 Arina Puzriakova gene: ELFN1 was added
gene: ELFN1 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: ELFN1.
Mode of inheritance for gene: ELFN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ELFN1 were set to 40576023; 34509675; 34452636
Phenotypes for gene: ELFN1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: ELFN1 was set to GREEN
Added comment: Total of 14 individuals from 7 unrelated families with biallelic loss of function variants in ELFN1 and a neurodevelopmental disorder comprising DD/ID ranging from moderate to severe (13/13) and epilepsy (12/13). Other features included dysmorphic features, behavioural disturbances, ADHD, ASD, hypotonia, muscle weakness, ataxia. Knockout and haploinsufficiency studies in mice resulted in detectable phenotypes compatible with ELFN1 deficiency disorder.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.67 FGFR3 Achchuthan Shanmugasundram Classified gene: FGFR3 as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v7.67 FGFR3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is no evidence directly linking FGFR3 variants to any cardiac phenotype except one patient reported from the reanalysis of the UK 100,000 genomes cohort. The phenotype was not fully explained by the genotype in this patient.

Hence, there is no reliable evidence for this association and the gene should be rated red.
Paediatric or syndromic cardiomyopathy v7.67 FGFR3 Achchuthan Shanmugasundram Gene: fgfr3 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v7.66 FGFR3 Achchuthan Shanmugasundram gene: FGFR3 was added
gene: FGFR3 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: FGFR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGFR3 were set to 39472908
Review for gene: FGFR3 was set to RED
Added comment: All reported FGFR3 variants cause skeletal or craniofacial syndromes (e.g. achondroplasia, thanatophoric dysplasia) and there are no reports of FGFR3 variants causing cardiomyopathy as a direct phenotype.

It is reported in Rare disease advisor (https://www.rarediseaseadvisor.com/disease-info-pages/achondroplasia-comorbidities/) that some children with achondroplasia (MIM #100800) develop hypertrophic cardiomyopathy or heart failure secondary to severe obstructive sleep apnea and obesity – but the FGFR3 variant itself only indirectly contributes via these complications . Lethal de novo FGFR3 variants cause perinatal dwarfism syndromes; affected infants die from respiratory insufficiency before cardiomyopathy could manifest, and no survivors with these variants have been reported to develop cardiomyopathy.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with dilated cardiomyopathy was identified with heterozygous missense variant in FGFR3 gene (c.667C>T/ p.Arg223Cys) via reanalysis of data from trio genome sequencing. This variant was reported as hot VUS and the publication states that the cardiomyopathy phenotype was not fully explained by the genotype.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.65 TKFC Achchuthan Shanmugasundram Classified gene: TKFC as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.65 TKFC Achchuthan Shanmugasundram Added comment: Comment on list classification: Three unrelated cases reported with TKFC variants (two missense and one nonsense) and cardiomyopathy. However, the phenotype did not completely segregate with variant in one family.

This gene should be rated amber with the current evidence. The 'watchlist' tag has been added to review the gene in future in light of new evidence.
Paediatric or syndromic cardiomyopathy v7.65 TKFC Achchuthan Shanmugasundram Gene: tkfc has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.64 TKFC Achchuthan Shanmugasundram gene: TKFC was added
gene: TKFC was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
watchlist tags were added to gene: TKFC.
Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TKFC were set to 32004446; 39251934; 39472908
Phenotypes for gene: TKFC were set to Triokinase and FMN cyclase deficiency syndrome, OMIM:618805; triokinase and FMN cyclase deficiency syndrome, MONDO:0032927; cardiomyopathy, MONDO:0004994
Review for gene: TKFC was set to AMBER
Added comment: PMID:32004446 (2020) reported four affected individuals from 2 consanguineous families with congenital cataracts, developmental delay, liver dysfunction and microcytic anaemia. One of the infants also had fatal dilated cardiomyopathy (DCM) and lactic acidosis following a febrile illness. Both families were identified with homozygous missense variants in TKFC gene, and c.1628G>T (p.Arg543Ile) variant was present in the infant with DCM.

PMID:39251934 (2024) reported two deceased neonate siblings presenting with oculocutaneous albinism type1 (OCA1). They had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy (HCM). Upon performing WES and segregation analysis, positive co-segregation of nonsense homozygous c.346C > T (p.Arg116Ter) variant in TYR gene and missense homozygous c.598G > A (p.Val200Ile) variant in TKFC gene were identified in the two affected patients.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with DCM was identified with homozygous missense variant in TKFC gene (c.1628G>T/ p.Arg543Ile) via reanalysis of data from trio genome sequencing. This variant is reported as likely pathogenic and the publication states that the phenotype is explained by the genotype.

This gene has been associated with Triokinase and FMN cyclase deficiency syndrome (MIM #618805) in OMIM (phenotype accessed in OMIM on 01 September 2025), which includes DCM as one of the clinical manifestations.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.63 TREX1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases reported with cardiomyopathy (one with fetal CM abdominal other being paediatric). The paediatric case was from the UK 100,000 genomes cohort and with a missense variant. In addition, there is functional evidence from knockout mouse model.

This gene should be rated amber with the current evidence. However, the 'watchlist' tag has been added to review this gene in the future in light of new evidence.; to: Comment on list classification: There are two unrelated cases reported with cardiomyopathy (one with fetal CM abdominal other being paediatric). The paediatric case was from the UK 100,000 genomes cohort and with a missense hot VUS variant. In addition, there is functional evidence from knockout mouse model.

This gene should be rated amber with the current evidence. However, the 'watchlist' tag has been added to review this gene in the future in light of new evidence.
Paediatric or syndromic cardiomyopathy v7.63 TREX1 Achchuthan Shanmugasundram Classified gene: TREX1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.63 TREX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases reported with cardiomyopathy (one with fetal CM abdominal other being paediatric). The paediatric case was from the UK 100,000 genomes cohort and with a missense variant. In addition, there is functional evidence from knockout mouse model.

This gene should be rated amber with the current evidence. However, the 'watchlist' tag has been added to review this gene in the future in light of new evidence.
Paediatric or syndromic cardiomyopathy v7.63 TREX1 Achchuthan Shanmugasundram Gene: trex1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.62 TREX1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 01 September 2025.
Paediatric or syndromic cardiomyopathy v7.62 TREX1 Achchuthan Shanmugasundram Phenotypes for gene: TREX1 were changed from Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750; Aicardi-Goutieres syndrome 1, MONDO:0009165 to Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750; Aicardi-Goutieres syndrome 1, MONDO:0009165; cardiomyopathy, MONDO:0004994
Paediatric or syndromic cardiomyopathy v7.61 TREX1 Achchuthan Shanmugasundram edited their review of gene: TREX1: Changed phenotypes to: Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750, Aicardi-Goutieres syndrome 1, MONDO:0009165, cardiomyopathy, MONDO:0004994
Paediatric or syndromic cardiomyopathy v7.61 TREX1 Achchuthan Shanmugasundram gene: TREX1 was added
gene: TREX1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
watchlist tags were added to gene: TREX1.
Mode of inheritance for gene: TREX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TREX1 were set to 15254239; 36581356; 39472908
Phenotypes for gene: TREX1 were set to Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750; Aicardi-Goutieres syndrome 1, MONDO:0009165
Review for gene: TREX1 was set to AMBER
Added comment: PMID:36581356 (2022) reported a case of fetal cardiomyopathy whose postnatal symptoms resembled TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes and syphilis) infection. The mother had a history of two lost pregnancies due to fetal cardiomyopathy and the same was identified in the current pregnancy. A homozygous single base pair insertion in exon 2 of the TREX1 gene (chr3:g.48466711_48466712insG/ p.Glu20GlyfsTer82) was identified in the neonate and the parents were positive for the same heterozygous pathological variant.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with unspecified cardiomyopathy was identified with homozygous missense variant in TREX1 gene (c.45C>G/ p.Ile15Met) via reanalysis of data from trio genome sequencing. This variant is reported to be a hot VUS in the publication, which also stated that the phenotype was explained by the genotype.

PMID:15254239 (2004) reported the generation of Trex1(-/-) null mice, which exhibited a dramatically reduced survival, and developed inflammatory myocarditis leading to progressive, often dilated cardiomyopathy and circulatory failure.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.60 KLHL24 Achchuthan Shanmugasundram changed review comment from: Monoallelic cases:
PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them.

PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen.

PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G).

PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members.

Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel).

Biallelic cases:
PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His).

PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) .

PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing.

Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP).
Sources: Literature; to: Monoallelic cases:
PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them.

PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen.

PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G).

PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members.

Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel).

Biallelic cases:
PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His).

PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) .

PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. This variant was reported as hot VUS in the publication

Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.60 KLHL24 Achchuthan Shanmugasundram Classified gene: KLHL24 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.60 KLHL24 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic KLHL24 variants with dilated cardiomyopathy/ hypertrophic cardiopmyopathy. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.60 KLHL24 Achchuthan Shanmugasundram Gene: klhl24 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.59 KLHL24 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: KLHL24.
Paediatric or syndromic cardiomyopathy v7.59 KLHL24 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 01 September 2025.
Paediatric or syndromic cardiomyopathy v7.59 KLHL24 Achchuthan Shanmugasundram Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372 to Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372
Paediatric or syndromic cardiomyopathy v7.58 KLHL24 Achchuthan Shanmugasundram Publications for gene: KLHL24 were set to 27889062; 29779254; 30120936; 31649980; 32870709; 35975634; 36672924; 3947290
Paediatric or syndromic cardiomyopathy v7.57 KLHL24 Achchuthan Shanmugasundram edited their review of gene: KLHL24: Changed publications to: 27889062, 29779254, 30120936, 31649980, 32870709, 35975634, 36672924, 39472908
Paediatric or syndromic cardiomyopathy v7.57 KLHL24 Achchuthan Shanmugasundram changed review comment from: Monoallelic cases:
PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them.

PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen.

PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G).

PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members.

Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel).

Biallelic cases:
PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His).

PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) .

PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing.

Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP).
Sources: Literature; to: Monoallelic cases:
PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them.

PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen.

PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G).

PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members.

Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel).

Biallelic cases:
PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His).

PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) .

PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing.

Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.57 KLHL24 Achchuthan Shanmugasundram gene: KLHL24 was added
gene: KLHL24 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: KLHL24 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KLHL24 were set to 27889062; 29779254; 30120936; 31649980; 32870709; 35975634; 36672924; 3947290
Phenotypes for gene: KLHL24 were set to Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372
Mode of pathogenicity for gene: KLHL24 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KLHL24 was set to GREEN
Added comment: Monoallelic cases:
PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them.

PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen.

PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G).

PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members.

Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel).

Biallelic cases:
PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His).

PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) .

PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing.

Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.56 SCN8A Achchuthan Shanmugasundram Classified gene: SCN8A as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v7.56 SCN8A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case available in support of the association of monoallelic SCN8A variants with cardiomyopathy from UK 100,000 genomes cohort. The cardiomyopathy phenotype is not explained by the genotype in this patient.

Hence, there is no reliable evidence for this association and this gene should be rated red on this panel.
Paediatric or syndromic cardiomyopathy v7.56 SCN8A Achchuthan Shanmugasundram Gene: scn8a has been classified as Red List (Low Evidence).
Primary lymphoedema v4.7 UNC45A Matthew Edwards gene: UNC45A was added
gene: UNC45A was added to Primary lymphoedema. Sources: Expert Review
Mode of inheritance for gene: UNC45A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45A were set to PMID: 37328071; PMID: 39887522
Phenotypes for gene: UNC45A were set to lymphedema in the lower and upper limbs; cholestasis; hyperbilirubinemia; increased concentrations of bile acids in blood
Penetrance for gene: UNC45A were set to unknown
Review for gene: UNC45A was set to GREEN
Added comment: Confirmed cause of Aagenaes syndrome/lymphedema cholestasis syndrome 1. 4. Primary lymphoedema may be presenting feature
Sources: Expert Review
Paediatric or syndromic cardiomyopathy v7.55 SCN8A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 01 September 2025.
Paediatric or syndromic cardiomyopathy v7.55 SCN8A Achchuthan Shanmugasundram Phenotypes for gene: SCN8A were changed from Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364 to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364
Paediatric or syndromic cardiomyopathy v7.54 SCN8A Achchuthan Shanmugasundram changed review comment from: SCN8A is a well-established gene for complex neurodevelopmental disorder including early-onset epilepsy and developmental impairments. SCN8A has been associated with relevant phenotypes in OMIM (MIMs #614306, #614558, #617080 & #618364), Gene2Phenotype (with 'definitive' rating on the DD panel) and ClinGen ('definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Epilepsy GCEP). There is significant evidence that SCN8A variants can lead to cardiac arrhythmias (e.g. bradycardia) during epileptic seizures and increase risk for Sudden Unexpected Death in Epilepsy.

However, there is no published evidence associating SCN8A variants to cardiomyopathy except for a single patient reported in PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous missense variant in SCN8A gene (c.3967G>A/ p.Ala1323Thr) via reanalysis of data from trio genome sequencing. This variant is reported to be likely pathogenic in the publication. However, the publication states that the cardiomyopathy phenotype is not explained by the genotype.

In addition, no cardiac presentations has been recorded as part of the OMIM phenotypes.
Sources: Literature; to: SCN8A is a well-established gene for complex neurodevelopmental disorder including early-onset epilepsy and developmental impairments. SCN8A has been associated with relevant phenotypes in OMIM (MIMs #614306, #614558, #617080 & #618364), Gene2Phenotype (with 'definitive' rating on the DD panel) and ClinGen ('definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Epilepsy GCEP). There is significant evidence that SCN8A variants can lead to cardiac arrhythmias (e.g. bradycardia) during epileptic seizures and increase risk for Sudden Unexpected Death in Epilepsy.

However, there is no published evidence associating SCN8A variants to cardiomyopathy except for a single patient reported in PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous missense variant in SCN8A gene (c.3967G>A/ p.Ala1323Thr) via reanalysis of data from trio genome sequencing. This variant is reported to be likely pathogenic in the publication. However, the publication states that the cardiomyopathy phenotype is not explained by the genotype.

In addition, no cardiac presentations have been recorded as clinical manifestations for the OMIM phenotypes.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.54 SCN8A Achchuthan Shanmugasundram gene: SCN8A was added
gene: SCN8A was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: SCN8A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN8A were set to 3947290
Phenotypes for gene: SCN8A were set to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364
Review for gene: SCN8A was set to RED
Added comment: SCN8A is a well-established gene for complex neurodevelopmental disorder including early-onset epilepsy and developmental impairments. SCN8A has been associated with relevant phenotypes in OMIM (MIMs #614306, #614558, #617080 & #618364), Gene2Phenotype (with 'definitive' rating on the DD panel) and ClinGen ('definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Epilepsy GCEP). There is significant evidence that SCN8A variants can lead to cardiac arrhythmias (e.g. bradycardia) during epileptic seizures and increase risk for Sudden Unexpected Death in Epilepsy.

However, there is no published evidence associating SCN8A variants to cardiomyopathy except for a single patient reported in PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous missense variant in SCN8A gene (c.3967G>A/ p.Ala1323Thr) via reanalysis of data from trio genome sequencing. This variant is reported to be likely pathogenic in the publication. However, the publication states that the cardiomyopathy phenotype is not explained by the genotype.

In addition, no cardiac presentations has been recorded as part of the OMIM phenotypes.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.53 NPHP3 Achchuthan Shanmugasundram Classified gene: NPHP3 as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v7.53 NPHP3 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is primarily associated with nephronophthisis in > 20 unrelated cases. There is only one patient reported with a NPHP3 synonymous variant from UK 100,000 genomes cohort and the phenotype was not explained by the variant.

Hence, this gene does not have any evidence of reliable association with cardiomyopathy and should be rated red.
Paediatric or syndromic cardiomyopathy v7.53 NPHP3 Achchuthan Shanmugasundram Gene: nphp3 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v7.52 NPHP3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 01 September 2025.
Paediatric or syndromic cardiomyopathy v7.52 NPHP3 Achchuthan Shanmugasundram Phenotypes for gene: NPHP3 were changed from Renal-hepatic-pancreatic dysplasia 1, OMIM:208540; Nephronophthisis 3, OMIM:604387; Meckel syndrome 7, OMIM:267010 to Renal-hepatic-pancreatic dysplasia 1, OMIM:208540; Nephronophthisis 3, OMIM:604387; Meckel syndrome 7, OMIM:267010
Paediatric or syndromic cardiomyopathy v7.51 NPHP3 Achchuthan Shanmugasundram gene: NPHP3 was added
gene: NPHP3 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: NPHP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPHP3 were set to 34212438; 39472908
Phenotypes for gene: NPHP3 were set to Renal-hepatic-pancreatic dysplasia 1, OMIM:208540; Nephronophthisis 3, OMIM:604387; Meckel syndrome 7, OMIM:267010
Review for gene: NPHP3 was set to RED
Added comment: There are >20 unrelated patients reported with biallelic variants in NPHP3 and with nephronophthisis. occasionally, patients have presented with extra-renal features, including rare congenital heart defects in a small number of cases. There are three OMIM phenotypes associated with this gene, of which Renal-hepatic-pancreatic dysplasia 1 (MIM #208540) had recorded atrial septal defect, aortic stenosis, or situs abnormalities as potential cardiovascular presentations.

The only patient that was reported with cardiomyopathy was from PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous synonymous variant in NPHP3 gene (c.2805C>T/ p.Gly935=) via reanalysis of data from duo genome sequencing. The publication states that the cardiomyopathy phenotype is not explained by the genotype.

This variant was previously reported to be responsible for hepatorenal fibrocystic disease from PMID:34212438 in five unrelated families. The two patients from the UK 100,000 genomes cohort reported in this publication also had valvular cardiopathy.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.50 JAK1 Achchuthan Shanmugasundram changed review comment from: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort. One of these patients with dilated cardiomyopathy was identified with de novo heterozygous missense variant in JAK1 gene (c.2666T>C/ p.Val889Ala) via reanalysis of data from trio genome sequencing, as this gene was not originally included in the panel. This variant was reported as a likely pathogenic in the publication.

PMID:40744288 (2025) reported a mouse model with cardiomyocyte-specific deletion of JAK1, where JAK1 loss in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. In addition, cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterised by substantial myocardial fibrosis.
Sources: Literature; to: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort. One of these patients with dilated cardiomyopathy was identified with de novo heterozygous missense variant in JAK1 gene (c.2666T>C/ p.Val889Ala) via reanalysis of data from trio genome sequencing, as this gene was not originally included in the panel. This variant was reported as likely pathogenic in the publication.

PMID:40744288 (2025) reported a mouse model with cardiomyocyte-specific deletion of JAK1, where JAK1 loss in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. In addition, cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterised by substantial myocardial fibrosis.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.50 JAK1 Achchuthan Shanmugasundram Classified gene: JAK1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.50 JAK1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Monoallelic variants in JAK1 gene are primarily associated with 'Autoinflammation, immune dysregulation, and eosinophilia' (MIM #618999, accessed on 01 September 2025).

However, there is only one case from the UK 100,000 genomes cohort and functional evidence from mouse models in support of the association of monoallelic variants in this gene with dilated cardiomyopathy. Hence, this gene can only be rated amber with the current evidence.
Paediatric or syndromic cardiomyopathy v7.50 JAK1 Achchuthan Shanmugasundram Gene: jak1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.49 JAK1 Achchuthan Shanmugasundram Deleted their comment
Paediatric or syndromic cardiomyopathy v7.49 JAK1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 01 September 2025.
Paediatric or syndromic cardiomyopathy v7.49 JAK1 Achchuthan Shanmugasundram Phenotypes for gene: JAK1 were changed from Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999; autoinflammation, immune dysregulation, and eosinophilia, MONDO:0033558; dilated cardiomyopathy, MONDO:0005021 to Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999; autoinflammation, immune dysregulation, and eosinophilia, MONDO:0033558; dilated cardiomyopathy, MONDO:0005021
Paediatric or syndromic cardiomyopathy v7.48 JAK1 Achchuthan Shanmugasundram gene: JAK1 was added
gene: JAK1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: JAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAK1 were set to 39472908; 40744288
Phenotypes for gene: JAK1 were set to Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999; autoinflammation, immune dysregulation, and eosinophilia, MONDO:0033558; dilated cardiomyopathy, MONDO:0005021
Review for gene: JAK1 was set to AMBER
Added comment: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort. One of these patients with dilated cardiomyopathy was identified with de novo heterozygous missense variant in JAK1 gene (c.2666T>C/ p.Val889Ala) via reanalysis of data from trio genome sequencing, as this gene was not originally included in the panel. This variant was reported as a likely pathogenic in the publication.

PMID:40744288 (2025) reported a mouse model with cardiomyocyte-specific deletion of JAK1, where JAK1 loss in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. In addition, cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterised by substantial myocardial fibrosis.
Sources: Literature
Intellectual disability v9.66 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, OMIM:252940 to Mucopolysaccharidosis type IIID, OMIM:252940
Likely inborn error of metabolism v8.56 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from MPS IIID, Sanfilippo D disease (Mucopolysaccharidoses); Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis Type III; Mucopolysaccharidosis, Type III to Mucopolysaccharidosis type IIID, OMIM:252940
Mucopolysaccharideosis, Gaucher, Fabry v1.4 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis, Type III; Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis Type III to Mucopolysaccharidosis type IIID, OMIM:252940
Skeletal dysplasia v8.7 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID 252940 to Mucopolysaccharidosis type IIID, OMIM:252940
Lysosomal storage disorder v3.4 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID 252940 to Mucopolysaccharidosis type IIID, OMIM:252940
Intellectual disability v9.65 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, 252940; MUCOPOLYSACCHARIDOSIS TYPE 3D (MPS3D) to Mucopolysaccharidosis type IIID, OMIM:252940
Undiagnosed metabolic disorders v1.631 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from MPS IIID, Sanfilippo D disease (Mucopolysaccharidoses); Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis, Type III; Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis Type III to Mucopolysaccharidosis type IIID, OMIM:252940
Fetal anomalies v6.20 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from MUCOPOLYSACCHARIDOSIS TYPE 3D to Mucopolysaccharidosis type IIID, OMIM:252940
Paediatric or syndromic cardiomyopathy v7.47 GNS Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis, Type III; MPS IIID, Sanfilippo D disease (Mucopolysaccharidoses); Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis Type III to Mucopolysaccharidosis type IIID, OMIM:252940
Paediatric or syndromic cardiomyopathy v7.46 NF1 Achchuthan Shanmugasundram Classified gene: NF1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.46 NF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with monoallelic NF1 gene deletions and hypertrophic cardiomyopathy. In addition, three patients were reported with monoallelic NF1 small variants and cardiomyopathy.

Hence, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.46 NF1 Achchuthan Shanmugasundram Gene: nf1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.45 NF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NF1.
Paediatric or syndromic cardiomyopathy v7.45 NF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 29 August 2025.
Paediatric or syndromic cardiomyopathy v7.45 NF1 Achchuthan Shanmugasundram Phenotypes for gene: NF1 were changed from Neurofibromatosis, type 1 162200; Noonan syndrome; Neurofibromatosis syndrome 1; Neurofibromatosis-Noonan syndrome 601321; Neurofibromatosis Noonan syndrome; Neurofibromatosis-Noonan Syndrome to Neurofibromatosis, type 1, OMIM:162200; Neurofibromatosis, familial spinal, OMIM:162210; Neurofibromatosis-Noonan syndrome, OMIM:601321; Watson syndrome, OMIM:193520; cardiomyopathy, MONDO:0004994
Paediatric or syndromic cardiomyopathy v7.44 NF1 Achchuthan Shanmugasundram edited their review of gene: NF1: Changed phenotypes to: Neurofibromatosis, type 1, OMIM:162200, Neurofibromatosis, familial spinal, OMIM:162210, Neurofibromatosis-Noonan syndrome, OMIM:601321, Watson syndrome, OMIM:193520, cardiomyopathy, MONDO:0004994
Paediatric or syndromic cardiomyopathy v7.44 NF1 Achchuthan Shanmugasundram Publications for gene: NF1 were set to 12707950; 16380919; 19845691
Paediatric or syndromic cardiomyopathy v7.43 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278345, 30919579, 38654147, 39472908; Phenotypes: Neurofibromatosis, type 1, OMIM:162200, neurofibromatosis type 1, MONDO:0018975, cardiomyopathy, MONDO:0004994; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v7.43 NAA15 Achchuthan Shanmugasundram changed review comment from: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous frameshift variant in NAA15 gene (c.174_177del/ p.Arg313Pro & c.1232C>T/ p.Cys58TrpfsTer15). Only the patient genome was sequenced.; to: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous frameshift variant in NAA15 gene (c.174_177del/ p.Cys58TrpfsTer15). Only the patient genome was sequenced.
Paediatric or syndromic cardiomyopathy v7.43 NAA15 Achchuthan Shanmugasundram Classified gene: NAA15 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.43 NAA15 Achchuthan Shanmugasundram Added comment: Comment on list classification: The majority of the cases reported with heterozygous NAA15 variants do not present with cardiomyopathy, while a significant proportion of cases had congenital cardiac defects.

There were >50 cases reported in total. However, only three unrelated cases were reported with cardiomyopathy (two frameshift variants and one missense variant), of which one of the cases were from the UK 100,000 genomes project cohort.

Hence, this gene should remain as amber. The 'watchlist' tag has been added to review new evidence in the future.
Paediatric or syndromic cardiomyopathy v7.43 NAA15 Achchuthan Shanmugasundram Gene: naa15 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.42 NAA15 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 August 2025.
Paediatric or syndromic cardiomyopathy v7.42 NAA15 Achchuthan Shanmugasundram Phenotypes for gene: NAA15 were changed from hypertrophic cardiomyopathy, MONDO:0005045 to Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities, OMIM:617787; hypertrophic cardiomyopathy, MONDO:0005045
Paediatric or syndromic cardiomyopathy v7.41 NAA15 Achchuthan Shanmugasundram Publications for gene: NAA15 were set to 33103328
Paediatric or syndromic cardiomyopathy v7.40 NAA15 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: NAA15.
Paediatric or syndromic cardiomyopathy v7.40 NAA15 Achchuthan Shanmugasundram edited their review of gene: NAA15: Added comment: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous frameshift variant in NAA15 gene (c.174_177del/ p.Arg313Pro & c.1232C>T/ p.Cys58TrpfsTer15). Only the patient genome was sequenced.; Changed publications to: 33103328, 39472908
Paediatric or syndromic cardiomyopathy v7.40 NAA15 Achchuthan Shanmugasundram changed review comment from: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated cases reported with paediatric hypertrophic cardiomyopathy.

PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively.

Although none of the patients reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects.

Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).; to: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated cases reported with paediatric hypertrophic cardiomyopathy.

PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively.

Although none of the patients were reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects.

Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).
Paediatric or syndromic cardiomyopathy v7.40 NAA15 Achchuthan Shanmugasundram changed review comment from: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated c cases reported with paediatric hypertrophic cardiomyopathy.

PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively.

Although none of the patients reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects.

Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).; to: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated cases reported with paediatric hypertrophic cardiomyopathy.

PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively.

Although none of the patients reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects.

Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.13 GUK1 Arina Puzriakova Tag Q3_25_NHS_review was removed from gene: GUK1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.13 GUK1 Arina Puzriakova Entity copied from Mitochondrial disorders v9.26
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.13 GUK1 Arina Puzriakova gene: GUK1 was added
gene: GUK1 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature,Expert Review Amber
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: GUK1.
Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GUK1 were set to 39230499
Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome 21, OMIM:621071
Mitochondrial disorders v9.26 GUK1 Arina Puzriakova Classified gene: GUK1 as Amber List (moderate evidence)
Mitochondrial disorders v9.26 GUK1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 4 individuals from 3 unrelated families with biallelic variants leading to GUK1 deficiency. Muscle biopsies showed mtDNA depletion and/or deletions and reduced activities of mitochondrial respiratory chain enzymes.
Mitochondrial disorders v9.26 GUK1 Arina Puzriakova Gene: guk1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.25 GUK1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: GUK1.
Tag Q3_25_NHS_review tag was added to gene: GUK1.
Mitochondrial disorders v9.25 GUK1 Arina Puzriakova Publications for gene: GUK1 were set to PMID: 39230499
Mitochondrial disorders v9.24 GUK1 Arina Puzriakova Phenotypes for gene: GUK1 were changed from Mitochondrial DNA depletion syndrome 21 to Mitochondrial DNA depletion syndrome 21, OMIM:621071
Primary immunodeficiency or monogenic inflammatory bowel disease v8.41 EFL1 Arina Puzriakova Phenotypes for gene: EFL1 were changed from Shwachman-Diamond syndrome 2, MIM# 617941 to Shwachman-Diamond syndrome 2, OMIM:617941
Cytopenia - NOT Fanconi anaemia v4.22 EFL1 Arina Puzriakova Phenotypes for gene: EFL1 were changed from Shwachman-Diamond syndrome 2, 617941; 617941 Shwachman-Diamond syndrome 2 to Shwachman-Diamond syndrome 2, OMIM:617941
Paediatric or syndromic cardiomyopathy v7.40 MTO1 Achchuthan Shanmugasundram Classified gene: MTO1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.40 MTO1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are > 30 cases reported with biallelic MTO1 variants and hypertrophic cardiomyopathy as one of the hallmark presentations. Hence, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.40 MTO1 Achchuthan Shanmugasundram Gene: mto1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.39 MTO1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: MTO1.
Paediatric or syndromic cardiomyopathy v7.39 MTO1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM (MIM #614702) and Gene2Phenotype (with 'definitive' rating on the DD panel). OMIM phenotype was accessed on 29 August 2025.
Paediatric or syndromic cardiomyopathy v7.39 MTO1 Achchuthan Shanmugasundram Phenotypes for gene: MTO1 were changed from Combined oxidative phosphorylation deficiency 10, OMIM:614702; mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, MONDO:0013865 to Combined oxidative phosphorylation deficiency 10, OMIM:614702; mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, MONDO:0013865
Paediatric or syndromic cardiomyopathy v7.38 MTO1 Achchuthan Shanmugasundram gene: MTO1 was added
gene: MTO1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: MTO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTO1 were set to 22608499; 23929671; 34547275; 34990597; 39472908
Phenotypes for gene: MTO1 were set to Combined oxidative phosphorylation deficiency 10, OMIM:614702; mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, MONDO:0013865
Review for gene: MTO1 was set to GREEN
Added comment: PMID:22608499 (2012) reported two infant siblings and an unrelated child of Italian descent with hypertrophic cardiomyopathy and neonatal lactic acidosis. The siblings died early in their life (when 19 days and 40 days old). The affected siblings were identified with compound heterozygous variants in MTO1 gene – a maternal frameshift variant (c.1858dup/ p.Arg620Lysfs(∗)8) and a paternal missense variant (c.1282G>A/ p.Ala428Thr). The unrelated patient was homozygous for the same missense variant (c.1282G>A).

PMID:23929671 (2013) reported five additional patients from three unrelated families, who also presented with hypertrophic cardiomyopathy and lactic acidosis, in addition to other variable phenotypes including psychomotor delay, hypotonia, feeding difficulties and respiratory illness. The two sibling pairs were identified with homozygous missense variants (c.1232C>T/ p.Thr411Ile), while the unrelated patient was reported with compound heterozygous missense variants (c.1402G>A/ p.Ala428Thr & c.1430G>A/ p.Arg477His).

PMID:34547275 (2021) reported the identification of compound heterozygous variants in MTO1 gene in a Chinese patient with complex oxidative phosphorylation deficiency type 10 (COXPD10). This patient had lactic acidosis and cardia abnormalities such as myocarditis and tachycardia, but not hypertrophic cardiomyopathy. The identified variants are c.344delA (p.Asn115Thrfs*11, frameshift) and c.1055C>T (p.Thr352Met, missense).

PMID:34990597 (2022) reported a patient with COXPD10 presenting with multiple organ failure, severe pneumonia, sepsis, hyperlactatemia, metabolic acidosis, and moderate anaemia. The patient was identified with compound heterozygous variants in MTO1 gene (c.1291C > T/ p.Arg431Trp and c.1390C > T/ p.Arg464Cys). The patient also showed HCM. This study also reviewed previously published cases of confirmed MTO1 deficiency. Of 42 total cases including the patient reported in this study, 32 patients were reported with HCM and one additional patient was reported with dilated cardiomyopathy.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient with unspecified cardiomyopathy was identified with compound heterozygous missense variants in MTO1 gene (c.938G>C/ p.Arg313Pro & c.1232C>T/ p.Thr411Ile).

There is also functional evidence available in support of the disease association.
Sources: Literature
Arthrogryposis v9.7 AGRN Arina Puzriakova Classified gene: AGRN as Amber List (moderate evidence)
Arthrogryposis v9.7 AGRN Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber as two families have now been identified with FADS which presents with multiple joint contractures (PMID: 31730230; 39807604)
Arthrogryposis v9.7 AGRN Arina Puzriakova Gene: agrn has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.19 AGRN Arina Puzriakova Publications for gene: AGRN were set to 31730230
Arthrogryposis v9.6 AGRN Arina Puzriakova Publications for gene: AGRN were set to 31730230
Fetal anomalies v6.18 AGRN Arina Puzriakova Phenotypes for gene: AGRN were changed from Fetal akinesia deformation sequence (FADS) to Fetal akinesia deformation sequence, MONDO:0008824
Arthrogryposis v9.5 AGRN Arina Puzriakova Phenotypes for gene: AGRN were changed from Fetal akinesia deformation sequence (FADS) to Fetal akinesia deformation sequence, MONDO:0008824
Arthrogryposis v9.4 AGRN Arina Puzriakova edited their review of gene: AGRN: Added comment: PMID: 39807604 (2025) - biallelic null variants in AGRN leading to a fetal akinesia deformation sequence (FADS) identified in a second family affecting three pregnancies. WES revealed a maternally inherited heterozygous variant c.952+1_952+3del and split-read analysis identified a paternally inherited heterozygous 41.33 kb deletion, encompassing exons 1 and 2 of AGRN.; Changed publications to: 31730230, 39807604; Changed phenotypes to: Fetal akinesia deformation sequence, MONDO:0008824
Retinal disorders v8.23 SPG11 Achchuthan Shanmugasundram Classified gene: SPG11 as Amber List (moderate evidence)
Retinal disorders v8.23 SPG11 Achchuthan Shanmugasundram Gene: spg11 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.22 SPG11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 August 2025.
Retinal disorders v8.22 SPG11 Achchuthan Shanmugasundram Phenotypes for gene: SPG11 were changed from Retinal dystrophy; spastic paraplegia to Spastic paraplegia 11, autosomal recessive, OMIM:604360; retinal disorder, MONDO:0005283
Retinal disorders v8.21 SPG11 Achchuthan Shanmugasundram Publications for gene: SPG11 were set to PMID: 19194956, 36343909, 38613257,21035867
Retinal disorders v8.20 SPG11 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SPG11.
Tag Q3_25_NHS_review tag was added to gene: SPG11.
Retinal disorders v8.20 DYRK1A Achchuthan Shanmugasundram Classified gene: DYRK1A as Amber List (moderate evidence)
Retinal disorders v8.20 DYRK1A Achchuthan Shanmugasundram Gene: dyrk1a has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.19 DYRK1A Achchuthan Shanmugasundram Tag Q3_25_NHS_review tag was added to gene: DYRK1A.
Retinal disorders v8.19 DYRK1A Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: DYRK1A.
Retinal disorders v8.19 DYRK1A Achchuthan Shanmugasundram Phenotypes for gene: DYRK1A were changed from FEVR to Intellectual developmental disorder, autosomal dominant 7, OMIM:614104; Retinal disorder, MONDO:0005283
Retinal disorders v8.18 DYRK1A Achchuthan Shanmugasundram Publications for gene: DYRK1A were set to PMID: 40405340; 36736451
Neurological ciliopathies v6.1 EVC2 Ida Ertmanska commented on gene: EVC2: Comment on mode of inheritance: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
Neurological ciliopathies v6.1 EVC2 Ida Ertmanska reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38531627, 23220543, 19810119, 16404586; Phenotypes: Weyers acrofacial dysostosis, OMIM:193530, acrofacial dysostosis, Weyers type, MONDO:0008673; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal ciliopathies v6.1 EVC2 Ida Ertmanska commented on gene: EVC2: Comment on mode of inheritance: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
Retinal disorders v8.17 CFI Achchuthan Shanmugasundram Classified gene: CFI as Red List (low evidence)
Retinal disorders v8.17 CFI Achchuthan Shanmugasundram Gene: cfi has been classified as Red List (Low Evidence).
Skeletal ciliopathies v6.1 EVC2 Ida Ertmanska reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38531627, 23220543, 19810119, 16404586; Phenotypes: Weyers acrofacial dysostosis, OMIM:193530, acrofacial dysostosis, Weyers type, MONDO:0008673; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v8.16 CFI Achchuthan Shanmugasundram Publications for gene: CFI were set to
Retinal disorders v8.15 CFI Achchuthan Shanmugasundram Phenotypes for gene: CFI were changed from Early Onset Drsen Maculopathy to Macular degeneration, age related, 13, susceptibility to, OMIM:615439; retinal disorder, MONDO:0005283
Skeletal dysplasia v8.6 EVC2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.; to: Comment on mode of inheritance: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
Fetal anomalies v6.17 EVC2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.; to: Comment on mode of inheritance: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
Fetal anomalies v6.17 EVC2 Ida Ertmanska commented on gene: EVC2: Comment on list classification: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
Fetal anomalies v6.17 EVC2 Ida Ertmanska reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38531627, 23220543, 19810119, 16404586; Phenotypes: Weyers acrofacial dysostosis, OMIM:193530, acrofacial dysostosis, Weyers type, MONDO:0008673; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.17 ACO2 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BIALLELIC, autosomal or pseudoautosomal' as isolated optic atrophy caused by heterozygous variants in this gene is not relevant to the fetal panel. Extraocular features are rare in dominant cases (11%) and would also not be relevant to this panel (e.g. hearing loss, ataxia, nystagmus, metabolic dysfunction) (PMID: 34056600)
Fetal anomalies v6.17 ACO2 Arina Puzriakova Mode of inheritance for gene: ACO2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.16 ACO2 Arina Puzriakova Phenotypes for gene: ACO2 were changed from INFANTILE CEREBELLAR-RETINAL DEGENERATION to Infantile cerebellar-retinal degeneration, OMIM:614559
Skeletal dysplasia v8.6 EVC2 Ida Ertmanska commented on gene: EVC2: Comment on list classification: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
Skeletal dysplasia v8.6 EVC2 Ida Ertmanska reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38531627, 23220543, 19810119, 16404586; Phenotypes: Weyers acrofacial dysostosis, OMIM:193530, acrofacial dysostosis, Weyers type, MONDO:0008673; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v8.14 DYRK1A Ida Ertmanska commented on gene: DYRK1A: Comment on list classification: DYRK1A syndrome patients may present with vision abnormalities, including retinal involvement. There is sufficient evidence available (4 unrelated patients with a retinal phenotype) for the association of monoallelic DYRK1A variants with retinal disorders, which fits into the scope of this panel. Hence, this gene can be promoted to green rating in the next GMS update.
Retinal disorders v8.14 DYRK1A Ida Ertmanska reviewed gene: DYRK1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33159716, 36736451, 40405340, 19081073; Phenotypes: Intellectual developmental disorder, autosomal dominant 7, OMIM:614104, Retinal disorder, MONDO:0005283; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.14 SPG11 Ida Ertmanska reviewed gene: SPG11: Rating: GREEN; Mode of pathogenicity: None; Publications: 19194956, 36343909, 38613257, 39391989; Phenotypes: Spastic paraplegia 11, autosomal recessive, OMIM:604360, retinal disorder, MONDO:0005283; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.14 CFI Ida Ertmanska commented on gene: CFI: Comment on list classification: Macular degeneration was reported in two Tunisian patients, heterozygous for a CFI variant. The reported variant is also common in healthy Tunisian controls. Hence, the gene can only be rated as Red with the current evidence.
Retinal disorders v8.14 CFI Ida Ertmanska changed review comment from: PMID: 25986072 – Two families with carriers of CFI:c.1234G>A p.(Val412Met). 24yo heterozygous carrier Fam3-01 displayed early-onset drusen maculopathy. Individual Fam1-01, 68yo, had advanced age-related macular degeneration – time of onset unknown. 10/200 unrelated Tunisian Jewish controls were reported to carry for the variant (5% allele freq) - too high to cause the disorder. The variant is also present in gnomAD v4.1.0: highest allele freq = 0.0004954 (Middle Eastern population; no homozygotes).
OMIM reports a gene association with disease susceptibility (OMIM:615439 Macular degeneration, age related, 13, susceptibility to; accessed 20th Aug 2025).; to: PMID: 25986072 – Two families with carriers of CFI:c.1234G>A p.(Val412Met). 24yo heterozygous carrier Fam3-01 displayed early-onset drusen maculopathy. Individual Fam1-01, 68yo, had advanced age-related macular degeneration – time of onset unknown. 10/200 unrelated Tunisian Jewish controls were reported to carry for the variant (5% allele freq) - too high to cause the disorder. The variant is also present in gnomAD v4.1.0: highest allele freq = 0.0004954 (Middle Eastern population; no homozygotes).
OMIM reports a gene association with disease susceptibility (OMIM:615439 Macular degeneration, age related, 13, susceptibility to; accessed 20th Aug 2025).
Retinal disorders v8.14 CFI Ida Ertmanska reviewed gene: CFI: Rating: RED; Mode of pathogenicity: None; Publications: 25986072; Phenotypes: Macular degeneration, age related, 13, susceptibility to, OMIM:615439, retinal disorder, MONDO:0005283; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.14 CFI Ida Ertmanska Deleted their review
Retinal disorders v8.14 CFI Ida Ertmanska reviewed gene: CFI: Rating: RED; Mode of pathogenicity: None; Publications: 25986072; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v7.37 NEB Achchuthan Shanmugasundram Classified gene: NEB as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v7.37 NEB Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only patient reported in a large cohort study (UK 100,000 genomes project) with unspecified cardiomyopathy and homozygous NEB variant. No further phenotypic information was reported in the publication (PMID:39472908).

All other reported cases did not have confirmed cardiomyopathy (despite some cardiac involvement in a few cases) or had Nemaline myopathy and cardiomyopathy with variants in other genes (e.g. ACTA1).

There is no functional evidence to suggest the association of NEB with cardiomyopathy.

Hence, this gene should be rated red.
Paediatric or syndromic cardiomyopathy v7.37 NEB Achchuthan Shanmugasundram Gene: neb has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v7.36 NEB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 28 August 2025.
Paediatric or syndromic cardiomyopathy v7.36 NEB Achchuthan Shanmugasundram Phenotypes for gene: NEB were changed from Nemaline myopathy 2, autosomal recessive, OMIM:256030 to Nemaline myopathy 2, autosomal recessive, OMIM:256030
Paediatric or syndromic cardiomyopathy v7.35 NEB Achchuthan Shanmugasundram gene: NEB was added
gene: NEB was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: NEB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEB were set to 23650303; 26321576; 28131200; 29070751; 29070751; 39472908
Phenotypes for gene: NEB were set to Nemaline myopathy 2, autosomal recessive, OMIM:256030
Review for gene: NEB was set to RED
Added comment: Biallelic variants in NEB are reported to cause Nemaline myopathy 2 (MIM #256030), which is a skeletal muscle disorder with a wide range of severity and age-of-onset. The most common clinical presentation is early-onset (in infancy or childhood) muscle weakness predominantly affecting proximal limb muscles. The OMIM record (MIM #256030) does not list any cardiac presentations as part of the phenotype.

Cardiac involvement has only been reported in very few cases with NEB-related nemaline myopathy in the literature. However, there is no evidence available to suggest that these patients presented with cardiomyopathy (PMIDs: 28131200 (2016); 29070751 (2017, Article in Japanese); 29070751 (2020).

Although a 9-year-old male patient with nemaline myopathy with dilated cardiomyopathy reported in PMID:23650303 (2013), the patient harboured a novel heterozygous ACTA1 variant, which is causative of the disease.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one male patient with unspecified cardiomyopathy was identified with a homozygous splice donor variant in NEB gene (c.2415+1G>A). However, no further information on patient phenotypes was provided in the patient.

Nebulin is primarily expressed in skeletal muscles and expressed at very low levels in heart. In addition, no cardiac phenotype was reported in NEB knockout mouse models (PMID: 26321576, 2015), suggesting that the any cardiac failure in patients with NEB-related Nemaline myopathy may be secondary to respiratory failure.
Sources: Literature
Rare genetic inflammatory skin disorders v4.1 FECH Sharon Whatley gene: FECH was added
gene: FECH was added to Rare genetic inflammatory skin disorders. Sources: Literature
Mode of inheritance for gene: FECH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FECH were set to 7857832; 16911284; 39969427; 32873934; 38940544; 11753383; 16385445
Phenotypes for gene: FECH were set to 177000
Penetrance for gene: FECH were set to Complete
Review for gene: FECH was set to GREEN
Added comment: Relevant metabolic investigation: Erythrocyte metal free protoporphyrin

PMID: 7857832 Todd reports that erythropoietic protoporphyria (EPP) is a rare disorder caused by the partial deficiency of ferrochelatase, the terminal enzyme of haem biosynthesis that is coded by the FECH gene. This results in an increase in protoporphyrin IX that is released from erythroid cells into the vascular endothelium and surrounding tissues. It is activated by visible light, triggering oxidative stress and inflammation. Affected patients usually present with episodes of severe phototoxic pain in light exposed skin.

PMID: 16911284 Holme found the median age of presentation to be less than one year of age although diagnosis was delayed until a median age of 12 years. Infants are extremely sensitive to sunlight, experiencing pain, burning, and swelling of the skin and may present with crying or screaming after being exposed. This acute photosensitivity of sun exposed areas is lifelong.

PMID: 39969427 Levy reported that the accumulation of protoporphyrin in the liver caused cholestatic liver injury in 3.4% of 322 patients with EPP and progressed to severe liver failure in 2.5%.

PMID: 32873934 Dickey reports the EPP prevalence to be 0.0059% (~1 in 17,000) from the UK biobank and suggests that the disorder is underreported. Among more than 155 family cohorts of EPP patients that have been published in the literature, no occurrence of a nonpenetrant disease-associated genotype has been reported. It is therefore assumed that EPP is fully penetrant.

PMID: 38940544 Aarsand reports that the genetics of EPP is complex with ~5% of cases of unknown genomic pathology. There are several different known genetic mechanisms that cause the EPP phenotype including defects in other genes such as ALAS2 found in 2-10% of EPP patients and ALAS2 together with CLPX identified in one patient. Rarely EPP can develop in later life due to genomic instability affecting the FECH gene in myelodysplastic syndromes. Approximately 4% of EPP patients have biallelic pathogenic variants in the FECH gene while most EPP cases are due to a pathogenic FECH variant trans to an intronic variant (c.315-48T>C) that causes low expression of that allele.

PMID: 11753383 Gouya discovered an intronic single nucleotide change c.315-48T>C in intron 3 of the FECH gene that modulates the use of an aberrant splice acceptor site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, producing a decreased level of mRNA. This, in trans to a pathogenic variant was found to cause phenotypic expression of EPP.

PMID: 16385445 Gouya reports that this intronic variant is present in >90% of EPP patients.

The FECH low-expression variant c.315-48T>C has a total allele frequency of 0.06713 and an allele frequency of 0.3803 in those of East Asian ancestry with ~7% of these being homozygotes (GnomAD v4.10). However clinical detection of EPP remains low. Even taking into account underreporting, this suggests that the low expression variant in the homozygous form causes a reduction in the ferrochelatase enzyme activity but not to a level that causes disease, otherwise EPP would be much more common.

It is essential that any genetic sequencing includes the region of intron 3 (c.315-48T>C) that harbours the low expression variant.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v7.3 FECH Sharon Whatley reviewed gene: FECH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v8.55 FECH Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 16911284, 39969427, 32873934, 38940544, 11753383, 16385445; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.630 FECH Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 16911284, 39969427, 32873934, 38940544, 11753383, 16385445; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Iron metabolism disorders - NOT common HFE mutations v3.1 FECH Sharon Whatley reviewed gene: FECH: Rating: RED; Mode of pathogenicity: None; Publications: 28185024; Phenotypes: ; Mode of inheritance: None
Vascular skin disorders v2.1 FECH Sharon Whatley reviewed gene: FECH: Rating: RED; Mode of pathogenicity: None; Publications: 7857832; Phenotypes: ; Mode of inheritance: None
Cutaneous photosensitivity with a likely genetic cause v3.9 FECH Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 16911284, 39969427, 32873934, 38940544, 11753383, 16385445; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Non-acute porphyrias v1.26 FECH Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 16911284, 39969427, 32873934, 38940544, 11753383, 16385445; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Erythropoietic protoporphyria, mild variant v1.3 FECH Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 18760763, 33596641; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v7.34 PLD1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort.

As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has recently been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.; to: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort.

As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.
Paediatric or syndromic cardiomyopathy v7.34 NDUFA4 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there are at least three unrelated patients reported with biallelic variants in NDUFA4 gene, only one patient (one from 100,000 genomes project) presented with cardiomyopathy. Hence, this gene can only be rated red with the current evidence.; to: Comment on list classification: Although there are at least three unrelated patients reported with biallelic variants in NDUFA4 gene, only one patient (one from the UK 100,000 genomes project) presented with cardiomyopathy. Hence, this gene can only be rated red with the current evidence.
Neurological segmental overgrowth v3.1 PIK3CA Eleanor Williams Tag mosaicism tag was added to gene: PIK3CA.
Tag somatic tag was added to gene: PIK3CA.
Paediatric or syndromic cardiomyopathy v7.34 SGCG Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies.

As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.; to: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies.

There is also functional evidence from mice model, which supports the association of SGCG gene with cardiomyopathy.

As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.34 SGCG Achchuthan Shanmugasundram Publications for gene: SGCG were set to 10942431; 11053682; 24464767; 39472908
Paediatric or syndromic cardiomyopathy v7.33 SGCG Achchuthan Shanmugasundram edited their review of gene: SGCG: Changed publications to: 10942431, 11053682, 14991064, 24464767, 39472908
Paediatric or syndromic cardiomyopathy v7.33 SGCG Achchuthan Shanmugasundram changed review comment from: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT).

PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction.

PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%).

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation).
Sources: Literature; to: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT).

PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction.

PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%).

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation).

PMID:14991064 provided functional evidence from Sgcg knockout mice, which develop a progressive cardiomyopathy characterised by focal myocardial degeneration and fibrosis. Transgenic rescue experiments in mice showed that re-expressing SGCG only in cardiac muscle (but not in vascular muscle) was sufficient to prevent the cardiomyopathy in Sgcg-null mice.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.33 SGCG Achchuthan Shanmugasundram Classified gene: SGCG as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.33 SGCG Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies.

As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.33 SGCG Achchuthan Shanmugasundram Gene: sgcg has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.32 SGCG Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SGCG.
Paediatric or syndromic cardiomyopathy v7.32 SGCG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 26 August 2025.
Paediatric or syndromic cardiomyopathy v7.32 SGCG Achchuthan Shanmugasundram Phenotypes for gene: SGCG were changed from Muscular dystrophy, limb-girdle, autosomal recessive 5, OMIM:253700; autosomal recessive limb-girdle muscular dystrophy type 2C, MONDO:0009677 to Muscular dystrophy, limb-girdle, autosomal recessive 5, OMIM:253700; autosomal recessive limb-girdle muscular dystrophy type 2C, MONDO:0009677
Paediatric or syndromic cardiomyopathy v7.31 SGCG Achchuthan Shanmugasundram gene: SGCG was added
gene: SGCG was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: SGCG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGCG were set to 10942431; 11053682; 24464767; 39472908
Phenotypes for gene: SGCG were set to Muscular dystrophy, limb-girdle, autosomal recessive 5, OMIM:253700; autosomal recessive limb-girdle muscular dystrophy type 2C, MONDO:0009677
Review for gene: SGCG was set to GREEN
Added comment: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT).

PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction.

PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%).

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.30 PLD1 Achchuthan Shanmugasundram Classified gene: PLD1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.30 PLD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort.

As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has recently been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.
Paediatric or syndromic cardiomyopathy v7.30 PLD1 Achchuthan Shanmugasundram Gene: pld1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.29 PLD1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 26 August 2025.
Paediatric or syndromic cardiomyopathy v7.29 PLD1 Achchuthan Shanmugasundram Phenotypes for gene: PLD1 were changed from Cardiac valvular dysplasia 1, OMIM:212093; cardiac valvular defect, developmental, MONDO:0008913; neonatal cardiomyopathy to Cardiac valvular dysplasia 1, OMIM:212093; cardiac valvular defect, developmental, MONDO:0008913; neonatal cardiomyopathy
Paediatric or syndromic cardiomyopathy v7.28 PLD1 Achchuthan Shanmugasundram Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093; neonatal cardiomyopathy to Cardiac valvular dysplasia 1, OMIM:212093; cardiac valvular defect, developmental, MONDO:0008913; neonatal cardiomyopathy
Paediatric or syndromic cardiomyopathy v7.27 PLD1 Achchuthan Shanmugasundram Publications for gene: PLD1 were set to 27799408; 33645542
Paediatric or syndromic cardiomyopathy v7.26 PLD1 Achchuthan Shanmugasundram reviewed gene: PLD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39472908; Phenotypes: Cardiac valvular dysplasia 1, OMIM:212093, cardiac valvular defect, developmental, MONDO:0008913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v7.26 NDUFA4 Achchuthan Shanmugasundram Classified gene: NDUFA4 as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v7.26 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are at least three unrelated patients reported with biallelic variants in NDUFA4 gene, only one patient (one from 100,000 genomes project) presented with cardiomyopathy. Hence, this gene can only be rated red with the current evidence.
Paediatric or syndromic cardiomyopathy v7.26 NDUFA4 Achchuthan Shanmugasundram Gene: ndufa4 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v7.25 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 26 August 2025.
Paediatric or syndromic cardiomyopathy v7.25 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Paediatric or syndromic cardiomyopathy v7.24 NDUFA4 Achchuthan Shanmugasundram Publications for gene: NDUFA4 were set to 23746447, 29636225
Paediatric or syndromic cardiomyopathy v7.23 NDUFA4 Achchuthan Shanmugasundram reviewed gene: NDUFA4: Rating: RED; Mode of pathogenicity: None; Publications: 23746447, 38674434, 39472908; Phenotypes: ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065, mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v7.23 NAXD Achchuthan Shanmugasundram Classified gene: NAXD as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.23 NAXD Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >10 unrelated patients reported with biallelic NAXD variants and with 'Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2' (MIM #618321). However, the disease has a variable presentation and cardiomyopathy was reported in four unrelated patients. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.23 NAXD Achchuthan Shanmugasundram Gene: naxd has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.22 NAXD Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NAXD.
Paediatric or syndromic cardiomyopathy v7.22 NAXD Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 25 August 2025.
Paediatric or syndromic cardiomyopathy v7.22 NAXD Achchuthan Shanmugasundram Phenotypes for gene: NAXD were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321; NAD(P)HX dehydratase deficiency, MONDO:0034121 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321; NAD(P)HX dehydratase deficiency, MONDO:0034121
Paediatric or syndromic cardiomyopathy v7.21 NAXD Achchuthan Shanmugasundram gene: NAXD was added
gene: NAXD was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410; 32462209; 39472908; 39822994
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321; NAD(P)HX dehydratase deficiency, MONDO:0034121
Review for gene: NAXD was set to GREEN
Added comment: PMID:30576410 (2019) reported six unrelated individuals with biallelic NAXD variants, and with encephalopathy precipitated by febrile illnesses. They all had severe neurological deterioration and died in early childhood. One of these six patients, who is a girl of Indian descent developed dilated cardiomyopathy and heart failure, and was identified with homozygous c.54_57delAAGA (p.Ala20Phefs*9) variant.

PMID: 32462209 (2020) reported a seven-year-old male patient that experienced rapid deterioration and after gastroenteritis and died suddenly. An autopsy imaging CT scan showed thickening of the myocardial wall and gross hypertrophic cardiomyopathy in the patient. His paternal uncle also died due to acute myocardial infarction at the age of 28. Biallelic variants (c.44delG/ p.Arg15Glnfs*3 & c.54_57delAAGA/ p.Ala20Phefs*9) were identified by WES in the patient and these variants are present in heterozygous state in the parents.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one female patient with dilated cardiomyopathy was identified with homozygous variant in NAXD gene (c.54_57del/ p.Ala20PhefsTer9).

PMID:39822994 (2024) reported a 47-month-old male patient of Chinese descent that experienced a sharp deterioration after febrile illness, causing heart failure, cardiogenic shock, and ultimately death. This patient was diagnosed with myocarditis and dilated cardiomyopathy and was identified with compound heterozygous variants in NAXD gene (c.43C>T/ p.Arg15Ter & c.781G>T/ p.Gly261Cys).

This gene has been associated with MIM #618321 in OMIM, which mentions cardiomyopathy as one of the clinical presentations that is observed in some patients.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.20 AIFM1 Achchuthan Shanmugasundram Classified gene: AIFM1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.20 AIFM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >20 unrelated patients reported with hemizygous AIFM1 variants and with Combined oxidative phosphorylation deficiency 6 (MIM #300816). However, the disease has a variable presentation and cardiomyopathy was reported in four unrelated patients. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.20 AIFM1 Achchuthan Shanmugasundram Gene: aifm1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.19 AIFM1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: AIFM1.
Paediatric or syndromic cardiomyopathy v7.19 AIFM1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 25 August 2025.
Paediatric or syndromic cardiomyopathy v7.19 AIFM1 Achchuthan Shanmugasundram Phenotypes for gene: AIFM1 were changed from Combined oxidative phosphorylation deficiency 6, OMIM:300816 to Combined oxidative phosphorylation deficiency 6, OMIM:300816; severe X-linked mitochondrial encephalomyopathy, MONDO:0010437
Paediatric or syndromic cardiomyopathy v7.18 AIFM1 Achchuthan Shanmugasundram edited their review of gene: AIFM1: Changed phenotypes to: Combined oxidative phosphorylation deficiency 6, OMIM:300816, severe X-linked mitochondrial encephalomyopathy, MONDO:0010437
Paediatric or syndromic cardiomyopathy v7.18 AIFM1 Achchuthan Shanmugasundram gene: AIFM1 was added
gene: AIFM1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: AIFM1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AIFM1 were set to 22019070; 28967629; 34117073; 39472908
Phenotypes for gene: AIFM1 were set to Combined oxidative phosphorylation deficiency 6, OMIM:300816
Review for gene: AIFM1 was set to GREEN
Added comment: PMID:22019070 (2011) reported three siblings of Palestinian descent with early prenatal verntriculomegaly, of which two brothers were investigated further. The two brothers presented with infantile encephalomyopathy. One of them died at the age of 4 years due to cardiac failure secondary to aspiration pneumonia, and the other died at 3 months of age because of hypertrophic cardiomyopathy and aspiration pneumonia. Using linkage analysis in the family, followed by whole exome sequencing, a pathogenic variant in the AIFM1 gene was identified in patient B (c.923G > A/ p.Gly308Glu), which segregated with the disease state and was absent in 86 anonymous controls.

PMID:28967629 (2018) reported two unrelated male patients with AIFM1 variants and they displayed distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. Cardiomyopathy was only reported in patient 2, who also displayed severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, and hyporeflexia. The c.422C > T (p.Thr141Ile) hemizygous variant was identified in this patient via WES and validated by Sanger sequencing and was confirmed de novo.

PMID:34117073 (2021) reported three affected males (proband, brother and maternal uncle) exhibiting severe multisystem pathology, metabolic acidosis, and early demise. Biventricular hypertrophy was observed via foetal heart echocardiogram in the proband, and by limited autopsy in the maternal uncle. A missense hemizygous AIFM1 variant (c.506C > T/ p.Pro169Leu) was identified in the proband and sibling and this variant is absent in reference population databases, as discussed in this publication.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient was identified with hemizygous variant in AIFM1 gene (c.603_605del/ p.Arg201del?).

This gene is associated with Combined oxidative phosphorylation deficiency 6 (MIM #300816) in OMIM, which includes hypertrophic cardiomyopathy as one of the variable clinical presentations.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.17 FBXL4 Achchuthan Shanmugasundram changed review comment from: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1.

PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter].

PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function.

PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)).

PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter

There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748).
Sources: Literature; to: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1.

PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter].

PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function.

PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)).

PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter).

There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748).
Sources: Literature
Hereditary neuropathy or pain disorder v7.5 COX18 Alexander Rossor gene: COX18 was added
gene: COX18 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: COX18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX18 were set to 40830826
Phenotypes for gene: COX18 were set to peripheral neuropathy
Penetrance for gene: COX18 were set to Complete
Review for gene: COX18 was set to GREEN
Added comment: 8 individuals from 3 families
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.17 FBXL4 Achchuthan Shanmugasundram Classified gene: FBXL4 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.17 FBXL4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >90 patients reported with biallelic FBXL4 variants and mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) (MIM #615471). Of these, ~20% of patients are reported with early-onset hypertrophic cardiomyopathy. As there are >15 patients reported with cardiomyopathy, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.17 FBXL4 Achchuthan Shanmugasundram Gene: fbxl4 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.16 FBXL4 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: FBXL4.
Paediatric or syndromic cardiomyopathy v7.16 FBXL4 Achchuthan Shanmugasundram gene: FBXL4 was added
gene: FBXL4 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: FBXL4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL4 were set to 23993193; 23993194; 25868664; 26404457; 28940506; 38359748; 39472908
Phenotypes for gene: FBXL4 were set to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), OMIM:615471
Review for gene: FBXL4 was set to GREEN
Added comment: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1.

PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter].

PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function.

PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)).

PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter

There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748).
Sources: Literature
Intellectual disability v9.64 UPF1 Karen Stals changed review comment from: At least 4 individuals reported in the literature with de novo variants in this gene and a neurodevelopmental disorder. Additional patient identified in Exeter. Moderate gene-disease association in Gene2Phenotype.; to: At least 4 individuals described in the literature with de novo variants in this gene and a neurodevelopmental disorder. Additional patient identified in Exeter. Moderate gene-disease association in Gene2Phenotype.
Intellectual disability v9.64 UPF1 Karen Stals reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39993774, PMID: 39571789, PMID: 28539120; Phenotypes: Developmental delay, autism, intellectual disability, speech delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Autoinflammatory disorders v2.29 ITCH Nicholas Head gene: ITCH was added
gene: ITCH was added to Autoinflammatory disorders. Sources: Other
Mode of inheritance for gene: ITCH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITCH were set to PMID: 36338154
Phenotypes for gene: ITCH were set to Autoimmune disease, multisystem, with facial dysmorphism, 613385
Review for gene: ITCH was set to GREEN
gene: ITCH was marked as current diagnostic
Added comment: Currently listed as a green gene on R15 panel. Causes a autoinflammatory disorder with multisystem involvement.
Sources: Other
Paediatric or syndromic cardiomyopathy v7.15 FLII Achchuthan Shanmugasundram changed review comment from: PMID:32870709 (2020) reported a large cohort of 205 unrelated patients with various forms of childhood-onset cardiomyopathy (CM), in which two unrelated patients of Saudi Arabian decent with infantile-onset dilated CM were identified with homozygous missense variants (p.Leu674Val & p.Arg1240Cys).

PMID:37561591 (2023) identified biallelic variants in FLII gene in three unrelated families with idiopathic, early-onset dilated CM of which two patients were the ones that were already reported in PMID:32870709. The third patient was a girl of Dutch decent that had onset of CM at around 2 months of age. This patient was identified with compound heterozygous variants (p.Gln454Ter & p.Arg1168Trp).

Introduction of patient-specific FLII variants into the zebrafish genome using CRISPR/Cas9 genome editing resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in the patients. In addition, functional studies also provided insights into the function of Flii during ventricular chamber morphogenesis that involves myocardial cell adhesion and myofibril organisation.

This gene has been associated with dilated CM phenotype in OMIM (MIM #620635).; to: PMID:32870709 (2020) reported a large cohort of 205 unrelated patients with various forms of childhood-onset cardiomyopathy (CM), in which two unrelated patients of Saudi Arabian descent with infantile-onset dilated CM were identified with homozygous missense variants (p.Leu674Val & p.Arg1240Cys).

PMID:37561591 (2023) identified biallelic variants in FLII gene in three unrelated families with idiopathic, early-onset dilated CM of which two patients were the ones that were already reported in PMID:32870709. The third patient was a girl of Dutch descent that had onset of CM at around 2 months of age. This patient was identified with compound heterozygous variants (p.Gln454Ter & p.Arg1168Trp).

Introduction of patient-specific FLII variants into the zebrafish genome using CRISPR/Cas9 genome editing resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in the patients. In addition, functional studies also provided insights into the function of Flii during ventricular chamber morphogenesis that involves myocardial cell adhesion and myofibril organisation.

This gene has been associated with dilated CM phenotype in OMIM (MIM #620635).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.40 REXO2 Achchuthan Shanmugasundram Classified gene: REXO2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.40 REXO2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one patient reported with monoallelic variant in REXO2, and functional evidence is available in support of the association. Hence, this gene should be rated amber with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.40 REXO2 Achchuthan Shanmugasundram Gene: rexo2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.39 REXO2 Achchuthan Shanmugasundram Phenotypes for gene: REXO2 were changed from to type 1 interferonopathy, MONDO:0700264
Primary immunodeficiency or monogenic inflammatory bowel disease v8.38 REXO2 Achchuthan Shanmugasundram Publications for gene: REXO2 were set to PMID: 39107301
Primary immunodeficiency or monogenic inflammatory bowel disease v8.37 REXO2 Achchuthan Shanmugasundram reviewed gene: REXO2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 39107301; Phenotypes: type 1 interferonopathy, MONDO:0700264; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v8.37 GTF3A Achchuthan Shanmugasundram Classified gene: GTF3A as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.37 GTF3A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one family reported with immunodeficiency and biallelic GTF3A variants, and functional evidenced available in support of the association. Hence, this gene can be rated amber with current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.37 GTF3A Achchuthan Shanmugasundram Gene: gtf3a has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.36 GTF3A Achchuthan Shanmugasundram Phenotypes for gene: GTF3A were changed from CVID with HSV encephalitis to common variable immunodeficiency, MONDO:001551
Primary immunodeficiency or monogenic inflammatory bowel disease v8.35 GTF3A Achchuthan Shanmugasundram Publications for gene: GTF3A were set to PMID: 36399538
Primary immunodeficiency or monogenic inflammatory bowel disease v8.34 GTF3A Achchuthan Shanmugasundram reviewed gene: GTF3A: Rating: AMBER; Mode of pathogenicity: None; Publications: 36399538; Phenotypes: common variable immunodeficiency, MONDO:0015517; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.34 GTF3AP5 Achchuthan Shanmugasundram Classified gene: GTF3AP5 as No list
Primary immunodeficiency or monogenic inflammatory bowel disease v8.34 GTF3AP5 Achchuthan Shanmugasundram Added comment: Comment on list classification: PMID:36399538 reports the association of GTF3A to immunodeficiency rather than GTF3AP5. Hence, the reviewer removed their review. This gene is therefore rated grey on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.34 GTF3AP5 Achchuthan Shanmugasundram Gene: gtf3ap5 has been removed from the panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.33 GTF3AP5 Achchuthan Shanmugasundram Tag curated_removed tag was added to gene: GTF3AP5.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.33 GTF3AP5 Achchuthan Shanmugasundram Classified gene: GTF3AP5 as No list
Primary immunodeficiency or monogenic inflammatory bowel disease v8.33 GTF3AP5 Achchuthan Shanmugasundram Gene: gtf3ap5 has been removed from the panel.
Paediatric or syndromic cardiomyopathy v7.15 FLII Achchuthan Shanmugasundram Classified gene: FLII as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.15 FLII Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.15 FLII Achchuthan Shanmugasundram Gene: flii has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.14 FLII Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: FLII.
Paediatric or syndromic cardiomyopathy v7.14 FLII Achchuthan Shanmugasundram Phenotypes for gene: FLII were changed from Dilated cardiomyopathy, MONDO:0005021 to Cardiomyopathy, dilated, 2J, OMIM:620635
Paediatric or syndromic cardiomyopathy v7.13 FLII Achchuthan Shanmugasundram Publications for gene: FLII were set to 32870709
Paediatric or syndromic cardiomyopathy v7.12 FLII Achchuthan Shanmugasundram reviewed gene: FLII: Rating: GREEN; Mode of pathogenicity: None; Publications: 32870709, 37561591; Phenotypes: Cardiomyopathy, dilated, 2J, OMIM:620635; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v4.20 HNRNPC Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) missense variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations.

PMID:40004505 reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:37541189 (2023) reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) missense variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations.

PMID:40004505 (2025) reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Structural eye disease v4.20 HNRNPC Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations.

PMID:40004505 reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) missense variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations.

PMID:40004505 reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Structural eye disease v4.20 HNRNPC Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are only two unrelated patients reported with monoallelic HNRNPC variants and bilateral colobomatous microphthalmia. They were both identified with the same missense variant and only in silico structural modelling data available for the variant. Hence, this gene can only be rated amber with the current evidence.; to: Comment on list classification: There are only two unrelated patients reported with monoallelic HNRNPC variants and bilateral colobomatous microphthalmia. They were both identified with the same missense variant, the only functional evidence available for this variant is from in silico structural modelling. Hence, this gene can only be rated amber with the current evidence.
Structural eye disease v4.20 HNRNPC Achchuthan Shanmugasundram Classified gene: HNRNPC as Amber List (moderate evidence)
Structural eye disease v4.20 HNRNPC Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated patients reported with monoallelic HNRNPC variants and bilateral colobomatous microphthalmia. They were both identified with the same missense variant and only in silico structural modelling data available for the variant. Hence, this gene can only be rated amber with the current evidence.
Structural eye disease v4.20 HNRNPC Achchuthan Shanmugasundram Gene: hnrnpc has been classified as Amber List (Moderate Evidence).
Structural eye disease v4.19 HNRNPC Achchuthan Shanmugasundram gene: HNRNPC was added
gene: HNRNPC was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: HNRNPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPC were set to 37541189; 40004505
Phenotypes for gene: HNRNPC were set to Intellectual developmental disorder, autosomal dominant 74, OMIM:620688; microphthalmia, isolated, with coloboma, MONDO:0000170
Review for gene: HNRNPC was set to AMBER
Added comment: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations.

PMID:40004505 reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.64 HNRNPC Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant, and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.64 HNRNPC Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.64 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Changed rating: GREEN
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Classified gene: UNC13A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated patients and functional studies) for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Gene: unc13a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.22 UNC13A Achchuthan Shanmugasundram gene: UNC13A was added
gene: UNC13A was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: UNC13A.
Mode of inheritance for gene: UNC13A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC13A were set to 28192369; 39634123
Phenotypes for gene: UNC13A were set to developmental and epileptic encephalopathy, MONDO:0100620
Review for gene: UNC13A was set to GREEN
Added comment: PMID:28192369 (2017) reported a 6-year-old male patient presenting with a disorder characterised by a dyskinetic movement disorder, developmental delay, and autism, and identified with a rare de novo heterozygous missense variant (p.Pro814Leu) in UNC13A gene. Sanger sequencing was done in parents and de novo inheritance was confirmed. This patient also presented with febrile seizures.

PMID:39634123 (2024) reported three unrelated patients presenting with clinical phenotypes consistent with developmental and epileptic encephalopathy including status epilepticus, focal onset seizures in both febrile and afebrile states, and intellectual disability. They were identified with three different de novo heterozygous missense variants (p.Met631Lys, p.Phe649Leu & p.Pro814Leu) based on trio exome sequencing. There is also functional evidence available from CRISPR/Cas9 zebrafish mutants in support of the association of UNC13A to epilepsy.

This gene is currently associated with congenital nervous system disorder (MONDO:0002320) in ClinGen with 'Limited' rating by Syndromic Disorders expert panel (https://search.clinicalgenome.org/CCID:008453).
Sources: Literature
Intellectual disability v9.64 UNC13A Achchuthan Shanmugasundram Classified gene: UNC13A as Amber List (moderate evidence)
Intellectual disability v9.64 UNC13A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with three different monoallelic UNC13A variants and with intellectual disability/ developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.64 UNC13A Achchuthan Shanmugasundram Gene: unc13a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.63 UNC13A Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UNC13A.
Tag Q3_25_NHS_review tag was added to gene: UNC13A.
Intellectual disability v9.63 UNC13A Achchuthan Shanmugasundram Phenotypes for gene: UNC13A were changed from to developmental and epileptic encephalopathy, MONDO:0100620
Intellectual disability v9.62 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369
Intellectual disability v9.61 UNC13A Achchuthan Shanmugasundram reviewed gene: UNC13A: Rating: ; Mode of pathogenicity: None; Publications: 28192369, 39634123; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v8.8 INPP4A Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.8 INPP4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (10 patients from 9 families and functional studies) for the promotion of this gene to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.8 INPP4A Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.7 INPP4A Achchuthan Shanmugasundram gene: INPP4A was added
gene: INPP4A was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: INPP4A.
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 39315527; 40748307; 40772914
Phenotypes for gene: INPP4A were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: INPP4A was set to GREEN
Added comment: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Nine patients from eight families were reported with spasticity, of which six had LoF variants downstream of exon 4 and the remaining three had missense variants. Although age of onset was not provided for these patients, the age of last examination for eight of nine patients were below 16.

There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. This patient had spasticity.
Sources: Literature
Severe microcephaly v8.11 INPP4A Achchuthan Shanmugasundram changed review comment from: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature; to: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants.

There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.15 INPP4A Achchuthan Shanmugasundram changed review comment from: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature; to: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants.

There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature
Severe microcephaly v8.11 INPP4A Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
Severe microcephaly v8.11 INPP4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 11 patients from eight unrelated families reported with biallelic INPP4A variants and severe microcephaly. Hence, this gene can be promoted to green rating in the next GMS update.
Severe microcephaly v8.11 INPP4A Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.15 INPP4A Achchuthan Shanmugasundram changed review comment from: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalied hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature; to: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature
Severe microcephaly v8.10 INPP4A Achchuthan Shanmugasundram gene: INPP4A was added
gene: INPP4A was added to Severe microcephaly. Sources: Literature
Q3_25_promote_green tags were added to gene: INPP4A.
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 39315527; 40748307; 40772914
Phenotypes for gene: INPP4A were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: INPP4A was set to GREEN
Added comment: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.15 INPP4A Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.15 INPP4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (15 patients from 11 families) for the promotion of this gene to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.15 INPP4A Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.14 INPP4A Achchuthan Shanmugasundram gene: INPP4A was added
gene: INPP4A was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q3_25_promote_green tags were added to gene: INPP4A.
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 39315527; 40748307; 40772914
Phenotypes for gene: INPP4A were set to neurodevelopmental disorder, MONDO:0700092; Cerebellar hypoplasia, HP:0001321
Review for gene: INPP4A was set to GREEN
Added comment: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalied hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature
Early onset or syndromic epilepsy v8.21 INPP4A Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.21 INPP4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are a total of 33 patients from 19 unrelated families reported with biallelic INPP4A variants and a neurodevelopmental disorder. Of these, 13 patients from 12 families presented with seizures. Hence, this gene should be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.21 INPP4A Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.20 INPP4A Achchuthan Shanmugasundram edited their review of gene: INPP4A: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v8.20 INPP4A Achchuthan Shanmugasundram Phenotypes for gene: INPP4A were changed from Intellectual disability; Seizures to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v8.19 INPP4A Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678
Early onset or syndromic epilepsy v8.18 INPP4A Achchuthan Shanmugasundram reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39315527, 40748307, 40772914; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.61 INPP4A Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
Intellectual disability v9.61 INPP4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are a total of 33 patients from 19 unrelated families reported with biallelic INPP4A variants and a neurodevelopmental disorder. Of these, 29 patients presented with severe or profound intellectual disability/ global developmental delay. Hence, this gene should be promoted to green rating in the next GMS update.
Intellectual disability v9.61 INPP4A Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.60 INPP4A Achchuthan Shanmugasundram edited their review of gene: INPP4A: Changed publications to: 39315527, 40748307, 40772914
Intellectual disability v9.60 INPP4A Achchuthan Shanmugasundram Phenotypes for gene: INPP4A were changed from Intellectual disability; Seizures to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.59 INPP4A Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678; 39315527; 4074830740772914
Intellectual disability v9.58 INPP4A Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678
Intellectual disability v9.57 INPP4A Achchuthan Shanmugasundram reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39315527, 4074830740772914; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v4.18 NTN1 Hannah Knight gene: NTN1 was added
gene: NTN1 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NTN1 were set to PMID: 39648562
Phenotypes for gene: NTN1 were set to Chorioretinal Coloboma; Sensorineural Hearing Loss; Polydactyly
Review for gene: NTN1 was set to AMBER
Added comment: PMID: 39648562 reported a patient with chorioretinal coloboma and microphthalmia who carried a heterozygous NTN1 variant, c.1483T>A p.(Tyr495Asn). Patient also had bilateral sensorineural hearing loss which was investigated by examining the sensory hair cells of ntn1a morphant zebrafish, suggesting a role for netrin‐1 in hair cell development.

NTN1 was previously identified as a mediator of optic fissure closure from transcriptome analyses of chick and zebrafish and was shown to cause ocular coloboma when knocked out in both mouse and zebrafish.
Sources: Literature
Structural eye disease v4.18 MYH10 Hannah Knight gene: MYH10 was added
gene: MYH10 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: MYH10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYH10 were set to PMID: 40044823
Phenotypes for gene: MYH10 were set to Autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features
Review for gene: MYH10 was set to GREEN
Added comment: PMID: 40044823 reported six individuals from 3 unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features suggesting Baraitser-Winter cerebrofrontofacial syndrome. No neurodevelopmental features.
3 novel heterozygous variants in the MYH10 gene reported.
Sources: Literature
Primary ciliary disorders v1.47 HYDIN Arina Puzriakova Publications for gene: HYDIN were set to
Respiratory ciliopathies including non-CF bronchiectasis v4.46 HYDIN Arina Puzriakova Publications for gene: HYDIN were set to
Respiratory ciliopathies including non-CF bronchiectasis v4.45 HYDIN Arina Puzriakova Phenotypes for gene: HYDIN were changed from Ciliary dyskinesia, primary, 5, 608647 to Ciliary dyskinesia, primary, 5, OMIM:608647
Primary ciliary disorders v1.46 HYDIN Arina Puzriakova Phenotypes for gene: HYDIN were changed from Ciliary dyskinesia, primary, 5, 608647 to Ciliary dyskinesia, primary, 5, OMIM:608647
Childhood onset dystonia, chorea or related movement disorder v7.3 ADCY5 Cassandra Smith reviewed gene: ADCY5: Rating: GREEN; Mode of pathogenicity: None; Publications: 28971144, 30975617, 34631954, 33704598; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01082 Hannah Robinson gene: LINC01082 was added
gene: LINC01082 was added to Alveolar capillary dysplasia with misalignment of pulmonary veins. Sources: NHS GMS
Mode of inheritance for gene: LINC01082 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317
Phenotypes for gene: LINC01082 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins
Penetrance for gene: LINC01082 were set to Complete
Review for gene: LINC01082 was set to GREEN
gene: LINC01082 was marked as current diagnostic
Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele.
Sources: NHS GMS
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Hannah Robinson gene: LINC01081 was added
gene: LINC01081 was added to Alveolar capillary dysplasia with misalignment of pulmonary veins. Sources: NHS GMS
Mode of inheritance for gene: LINC01081 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317
Phenotypes for gene: LINC01081 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins
Penetrance for gene: LINC01081 were set to Complete
Review for gene: LINC01081 was set to GREEN
gene: LINC01081 was marked as current diagnostic
Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele.
Sources: NHS GMS
Fetal anomalies v6.15 LINC01082 Hannah Robinson gene: LINC01082 was added
gene: LINC01082 was added to Fetal anomalies. Sources: NHS GMS
Mode of inheritance for gene: LINC01082 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317
Phenotypes for gene: LINC01082 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins
Penetrance for gene: LINC01082 were set to Complete
Review for gene: LINC01082 was set to GREEN
gene: LINC01082 was marked as current diagnostic
Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele.
Sources: NHS GMS
Fetal anomalies v6.15 LINC01081 Hannah Robinson gene: LINC01081 was added
gene: LINC01081 was added to Fetal anomalies. Sources: NHS GMS
Mode of inheritance for gene: LINC01081 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317
Phenotypes for gene: LINC01081 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins
Penetrance for gene: LINC01081 were set to Complete
Review for gene: LINC01081 was set to GREEN
gene: LINC01081 was marked as current diagnostic
Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele.
Sources: NHS GMS
Non-syndromic familial congenital anorectal malformations v1.9 LINC01082 Hannah Robinson gene: LINC01082 was added
gene: LINC01082 was added to Non-syndromic familial congenital anorectal malformations. Sources: NHS GMS
Mode of inheritance for gene: LINC01082 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317
Phenotypes for gene: LINC01082 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins
Penetrance for gene: LINC01082 were set to Complete
Review for gene: LINC01082 was set to GREEN
gene: LINC01082 was marked as current diagnostic
Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele.
Sources: NHS GMS
Non-syndromic familial congenital anorectal malformations v1.9 LINC01081 Hannah Robinson gene: LINC01081 was added
gene: LINC01081 was added to Non-syndromic familial congenital anorectal malformations. Sources: NHS GMS
Mode of inheritance for gene: LINC01081 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317
Phenotypes for gene: LINC01081 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins
Penetrance for gene: LINC01081 were set to Complete
Review for gene: LINC01081 was set to GREEN
gene: LINC01081 was marked as current diagnostic
Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele.
Sources: NHS GMS
Clefting v6.9 MED16 Achchuthan Shanmugasundram Classified gene: MED16 as Amber List (moderate evidence)
Clefting v6.9 MED16 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (seven unrelated families) available for the promotion of this gene to green rating in the next GMS update.
Clefting v6.9 MED16 Achchuthan Shanmugasundram Gene: med16 has been classified as Amber List (Moderate Evidence).
Clefting v6.8 MED16 Achchuthan Shanmugasundram gene: MED16 was added
gene: MED16 was added to Clefting. Sources: Literature
Q3_25_promote_green tags were added to gene: MED16.
Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED16 were set to 40081376
Phenotypes for gene: MED16 were set to Guillouet-Gordon syndrome, OMIM:621220
Review for gene: MED16 was set to GREEN
Added comment: PMID:40081376 (2025) reported 25 patients from 18 families with biallelic MED16 variants and multiple congenital anomalies (MCAs)-intellectual disability syndrome.

Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent.

There were a total of 8 predicted protein-truncating and 18 missense or in-frame duplication variants identified from these patients.

Clefting was reported in eight patients from seven different families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621220), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.57 MED16 Achchuthan Shanmugasundram Classified gene: MED16 as Amber List (moderate evidence)
Intellectual disability v9.57 MED16 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (10 unrelated families) available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.57 MED16 Achchuthan Shanmugasundram Gene: med16 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.56 MED16 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: MED16.
Tag Q3_25_NHS_review tag was added to gene: MED16.
Intellectual disability v9.56 MED16 Achchuthan Shanmugasundram Phenotypes for gene: MED16 were changed from developmental delay; multiple congenital abnormalities; Medopathy to Guillouet-Gordon syndrome, OMIM:621220
Intellectual disability v9.56 MED16 Achchuthan Shanmugasundram Publications for gene: MED16 were set to PMID: 40081376
Intellectual disability v9.55 MED16 Achchuthan Shanmugasundram reviewed gene: MED16: Rating: GREEN; Mode of pathogenicity: None; Publications: 40081376; Phenotypes: Guillouet-Gordon syndrome, OMIM:621220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.8 PDE12 Achchuthan Shanmugasundram changed review comment from: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Fetal anomalies v6.15 PDE12 Achchuthan Shanmugasundram Classified gene: PDE12 as Amber List (moderate evidence)
Fetal anomalies v6.15 PDE12 Achchuthan Shanmugasundram Added comment: Comment on list classification: Of the three unrelated families reported with biallelic PDE12 variants, foetal anomalies were reported in two families. There is also functional and in silico evidence available. Hence, this gene can be promoted to green rating in the next GMS update.
Fetal anomalies v6.15 PDE12 Achchuthan Shanmugasundram Gene: pde12 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.14 PDE12 Achchuthan Shanmugasundram changed review comment from: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

Of these, the patient from family 2 (died on day 2 after birth), and the two foetuses from family 3 had foetal anomalies detected via prenatal ultrasound. The patient from family 2 had brain anomalies. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mitochondrial disorders v9.23 PDE12 Achchuthan Shanmugasundram changed review comment from: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Possible mitochondrial disorder - nuclear genes v4.8 PDE12 Achchuthan Shanmugasundram Classified gene: PDE12 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v4.8 PDE12 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated families and functional evidence) available for the association of biallelic variants in this gene with mitochondrial disease. Hence, this gene can be promoted to green rating in the next GMS update.
Possible mitochondrial disorder - nuclear genes v4.8 PDE12 Achchuthan Shanmugasundram Gene: pde12 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.14 PDE12 Achchuthan Shanmugasundram gene: PDE12 was added
gene: PDE12 was added to Fetal anomalies. Sources: Literature
Q3_25_promote_green tags were added to gene: PDE12.
Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE12 were set to 39567835
Phenotypes for gene: PDE12 were set to mitochondrial disease, MONDO:0044970
Review for gene: PDE12 was set to GREEN
Added comment: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Possible mitochondrial disorder - nuclear genes v4.7 PDE12 Achchuthan Shanmugasundram gene: PDE12 was added
gene: PDE12 was added to Possible mitochondrial disorder - nuclear genes. Sources: Literature
Q3_25_promote_green tags were added to gene: PDE12.
Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE12 were set to 39567835
Phenotypes for gene: PDE12 were set to mitochondrial disease, MONDO:0044970
Review for gene: PDE12 was set to GREEN
Added comment: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis.

In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks.

All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population.

Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Mitochondrial disorders v9.23 PDE12 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PDE12.
Tag Q3_25_NHS_review tag was added to gene: PDE12.
Mitochondrial disorders v9.23 PDE12 Achchuthan Shanmugasundram Classified gene: PDE12 as Amber List (moderate evidence)
Mitochondrial disorders v9.23 PDE12 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Karen Stals, there is sufficient evidence (three unrelated families and functional evidence) available for the association of biallelic variants in this gene with mitochondrial disease. Hence, this gene can be promoted to green rating in the next GMS update.
Mitochondrial disorders v9.23 PDE12 Achchuthan Shanmugasundram Gene: pde12 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.22 PDE12 Achchuthan Shanmugasundram Phenotypes for gene: PDE12 were changed from to mitochondrial disease, MONDO:0044970
Mitochondrial disorders v9.21 PDE12 Achchuthan Shanmugasundram Publications for gene: PDE12 were set to 29903433; 28745585
Mitochondrial disorders v9.20 PDE12 Achchuthan Shanmugasundram Mode of inheritance for gene: PDE12 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.19 PDE12 Achchuthan Shanmugasundram reviewed gene: PDE12: Rating: GREEN; Mode of pathogenicity: None; Publications: 39567835; Phenotypes: mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v6.35 DST Cassandra Smith gene: DST was added
gene: DST was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to 40497796
Review for gene: DST was set to GREEN
Added comment: 9 affected individuals from 14 unrelated families, with variants in exons 40-41, specific to the DST-b isoform expressed in muscle.

Phenotype: "severe neonatal myopathy characterized by arthrogryposis, hypotonia, and dilated cardiomyopathy"
Sources: Literature
Retinal disorders v8.14 CYP2U1 Arina Puzriakova Publications for gene: CYP2U1 were set to PMID: 26914923; 34828401; 39605873
Monogenic short stature v1.22 RREB1 Achchuthan Shanmugasundram edited their review of gene: RREB1: Changed rating: RED
Monogenic short stature v1.22 RREB1 Achchuthan Shanmugasundram Classified gene: RREB1 as Red List (low evidence)
Monogenic short stature v1.22 RREB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: The eligibility criteria for R453 in the National Genomic Test Directory specifies that the patients should have the height at <-3 SD below mean for the age to be included on this panel. As the reported patients do not meet this criteria, this gene has been rated red with the current evidence.

This gene has already been proposed for green rating on R29 Intellectual disability panel and hence will feed into R27 Paediatric disorders.
Monogenic short stature v1.22 RREB1 Achchuthan Shanmugasundram Gene: rreb1 has been classified as Red List (Low Evidence).
Monogenic short stature v1.21 RREB1 Achchuthan Shanmugasundram Phenotypes for gene: RREB1 were changed from Rasopathy; Noonan-like; developmental disorder to RASopathy, MONDO:0021060
Monogenic short stature v1.20 RREB1 Achchuthan Shanmugasundram Publications for gene: RREB1 were set to PMID: 40418122
Monogenic short stature v1.19 RREB1 Achchuthan Shanmugasundram changed review comment from: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms. The height and weight of the patient was <3 centile at 3.25 years of age.

PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). Although all reported patients had relative short stature, only one patient had -2SD below mean for the age.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms. The height and weight of the patient was <3 centile at 3.25 years of age.

PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). Only one of the six reported patients had the height of ~-2SD below mean for the age.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Monogenic short stature v1.19 RREB1 Achchuthan Shanmugasundram reviewed gene: RREB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 38332451, 40418122; Phenotypes: RASopathy, MONDO:0021060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram changed review comment from: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms.

PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms.

PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram changed review comment from: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability and general muscular hypotonia among other features.

PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms.

PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: RREB1.
Tag Q3_25_NHS_review tag was added to gene: RREB1.
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram Classified gene: RREB1 as Amber List (moderate evidence)
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Of the seven unrelated patients reported with monoallelic single nucleotide variants in RREB1 gene, three were reported with either intellectual disability or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.55 RREB1 Achchuthan Shanmugasundram Gene: rreb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.54 RREB1 Achchuthan Shanmugasundram Publications for gene: RREB1 were set to 38332451; 40418122
Intellectual disability v9.53 RREB1 Achchuthan Shanmugasundram Phenotypes for gene: RREB1 were changed from Rasopathy; Noonan-like; developmental disorder to RASopathy, MONDO:0021060
Intellectual disability v9.53 RREB1 Achchuthan Shanmugasundram Publications for gene: RREB1 were set to PMID: 40418122
Intellectual disability v9.52 RREB1 Achchuthan Shanmugasundram reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38332451, 40418122; Phenotypes: RASopathy, MONDO:0021060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Respiratory ciliopathies including non-CF bronchiectasis v4.44 DNAJB13 Steven Cowman reviewed gene: DNAJB13: Rating: GREEN; Mode of pathogenicity: None; Publications: 40637281; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.32 IRF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: IRF1.
Tag Q3_25_NHS_review tag was added to gene: IRF1.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.32 IRF1 Achchuthan Shanmugasundram Classified gene: IRF1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.32 IRF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two unrelated cases and functional evidence in support of the association of biallelic IRF1 variants to immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.32 IRF1 Achchuthan Shanmugasundram Gene: irf1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.31 IRF1 Achchuthan Shanmugasundram Phenotypes for gene: IRF1 were changed from Immunodeficiency 117, mycobacteriosis, autosomal recessive to Immunodeficiency 117, mycobacteriosis, autosomal recessive, OMIM:620668
Primary immunodeficiency or monogenic inflammatory bowel disease v8.30 IRF1 Achchuthan Shanmugasundram Publications for gene: IRF1 were set to PMID: 36736301
Primary immunodeficiency or monogenic inflammatory bowel disease v8.29 IRF1 Achchuthan Shanmugasundram reviewed gene: IRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36736301; Phenotypes: Immunodeficiency 117, mycobacteriosis, autosomal recessive, OMIM:620668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic short stature v1.19 QSOX2 Achchuthan Shanmugasundram Classified gene: QSOX2 as Amber List (moderate evidence)
Monogenic short stature v1.19 QSOX2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although all three families were reported with short stature in PMID:39341815, there was only one family reported with height < -3 SD below mean (the eligibility criteria specified in the National Genomic Test Directory). There is also functional evidence available. Hence, this gene can be rated amber with current evidence.
Monogenic short stature v1.19 QSOX2 Achchuthan Shanmugasundram Gene: qsox2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.29 QSOX2 Achchuthan Shanmugasundram Classified gene: QSOX2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.29 QSOX2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although recurrent respiratory infections and atopic eczema were reported in all three unrelated families from PMID:39341815, immunological profile showing immunodeficiency was reported only in one family.

As there is functional evidence available in addition to human cases, this gene can be rated amber with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.29 QSOX2 Achchuthan Shanmugasundram Gene: qsox2 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.18 QSOX2 Achchuthan Shanmugasundram gene: QSOX2 was added
gene: QSOX2 was added to Monogenic short stature. Sources: Literature
Mode of inheritance for gene: QSOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: QSOX2 were set to 39341815
Phenotypes for gene: QSOX2 were set to Maharaj Storr Syndrome
Review for gene: QSOX2 was set to AMBER
Added comment: PMID:39341815 reported five patients from three unrelated families presenting with short stature, immune dysfunction, atopic eczema and gastrointestinal dysmotility. They were identified with biallelic QSOX2 variants via whole exome/genome sequencing. A total of six different variants were identified from these patients.

Although all five patients were reported with short stature, only the twins from family 1 had height < -3 SD below mean for the age. Recurrent respiratory infections and atopic eczema was reported in four patients from three families, while this was absent in the father of family 2. Low IgM levels and abnormalities in some other immunological markers were only reported in twins from family 1.

There is also functional evidence available. Patient-derived fibroblasts showed defective STAT5B nuclear translocation despite enhanced phosphorylation, and demonstrated growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.28 QSOX2 Achchuthan Shanmugasundram gene: QSOX2 was added
gene: QSOX2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: QSOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: QSOX2 were set to 39341815
Phenotypes for gene: QSOX2 were set to Maharaj Storr Syndrome
Review for gene: QSOX2 was set to AMBER
Added comment: PMID:39341815 reported five patients from three unrelated families presenting with short stature, immune dysfunction, atopic eczema and gastrointestinal dysmotility. They were identified with biallelic QSOX2 variants via whole exome/genome sequencing. A total of six different variants were identified from these patients.

Although all five patients were reported with short stature, only the twins from family 1 had height < -3 SD below mean for the age. Recurrent respiratory infections and atopic eczema was reported in four patients from three families, while this was absent in the father of family 2. Low IgM levels and abnormalities in some other immunological markers were only reported in twins from family 1.

There is also functional evidence available. Patient-derived fibroblasts showed defective STAT5B nuclear translocation despite enhanced phosphorylation, and demonstrated growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential.
Sources: Literature
Congenital myopathy v6.35 SRPK3 Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the diagnostic panel (no evidence for monogenic association).; to: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the panel as Green (no evidence for monogenic association).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.12 SRPK3 Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the diagnostic panel (no evidence for monogenic association).; to: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the panel as Green (no evidence for monogenic association).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.12 SRPK3 Arina Puzriakova Classified gene: SRPK3 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.12 SRPK3 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the diagnostic panel (no evidence for monogenic association).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.12 SRPK3 Arina Puzriakova Gene: srpk3 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.35 SRPK3 Arina Puzriakova Classified gene: SRPK3 as Amber List (moderate evidence)
Congenital myopathy v6.35 SRPK3 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the diagnostic panel (no evidence for monogenic association).
Congenital myopathy v6.35 SRPK3 Arina Puzriakova Gene: srpk3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.27 FLT3LG Arina Puzriakova Publications for gene: FLT3LG were set to 38701783
Primary immunodeficiency or monogenic inflammatory bowel disease v8.26 FLT3LG Arina Puzriakova Classified gene: FLT3LG as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.26 FLT3LG Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further evidence - only a single family reported to date but phenotype is recapitulated by null mouse model.

- PMID: 38701783 (2024) - three sibs from a consanguineous family with a homozygous frameshift variant and recurrent infections, including severe cutaneous warts, and hypoplastic bone marrow.
- PMID: 10828034 (2000) - null mouse model recapitulates bone marrow findings
Primary immunodeficiency or monogenic inflammatory bowel disease v8.26 FLT3LG Arina Puzriakova Gene: flt3lg has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.25 FLT3LG Arina Puzriakova Phenotypes for gene: FLT3LG were changed from Immunodeficiency; warts to ?Immunodeficiency 125 , OMIM:620926
Hereditary diffuse gastric cancer v2.2 CDH1 Arina Puzriakova Phenotypes for gene: CDH1 were changed from to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
Adult solid tumours cancer susceptibility v2.30 CDH1 Arina Puzriakova Phenotypes for gene: CDH1 were changed from Hereditary Diffuse Gastric Cancer, Familial Lobular Breast Cancer to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
Inherited ovarian cancer (without breast cancer) v4.7 CDH1 Arina Puzriakova Phenotypes for gene: CDH1 were changed from Endometrial carcinoma, somatic, 608089; Ovarian carcinoma, somatic, 167000; {Breast cancer, lobular}, 114480; Gastric cancer, familial diffuse, with or without cleft lip and/or palate, 137215; {Prostate cancer, susceptibility to}, 176807; High Risk Breast Cancer; Breast and Ovarian Cancer to Ovarian cancer, somatic, OMIM:167000
Adult solid tumours for rare disease v1.41 CDH1 Arina Puzriakova Phenotypes for gene: CDH1 were changed from Hereditary Diffuse Gastric Cancer, Familial Lobular Breast Cancer to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
Clefting v6.7 CDH1 Arina Puzriakova Phenotypes for gene: CDH1 were changed from BLEPHAROCHEILODONTIC; Blepharocheilodontic syndrome 1 to Blepharocheilodontic syndrome 1, OMIM:119580; Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
Fetal anomalies v6.13 CDH1 Arina Puzriakova Phenotypes for gene: CDH1 were changed from Blepharo-cheiro-dontic syndrome to Blepharocheilodontic syndrome 1, OMIM:119580
Familial breast cancer v1.27 CDH1 Arina Puzriakova Phenotypes for gene: CDH1 were changed from Endometrial carcinoma, somatic, 608089; Ovarian carcinoma, somatic, 167000; {Breast cancer, lobular}, 114480; Gastric cancer, familial diffuse, with or without cleft lip and/or palate, 137215; {Prostate cancer, susceptibility to}, 176807; High Risk Breast Cancer; Breast and Ovarian Cancer; lobular breast cancer to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
Familial breast cancer v1.26 CDH1 Arina Puzriakova Publications for gene: CDH1 were set to
Familial breast cancer v1.25 CDH1 Arina Puzriakova Classified gene: CDH1 as Green List (high evidence)
Familial breast cancer v1.25 CDH1 Arina Puzriakova Added comment: Comment on list classification: Rating Green as this is a well established breast cancer gene. Germline heterozygous variants have been found in diffuse gastric and lobular breast cancer syndrome. Patients may develop lobular breast cancer only or lobular breast cancer with gastric cancer. Lobular carcinoma of the breast has been reported in up to 60% of female carriers.
Familial breast cancer v1.25 CDH1 Arina Puzriakova Gene: cdh1 has been classified as Green List (High Evidence).
Breast cancer pertinent cancer susceptibility v2.14 CDH1 Arina Puzriakova changed review comment from: Comment on list classification: Updated rating from Red to Amber in line with review by Dmitrijs Rots - well-known for the breast cancer; to: Comment on list classification: Updated rating from Red to Amber in line with review by Dmitrijs Rots - well established breast cancer gene but appropriate for breast cancer susceptibility panel
Breast cancer pertinent cancer susceptibility v2.14 CDH1 Arina Puzriakova edited their review of gene: CDH1: Changed rating: AMBER
Breast cancer pertinent cancer susceptibility v2.14 CDH1 Arina Puzriakova Classified gene: CDH1 as Amber List (moderate evidence)
Breast cancer pertinent cancer susceptibility v2.14 CDH1 Arina Puzriakova Added comment: Comment on list classification: Updated rating from Red to Amber in line with review by Dmitrijs Rots - well-known for the breast cancer
Breast cancer pertinent cancer susceptibility v2.14 CDH1 Arina Puzriakova Gene: cdh1 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.3 POC5 Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
Monogenic diabetes v3.3 POC5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Monogenic diabetes v3.3 POC5 Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
Lipodystrophy - childhood onset v4.62 POC5 Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
Lipodystrophy - childhood onset v4.62 POC5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Lipodystrophy - childhood onset v4.62 POC5 Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v5.3 POC5 Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
Ophthalmological ciliopathies v5.3 POC5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. This disorder is also relevant to the R27 Paediatric disorders superpanel, which will be added through inclusion on the Ophthalmological ciliopathies panel.
Ophthalmological ciliopathies v5.3 POC5 Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.2 POC5 Arina Puzriakova gene: POC5 was added
gene: POC5 was added to Monogenic diabetes. Sources: Literature
Q3_25_promote_green tags were added to gene: POC5.
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 29272404; 40590205
Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology
Review for gene: POC5 was set to GREEN
Added comment: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature
Lipodystrophy - childhood onset v4.61 POC5 Arina Puzriakova gene: POC5 was added
gene: POC5 was added to Lipodystrophy - childhood onset. Sources: Literature
Q3_25_promote_green tags were added to gene: POC5.
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 29272404; 40590205
Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology
Review for gene: POC5 was set to GREEN
Added comment: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature
Ophthalmological ciliopathies v5.2 POC5 Arina Puzriakova gene: POC5 was added
gene: POC5 was added to Ophthalmological ciliopathies. Sources: Literature
Q3_25_promote_green tags were added to gene: POC5.
Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POC5 were set to 29272404; 40590205
Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology
Review for gene: POC5 was set to GREEN
Added comment: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Sources: Literature
Retinal disorders v8.13 POC5 Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
Retinal disorders v8.13 POC5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
Retinal disorders v8.13 POC5 Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.12 POC5 Arina Puzriakova Phenotypes for gene: POC5 were changed from to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology
Retinal disorders v8.11 POC5 Arina Puzriakova Publications for gene: POC5 were set to
Retinal disorders v8.10 POC5 Arina Puzriakova Mode of inheritance for gene: POC5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.9 POC5 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: POC5.
Tag Q3_25_NHS_review tag was added to gene: POC5.
Paediatric or syndromic cardiomyopathy v7.12 EYA4 Arina Puzriakova Classified gene: EYA4 as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v7.12 EYA4 Arina Puzriakova Gene: eya4 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v7.11 EYA4 Arina Puzriakova Classified gene: EYA4 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.11 EYA4 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red - only single report of a case of DCM preceded by sensorineural hearing loss (possibly) associated with a deletion in EYA4 (PMID: 10769282). No other evidence of link with DCM, only definitive association is with non-syndromic hearing loss. Association is classified as provisional in OMIM and limited in ClinGen.
Paediatric or syndromic cardiomyopathy v7.11 EYA4 Arina Puzriakova Gene: eya4 has been classified as Amber List (Moderate Evidence).
Dilated Cardiomyopathy and conduction defects v1.96 EYA4 Arina Puzriakova Classified gene: EYA4 as Red List (low evidence)
Dilated Cardiomyopathy and conduction defects v1.96 EYA4 Arina Puzriakova Added comment: Comment on list classification: Demoting from Green to Red - only single report of a case of DCM preceded by sensorineural hearing loss (possibly) associated with a deletion in EYA4 (PMID: 10769282). No other evidence of link with DCM, only definitive association is with non-syndromic hearing loss. Association is classified as provisional in OMIM and limited in ClinGen.
Dilated Cardiomyopathy and conduction defects v1.96 EYA4 Arina Puzriakova Gene: eya4 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v7.10 EYA4 Arina Puzriakova Phenotypes for gene: EYA4 were changed from Cardiomyopathy, dilated, 1J to ?Cardiomyopathy, dilated, 1J, OMIM:605362
Dilated and arrhythmogenic cardiomyopathy v3.2 EYA4 Arina Puzriakova Phenotypes for gene: EYA4 were changed from ?Cardiomyopathy, dilated, 1J (605362); Cardiomyopathy, dilated, 1J; Deafness, autosomal dominant 10 (601316) to ?Cardiomyopathy, dilated, 1J, OMIM:605362
Dilated Cardiomyopathy and conduction defects v1.95 EYA4 Arina Puzriakova Phenotypes for gene: EYA4 were changed from ?Cardiomyopathy, dilated, 1J (605362); Deafness, autosomal dominant 10 (601316); Cardiomyopathy, dilated, 1J to ?Cardiomyopathy, dilated, 1J, OMIM:605362
Monogenic hearing loss v5.23 EYA4 Arina Puzriakova Phenotypes for gene: EYA4 were changed from hearing loss; Nonsyndromic Hearing Loss, Dominant; Deafness, autosomal dominant 10, 601316; Cardiomyopathy, dilated, 1J, 605362 to Deafness, autosomal dominant 10, OMIM:601316
Hereditary neuropathy or pain disorder v7.5 RCC1 Arina Puzriakova Phenotypes for gene: RCC1 were changed from to Severe, acute-onset axonal neuropathy following infection
Hereditary neuropathy v1.500 RCC1 Arina Puzriakova Phenotypes for gene: RCC1 were changed from axonal neuropathy; encephalopathy; infection-induced neuropathy to Severe, acute-onset axonal neuropathy following infection
Hereditary neuropathy or pain disorder v7.4 RCC1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RCC1.
Tag Q3_25_NHS_review tag was added to gene: RCC1.
Hereditary neuropathy or pain disorder v7.4 RCC1 Arina Puzriakova Publications for gene: RCC1 were set to
Hereditary neuropathy v1.499 RCC1 Arina Puzriakova Publications for gene: RCC1 were set to PMID: 40683276
Hereditary neuropathy v1.498 RCC1 Arina Puzriakova Classified gene: RCC1 as Green List (high evidence)
Hereditary neuropathy v1.498 RCC1 Arina Puzriakova Added comment: Comment on list classification: Rating Green on this 100K panel as there is a sufficient number of unrelated cases with the same phenotype and functional data to support this gene-disease association.

At least 12 unrelated families reported (PMID: 40683276) with biallelic variants in this gene associated with severe, acute-onset axonal neuropathy following infection. Eight different missense variants were identified. In vitro studies indicate that variants reduced the thermal stability of the RCC1 protein and some variants decreased GDP-to-GTP exchange activity. Patient fibroblasts under stress, revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model demonstrated that altered Rcc1 function leads to fatal intolerance to oxidative stress.
Hereditary neuropathy v1.498 RCC1 Arina Puzriakova Gene: rcc1 has been classified as Green List (High Evidence).
Hereditary neuropathy or pain disorder v7.3 RCC1 Arina Puzriakova Classified gene: RCC1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.3 RCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - number of cases with the same phenotype and functional support.

At least 12 unrelated families reported (PMID: 40683276) with biallelic variants in this gene associated with severe, acute-onset axonal neuropathy following infection. Eight different missense variants were identified. In vitro studies indicate that variants reduced the thermal stability of the RCC1 protein and some variants decreased GDP-to-GTP exchange activity. Patient fibroblasts under stress, revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model demonstrated that altered Rcc1 function leads to fatal intolerance to oxidative stress.
Hereditary neuropathy or pain disorder v7.3 RCC1 Arina Puzriakova Gene: rcc1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.5 GPKOW Arina Puzriakova Classified gene: GPKOW as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.5 GPKOW Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with a multisystemic disorder due to hypomorphic or possible dominant-negative variants in this gene (PMID: 28612833; 40221893).
Paediatric disorders - additional genes v7.5 GPKOW Arina Puzriakova Gene: gpkow has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.9 GPKOW Arina Puzriakova edited their review of gene: GPKOW: Changed rating: AMBER
Severe microcephaly v8.9 GPKOW Arina Puzriakova Tag watchlist tag was added to gene: GPKOW.
Severe microcephaly v8.9 GPKOW Arina Puzriakova Classified gene: GPKOW as Amber List (moderate evidence)
Severe microcephaly v8.9 GPKOW Arina Puzriakova Added comment: Comment on list classification: Rating Amber as severity of microcephaly is not within the scope of this panel (> -3SD) in all cases. Particularly, in family 1 from PMID: 40221893 where head size increased following birth. This classification could be reviewed if additional cases of severe microcephaly associated with this gene emerge in the future (adding watchlist tag).

PMID: 28612833 - 5 affected males from one family with microcephaly that could be considered within the scope of the panel where biparietal diameter (BPD) is specified (see supplemental).

PMID: 40221893 - 3 affected males from 2 families: F1, in individual 1 HC was −2.4 SD at birth, changing to −1.3 SD at a later examination at 7 weeks, while individual 2 had a HC −3.47 SD at birth and −2.22 SD at 3 months; in F2, individual 3 had HC −3.47 SD at 33-weeks when the pregnancy was terminated. Heterozygous female carriers in F2 also had severe microcephaly, including the mother and sister of individual 3.
Severe microcephaly v8.9 GPKOW Arina Puzriakova Gene: gpkow has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.4 GPKOW Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: GPKOW.
Tag Q3_25_promote_green tag was added to gene: GPKOW.
Severe microcephaly v8.8 GPKOW Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: GPKOW.
Paediatric disorders - additional genes v7.4 GPKOW Arina Puzriakova Entity copied from Fetal anomalies v6.12
Paediatric disorders - additional genes v7.4 GPKOW Arina Puzriakova gene: GPKOW was added
gene: GPKOW was added to Paediatric disorders - additional genes. Sources: Expert Review Amber,PAGE Additional Gene List
Q2_25_ promote_green tags were added to gene: GPKOW.
Mode of inheritance for gene: GPKOW was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GPKOW were set to 28612833; 40221893
Phenotypes for gene: GPKOW were set to microcephaly with intrauterine growth restriction
Severe microcephaly v8.8 GPKOW Arina Puzriakova Entity copied from Fetal anomalies v6.12
Severe microcephaly v8.8 GPKOW Arina Puzriakova gene: GPKOW was added
gene: GPKOW was added to Severe microcephaly. Sources: Expert Review Amber,PAGE Additional Gene List
Q2_25_ promote_green tags were added to gene: GPKOW.
Mode of inheritance for gene: GPKOW was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GPKOW were set to 28612833; 40221893
Phenotypes for gene: GPKOW were set to microcephaly with intrauterine growth restriction
Primary immunodeficiency or monogenic inflammatory bowel disease v8.24 ASXL1 Boaz Palterer gene: ASXL1 was added
gene: ASXL1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ASXL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASXL1 were set to 40742536
Phenotypes for gene: ASXL1 were set to chronic viral infections; viral-associated malignancies; combined immune deficiency
Penetrance for gene: ASXL1 were set to unknown
Review for gene: ASXL1 was set to RED
Added comment: Fu et al. present a single case report with biallelic germline missense variants in ASXL1. The patient had a history of hematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction, confirming the patient variants’ pathogenicity.
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v5.7 AMPD1 Arina Puzriakova Phenotypes for gene: AMPD1 were changed from Rhabdomyolysis; Myopathy due to myoadenylate deaminase deficiency 615511 to Myopathy due to myoadenylate deaminase deficiency, OMIM:615511
Acute rhabdomyolysis v2.2 AMPD1 Arina Puzriakova Classified gene: AMPD1 as Green List (high evidence)
Acute rhabdomyolysis v2.2 AMPD1 Arina Puzriakova Added comment: Comment on list classification: This gene was promoted to Green and added to the diagnostic panel, however as per review by Zornitza Stark (below), it has since come to light that several variants reported in patients have a high frequency in the general population, calling into question their pathogenicity. Hence, tagging for GMS expert review to determine whether this gene should be demoted on this panel.


Copied from Zornitza Stark (Australian Genomics) review on Rhabdomyolysis and metabolic muscle disorders (66) panel (v3.35):

Variable age of onset ranging from infancy to adulthood (OMIM), however, no new publications supporting gene disease association. PMID: 21343608: Reported an infancy presenting with congenital hypotonia and muscle weakness. Variant reported in as VUS in ClinVar (as Q45*) and present in gnomad (1470 homozygotes) PMID: 11102975: Adult patient reported however variants reported R425H (also R458H) present in gnomad (3 homozygotes) and R388W (also R421W) present in gnomad (2 homozygotes).

The observation of a high number of homozygotes in gnomad together with the absence of new reports raises significant concerns about the pathogenicity of these variants.
Acute rhabdomyolysis v2.2 AMPD1 Arina Puzriakova Gene: ampd1 has been classified as Green List (High Evidence).
Acute rhabdomyolysis v2.1 AMPD1 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: AMPD1.
Tag Q3_25_demote_red tag was added to gene: AMPD1.
Rhabdomyolysis and metabolic muscle disorders v5.6 AMPD1 Arina Puzriakova Classified gene: AMPD1 as Green List (high evidence)
Rhabdomyolysis and metabolic muscle disorders v5.6 AMPD1 Arina Puzriakova Added comment: Comment on list classification: This gene was promoted to Green and added to the diagnostic panel, however as per review by Zornitza Stark, it has since come to light that several variants reported in patients have a high frequency in the general population, calling into question their pathogenicity. Hence, tagging for GMS expert review to determine whether this gene should be demoted on this panel.
Rhabdomyolysis and metabolic muscle disorders v5.6 AMPD1 Arina Puzriakova Gene: ampd1 has been classified as Green List (High Evidence).
Rhabdomyolysis and metabolic muscle disorders v5.5 AMPD1 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: AMPD1.
Tag Q3_25_demote_red tag was added to gene: AMPD1.
Fetal anomalies v6.12 MYH3 Arina Puzriakova Phenotypes for gene: MYH3 were changed from DISTAL ARTHROGRYPOSIS TYPE 2B; DISTAL ARTHROGRYPOSIS TYPE 2A to Arthrogryposis, distal, type 2A (Freeman-Sheldon), OMIM:193700 (AD); Arthrogryposis, distal, type 2B3 (Sheldon-Hall), OMIM:618436 (AD); Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110 (AD); Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469 (AR)
Fetal anomalies v6.11 MYH3 Arina Puzriakova Publications for gene: MYH3 were set to
Fetal anomalies v6.10 MYH3 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next GMS panel update.

Monoallelic variants are associated with distal arthrogryposis conditions including Freeman-Sheldon syndrome and Sheldon-Hall syndrome.

Monoallelic and biallelic variants also underlie Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterised by extensive bony abnormalities in addition to congenital contractures. These features could be detected prenatally and therefore are relevant to this panel.

At least 3 unrelated recessive CPSFS cases have been reported with multiple contractures (PMID: 29805041). Additionally, two sibs from one family have been reported with distal arthrogryposis without additional features of CPSFS, who harboured two homozygous ultra-rare MYH3 variants (PMID: 38856159). Their presentation was assessed in a prenatal diagnostic setting. Overall this evidence supports an MOI of 'both mono- and biallelic' on this panel.
Fetal anomalies v6.10 MYH3 Arina Puzriakova Mode of inheritance for gene: MYH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.52 MYH3 Arina Puzriakova Mode of inheritance for gene: MYH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.9 MYH3 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: MYH3.
Arthrogryposis v9.4 MYH3 Arina Puzriakova Publications for gene: MYH3 were set to
Arthrogryposis v9.3 MYH3 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: MYH3.
Arthrogryposis v9.3 MYH3 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next GMS panel update.

Monoallelic variants are associated with distal arthrogryposis conditions including Freeman-Sheldon syndrome and Sheldon-Hall syndrome.

Monoallelic and biallelic variants also underlie Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterised by extensive bony abnormalities in addition to congenital contractures - a phenotype relevant to this panel.

At least 3 unrelated recessive CPSFS cases have been reported with multiple contractures (PMID: 29805041). Additionally, two sibs from one family have been reported with distal arthrogryposis without additional features of CPSFS, who harboured two homozygous ultra-rare MYH3 variants (PMID: 38856159). Overall this evidence supports an MOI of 'both mono- and biallelic' on this panel.
Arthrogryposis v9.3 MYH3 Arina Puzriakova Mode of inheritance for gene: MYH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arthrogryposis v9.2 MYH3 Arina Puzriakova Phenotypes for gene: MYH3 were changed from Arthrogryposis, distal, type 2A, 193700; Arthrogryposis, distal, type 2B, 601680; Arthrogryposis Multiplex Congenita to Arthrogryposis, distal, type 2A (Freeman-Sheldon), OMIM:193700 (AD); Arthrogryposis, distal, type 2B3 (Sheldon-Hall), OMIM:618436 (AD); Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110 (AD); Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469 (AR)
Ataxia and cerebellar anomalies - narrow panel v8.13 ZFHX3 Arina Puzriakova Classified gene: ZFHX3 as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v8.13 ZFHX3 Arina Puzriakova Gene: zfhx3 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.24 HSPA1L Arina Puzriakova Classified gene: HSPA1L as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.24 HSPA1L Arina Puzriakova Added comment: Comment on list classification: This gene was recently promoted to Green and added to the diagnostic panel, however as per review by Zornitza Stark, it has since come to light that several variants reported in patients have a high frequency in the general population, calling into question their pathogenicity. Hence, tagging for GMS expert review to determine whether this gene should be demoted on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.24 HSPA1L Arina Puzriakova Gene: hspa1l has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.23 HSPA1L Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: HSPA1L.
Tag Q3_25_demote_amber tag was added to gene: HSPA1L.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.23 AMFR Arina Puzriakova changed review comment from: Comment on list classification: Rating Red as currently there is only a single human case report linking this gene to immune dysfunction. Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.; to: Comment on list classification: Rating Red as currently there is only a single human case report linking this gene to immune dysfunction (PMID:38277122). Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.23 AMFR Arina Puzriakova changed review comment from: Comment on list classification: Rating Red as currently there is only a single report linking this gene to immune dysfunction. Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.; to: Comment on list classification: Rating Red as currently there is only a single human case report linking this gene to immune dysfunction. Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.23 AMFR Arina Puzriakova Classified gene: AMFR as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.23 AMFR Arina Puzriakova Added comment: Comment on list classification: Rating Red as currently there is only a single report linking this gene to immune dysfunction. Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.23 AMFR Arina Puzriakova Gene: amfr has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v8.18 MT-TK Arina Puzriakova Classified gene: MT-TK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.18 MT-TK Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
Early onset or syndromic epilepsy v8.18 MT-TK Arina Puzriakova Gene: mt-tk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.17 MT-TK Arina Puzriakova Classified gene: MT-TK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.17 MT-TK Arina Puzriakova Gene: mt-tk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.16 MT-TK Arina Puzriakova gene: MT-TK was added
gene: MT-TK was added to Early onset or syndromic epilepsy. Sources: Literature
locus-type-rna-transfer, Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: MT-TK.
Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL
Publications for gene: MT-TK were set to 1463006; 8228033; 18651333; 29663531; 33766967
Phenotypes for gene: MT-TK were set to MERRF syndrome, MONDO:0010790
Review for gene: MT-TK was set to GREEN
Added comment: Adding MT-TK to this panel by suggestion of North East and Yorkshire GLH where a patient was identified with a tier 3 diagnostic MT-TK variant due to absence of the gene on this applied panel.

MT-TK gene has been associated with severe mitochondrial diseases which includes myoclonic epilepsy - multiple (at least 8) unrelated cases with epilepsy as a presenting feature have been reported in the literature (PMID: 1463006; 8228033; 18651333; 29663531; 33766967)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.22 DPP9 Arina Puzriakova Classified gene: DPP9 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.22 DPP9 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Three unrelated families with four individuals with an immune disorder characterised by failure to thrive, skin manifestations, pancytopenia, recurrent fevers and recurrent infections. Supporting mouse and zebrafish models (PMID: 36112693)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.22 DPP9 Arina Puzriakova Gene: dpp9 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v4.3 MNS1 Karen Stals reviewed gene: MNS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38920647; Phenotypes: Laterality defects, ciliopathy disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v9.19 PDE12 Karen Stals reviewed gene: PDE12: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:39567835; Phenotypes: Neonatal mitochondrial disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.21 DPP9 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DPP9.
Tag Q3_25_NHS_review tag was added to gene: DPP9.
Intellectual disability v9.51 MED16 Karen Stals gene: MED16 was added
gene: MED16 was added to Intellectual disability. Sources: NHS GMS
Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED16 were set to PMID: 40081376
Phenotypes for gene: MED16 were set to developmental delay; multiple congenital abnormalities; Medopathy
Penetrance for gene: MED16 were set to unknown
Review for gene: MED16 was set to GREEN
gene: MED16 was marked as current diagnostic
Added comment: 25 individuals from 18 families reported with biallelic MED16 variants with multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. 8 predicted protein-truncating and 18 missense or in-frame duplication variants identified.
Sources: NHS GMS
Primary immunodeficiency or monogenic inflammatory bowel disease v8.21 DPP9 Arina Puzriakova Publications for gene: DPP9 were set to PMID: 36112693
Primary immunodeficiency or monogenic inflammatory bowel disease v8.20 DPP9 Arina Puzriakova Phenotypes for gene: DPP9 were changed from Hatipoglu immunodeficiency syndrome to Hatipoglu immunodeficiency syndrome, OMIM:620331
Fetal hydrops v1.89 RASA1 Karen Stals reviewed gene: RASA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36980822; Phenotypes: hydrops, chylothorax, Capillary malformation-arteriovenous malformation 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v9.51 RREB1 Karen Stals gene: RREB1 was added
gene: RREB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RREB1 were set to PMID: 40418122
Phenotypes for gene: RREB1 were set to Rasopathy; Noonan-like; developmental disorder
Penetrance for gene: RREB1 were set to Complete
Review for gene: RREB1 was set to GREEN
Added comment: 6 additional individuals with truncating variants in RREB1 gene and a Rasopathy phenotype, features including congenital heart disease, developmental delay, short stature, and dysmorphic facial features (PMID: 40418122). RREB1 encodes a transcriptional repressor of Ras-MAPK signalling. Supporting functional evidence and animal models.
Sources: Literature
Monogenic short stature v1.17 RREB1 Karen Stals gene: RREB1 was added
gene: RREB1 was added to Monogenic short stature. Sources: Literature
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RREB1 were set to PMID: 40418122
Phenotypes for gene: RREB1 were set to Rasopathy; Noonan-like; developmental disorder
Penetrance for gene: RREB1 were set to Complete
Review for gene: RREB1 was set to GREEN
Added comment: 6 additional individuals with truncating variants in RREB1 gene and a Rasopathy phenotype, features including congenital heart disease, developmental delay, short stature, and dysmorphic facial features (PMID: 40418122). RREB1 encodes a transcriptional repressor of Ras-MAPK signalling. Supporting functional evidence and animal models.
Sources: Literature
RASopathies v1.83 RREB1 Karen Stals reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40418122; Phenotypes: Rasopathy, Noonan-like, developmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v7.3 MC4R Arina Puzriakova Classified gene: MC4R as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.3 MC4R Arina Puzriakova Added comment: Comment on list classification: This gene should be promote to Green at the next GMS panel update. There is sufficient evidence to support this gene-disease association (variants in the MC4R gene are the most common cause of monogenic obesity, >3 cases). As highlighted in the review by Ian Berry, the R27 panel represents an alternative test to R149 that may be requested for these patients which warrants inclusion of the MC4R gene on this panel.
Paediatric disorders - additional genes v7.3 MC4R Arina Puzriakova Gene: mc4r has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.2 MC4R Arina Puzriakova Phenotypes for gene: MC4R were changed from to Obesity (BMIQ20), OMIM:618406; {Obesity, resistence to (BMIQ20)}, OMIM:618306
Paediatric disorders - additional genes v7.1 MC4R Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MC4R.
Tag Q3_25_NHS_review tag was added to gene: MC4R.
Structural eye disease v4.18 FOXE3 Arina Puzriakova Phenotypes for gene: FOXE3 were changed from Anterior segment mesenchymal dysgenesis, OMIM:107250; Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256 to Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Cataract 34, multiple types, OMIM:612968
Structural eye disease v4.17 FOXE3 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: FOXE3.
Tag Q3_25_MOI tag was added to gene: FOXE3.
Structural eye disease v4.17 FOXE3 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from ' BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' at the next GMS panel update.

As highlighted in review by Dorine Bax, at least 6 cases with heterozygous variants and cataracts and/or anterior segment dysgenesis have been reported, which appear to represent a spectrum of disease rather than separate disease entities. Both presentations are relevant to this panel and therefore should be included. AD inheritance is discussed in ClinGen and OMIM curations of this gene-disease association. Cases with AR inheritance generally have more severe presentation.
Structural eye disease v4.17 FOXE3 Arina Puzriakova Mode of inheritance for gene: FOXE3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v4.16 FOXE3 Arina Puzriakova Tag watchlist_moi was removed from gene: FOXE3.
Tag Q3_25_promote_green tag was added to gene: FOXE3.
Tag Q3_25_NHS_review tag was added to gene: FOXE3.
Hereditary neuropathy v1.497 RCC1 Bill Newman gene: RCC1 was added
gene: RCC1 was added to Hereditary neuropathy. Sources: Expert list
Mode of inheritance for gene: RCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RCC1 were set to PMID: 40683276
Phenotypes for gene: RCC1 were set to axonal neuropathy; encephalopathy; infection-induced neuropathy
Penetrance for gene: RCC1 were set to Complete
Review for gene: RCC1 was set to GREEN
Added comment: We have just described 12 families withbiallelic hylomorphic variants in this gene associated with acute onset axonal neuropathy mimicking Guillain Barre syndrome (ie post infective onset)
Sources: Expert list
Early onset or syndromic epilepsy v8.15 RNU5B-1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with variable degrees of intellectual disability reported in almost all cases. This disorder to relevant to the R27 Paediatric disorders superpanel, which will be added through inclusion on the Intellectual disability panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with seizures reported in 6 unrelated cases which can be an early presenting feature.
Early onset or syndromic epilepsy v8.15 RNU5B-1 Arina Puzriakova Entity copied from Intellectual disability v9.51
Early onset or syndromic epilepsy v8.15 RNU5B-1 Arina Puzriakova gene: RNU5B-1 was added
gene: RNU5B-1 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
locus-type-rna-small-nuclear, dd_review, Q3_25_promote_green tags were added to gene: RNU5B-1.
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5B-1 were set to 40379786; 40442284
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.14 RNU5A-1 Arina Puzriakova Entity copied from Intellectual disability v9.51
Early onset or syndromic epilepsy v8.14 RNU5A-1 Arina Puzriakova gene: RNU5A-1 was added
gene: RNU5A-1 was added to Early onset or syndromic epilepsy. Sources: Expert Review Red,Literature
locus-type-rna-small-nuclear tags were added to gene: RNU5A-1.
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.51 RNU5A-1 Arina Puzriakova Classified gene: RNU5A-1 as Red List (low evidence)
Intellectual disability v9.51 RNU5A-1 Arina Puzriakova Added comment: Comment on list classification: Rating Red awaiting further evidence - limited number of cases currently reported with variable neurodevelopmental phenotype. Variants have been classified as VUS and additional evidence is required to ascertain pathogenicity.
Intellectual disability v9.51 RNU5A-1 Arina Puzriakova Gene: rnu5a-1 has been classified as Red List (Low Evidence).
Intellectual disability v9.50 RNU5A-1 Arina Puzriakova gene: RNU5A-1 was added
gene: RNU5A-1 was added to Intellectual disability. Sources: Literature
locus-type-rna-small-nuclear tags were added to gene: RNU5A-1.
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder, MONDO:0700092
Added comment: PMID: 40379786 (2025) - three unrelated individuals with de novo variants in the RNU5A-1 gene (classified as VUS) and a neurodevelopmental disorder. Six individuals with rare de novo variants were identified in total but clinical details were only available for 3/6. Of these three individuals, two harboured the same variant (n.40_41insA) on the maternal allele, while the third individual harboured a different variant (n.39del) but also on the 5′ loop I domain of RNU5A-1. Clinical data showed neurodevelopmental abnormalities (mild ID (2), severe ID (1), epilepsy (2), brain MRI abnormalities (1)) with variable congenital malformations.
Sources: Literature
Intellectual disability v9.49 RNU2-2P Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679; 40442284
Intellectual disability v9.48 RNU5B-1 Arina Puzriakova Tag locus-type-rna-small-nuclear tag was added to gene: RNU5B-1.
Tag dd_review tag was added to gene: RNU5B-1.
Intellectual disability v9.48 RNU2-2P Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679
Early onset or syndromic epilepsy v8.13 RNU2-2P Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679
Intellectual disability v9.47 RNU5B-1 Arina Puzriakova Classified gene: RNU5B-1 as Amber List (moderate evidence)
Intellectual disability v9.47 RNU5B-1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with variable degrees of intellectual disability reported in almost all cases. This disorder to relevant to the R27 Paediatric disorders superpanel, which will be added through inclusion on the Intellectual disability panel.
Intellectual disability v9.47 RNU5B-1 Arina Puzriakova Gene: rnu5b-1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.46 RNU5B-1 Arina Puzriakova gene: RNU5B-1 was added
gene: RNU5B-1 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: RNU5B-1.
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5B-1 were set to 40379786; 40442284
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: RNU5B-1 was set to GREEN
Added comment: At least 19 individuals with de novo and/or recurrent variants in RNU5B-1 and a neurodevelopmental disorder characterised by ID/DD, brain MRI abnormalities, hypotonia, microcephaly or macrocephaly, failure to thrive, and in some cases seizures.

PMID: 40379786 (2025) - 15 unrelated probands with heterozygous variants in RNU5B-1. Clinical data was available for 9 individuals who presented with a neurodevelopmental disorder including severe ID/DD (although one patient had normal cognition but attention difficulties) and brain MRI abnormalities. Other features were variable and include hypotonia, epilepsy, ocular abnormalities, acquired microcephaly or macrocephaly and other variable congenital abnormalities. Variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. Functional studies demonstrate variant-specific splicing abnormalities in patient-derived cells which may underline the clinical variability observed in patients.

PMID: 40442284 (2025) - 9 unrelated individuals with de novo variants in RNU5B-1 and a neurodevelopmental disorder characterised by GDD/ID, macrocephaly, eye abnormalities, seizures, hypotonia and failure to thrive, among other variable features - based on 6 cases where phenotype information was available. Variants were again found in regions critical for splicing.

Both studies investigated participants of the 100KGP and/or NHS GMS (6 in PMID: 40379786 and 5 in PMID: 40442284) so likely refer to the same individuals.
Sources: Literature
Congenital myaesthenic syndrome v5.1 UNC13A Tom Hodgkinson reviewed gene: UNC13A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 28192369, 39634123.; Phenotypes: ; Mode of inheritance: None
Intellectual disability v9.45 UNC13A Tom Hodgkinson reviewed gene: UNC13A: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 8192369, 39634123; Phenotypes: ASD, dyskinetic movement disorder, febrile seizures, developmental delay, intellectual disability, ataxia; Mode of inheritance: None
DDG2P v6.1 ELFN1 Rhys Dore reviewed gene: ELFN1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 40576023, 34509675, 34452636; Phenotypes: intellectual disability, developmental delay, epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brugada syndrome and cardiac sodium channel disease v3.13 ANK2 Arina Puzriakova Tag disputed tag was added to gene: ANK2.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.19 IRF1 Hannah Knight gene: IRF1 was added
gene: IRF1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: IRF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IRF1 were set to PMID: 36736301
Phenotypes for gene: IRF1 were set to Immunodeficiency 117, mycobacteriosis, autosomal recessive
Review for gene: IRF1 was set to GREEN
Added comment: 2 unrelated children, each born of consanguineous parents of Latin American and Turkish descent, respectively, who presented in early childhood with recurrent and severe mycobacterial disease, including BCG infections and infections with M. avium complex. Two different homozygous nonsense variants in IRF1 (p.R129X and p.Q35X).
Also supportive functional data
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.19 DPP9 Hannah Knight gene: DPP9 was added
gene: DPP9 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: DPP9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPP9 were set to PMID: 36112693
Phenotypes for gene: DPP9 were set to Hatipoglu immunodeficiency syndrome
Review for gene: DPP9 was set to GREEN
Added comment: PMID: 36112693 reported four patients from three unrelated families with biallelic DPP9 variants causing Hatipoglu immunodeficiency syndrome:
- A 6-year-old boy, born of unrelated parents of Ashkenazi Jewish descent, with compound heterozygous variants (p.S214X and p.G167S)
- A 14-year-old boy, born of consanguineous Turkish parents, with a homozygous variant (p.Q851X)
- Two male patients from a consanguineous Bedouin family in Israel, with a homozygous variant (p.R111X)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.19 CD274 Hannah Knight gene: CD274 was added
gene: CD274 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: CD274 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD274 were set to PMID: 38634869
Phenotypes for gene: CD274 were set to ?Autoimmune disease, multisystem, infantile-onset, 5
Review for gene: CD274 was set to RED
Added comment: In 2 sibs, born of consanguineous Moroccan parents, PMID: 38634869 identified a homozygous splice site mutation in the CD274 gene.

Both presented with neonatal onset of type 1 diabetes mellitus.

The male proband subsequently developed asthma at 5 months of age, autoimmune hypothyroidism at age 3 years, and growth hormone deficiency at age 10. The boy also had mildly impaired intellectual development and speech delay that was attributed to a de novo heterozygous duplication at 7q11.23, which is associated with neurologic phenotypes and growth hormone deficiency. The sister, who did not have this duplication, had no clinical manifestations other than type 1 diabetes
Sources: Literature
Hereditary neuropathy or pain disorder v7.2 RCC1 Cassandra Smith reviewed gene: RCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40683276; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v4.7 HGF Achchuthan Shanmugasundram Classified gene: HGF as Amber List (moderate evidence)
Primary lymphoedema v4.7 HGF Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>10 unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.
Primary lymphoedema v4.7 HGF Achchuthan Shanmugasundram Gene: hgf has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v4.6 HGF Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: HGF.
Primary lymphoedema v4.6 HGF Achchuthan Shanmugasundram Phenotypes for gene: HGF were changed from to primary lymphedema, MONDO:0019175
Primary lymphoedema v4.5 HGF Achchuthan Shanmugasundram Publications for gene: HGF were set to 18564920
Primary lymphoedema v4.4 HGF Achchuthan Shanmugasundram Mode of inheritance for gene: HGF was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary lymphoedema v4.3 HGF Achchuthan Shanmugasundram reviewed gene: HGF: Rating: GREEN; Mode of pathogenicity: None; Publications: 38676400, 38791500; Phenotypes: primary lymphedema, MONDO:0019175; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.45 PRMT9 Achchuthan Shanmugasundram Phenotypes for gene: PRMT9 were changed from to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.44 PRMT9 Achchuthan Shanmugasundram Publications for gene: PRMT9 were set to 21937992
Intellectual disability v9.43 PRMT9 Achchuthan Shanmugasundram reviewed gene: PRMT9: Rating: RED; Mode of pathogenicity: None; Publications: 21937992, 38561334; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v7.9 ASNA1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Dmitrijs Rots, PMID:31461301 reported the identification of compound heterozygous variants in two siblings with early infantile-onset, rapidly progressive dilated cardiomyopathy. There were two variants reported on the paternal allele (p.Cys289Trp and p.Gln305Ter) and one variant on the maternal allele (p.Val163Ala). Unaffected sibling was heterozygous for maternal allele.

Functional studies showed that Val163Ala variant leads to protein misfolding as well as less effective tail-anchored protein insertion. Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality. In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype.

As there is only one case and functional evidence available in support of this association, this gene can only be rated amber now.; to: PMID:31461301 reported the identification of compound heterozygous variants in two siblings with early infantile-onset, rapidly progressive dilated cardiomyopathy. There were two variants reported on the paternal allele (p.Cys289Trp and p.Gln305Ter) and one variant on the maternal allele (p.Val163Ala). Unaffected sibling was heterozygous for maternal allele.

Functional studies showed that Val163Ala variant leads to protein misfolding as well as less effective tail-anchored protein insertion. Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality. In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype.

As there is only one case and functional evidence available in support of this association, this gene can only be rated amber now.
Paediatric or syndromic cardiomyopathy v7.9 ASNA1 Achchuthan Shanmugasundram Classified gene: ASNA1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.9 ASNA1 Achchuthan Shanmugasundram Gene: asna1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.8 ASNA1 Achchuthan Shanmugasundram Phenotypes for gene: ASNA1 were changed from Rapidly Progressive Pediatric Cardiomyopathy to ?Cardiomyopathy, dilated, 2H, OMIM:620203
Paediatric or syndromic cardiomyopathy v7.7 ASNA1 Achchuthan Shanmugasundram Publications for gene: ASNA1 were set to PMID: 31461301
Paediatric or syndromic cardiomyopathy v7.6 ASNA1 Achchuthan Shanmugasundram reviewed gene: ASNA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31461301; Phenotypes: ?Cardiomyopathy, dilated, 2H, OMIM:620203; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.12 UBR5 Achchuthan Shanmugasundram Classified gene: UBR5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.12 UBR5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.12 UBR5 Achchuthan Shanmugasundram Gene: ubr5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.11 UBR5 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UBR5.
Intellectual disability v9.43 UBR5 Achchuthan Shanmugasundram Classified gene: UBR5 as Amber List (moderate evidence)
Intellectual disability v9.43 UBR5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.43 UBR5 Achchuthan Shanmugasundram Gene: ubr5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.42 UBR5 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UBR5.
Early onset or syndromic epilepsy v8.11 UBR5 Achchuthan Shanmugasundram gene: UBR5 was added
gene: UBR5 was added to Early onset or syndromic epilepsy. Sources: Literature
dd_review tags were added to gene: UBR5.
Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBR5 were set to 39721588
Phenotypes for gene: UBR5 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: UBR5 was set to GREEN
Added comment: PMID:39721588 reported 29 unrelated individuals with a complex neurodevelopmental syndrome, which includes developmental delay (26/28), autism (16/26), intellectual disability (14/25), epilepsy (11/27), movement disorders (6/26) and/ or genital anomalies (4/25) as presenting phenotypes. They were all identified with variants in UBR5 gene, of which 28 had monoallelic inheritance (24 with de novo, 1 with maternal, 1 with maternal mosaic and 2 with unknown inheritance), while one had recessive inheritance.

Of the 28 patients with monoallelic variants, 16 had global developmental delay, 13 had ID and 10 patients had epilepsy/ seizures. The single patient with biallelic variant had severe/ profound ID, developmental delay and epileptic encephalopathy.

Functional evidence is also available from C. elegans and in vitro ubiquitination assays.

This gene is associated with phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.
Sources: Literature
Intellectual disability v9.42 UBR5 Achchuthan Shanmugasundram gene: UBR5 was added
gene: UBR5 was added to Intellectual disability. Sources: Literature
dd_review tags were added to gene: UBR5.
Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBR5 were set to 39721588
Phenotypes for gene: UBR5 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: UBR5 was set to GREEN
Added comment: PMID:39721588 reported 29 unrelated individuals with a complex neurodevelopmental syndrome, which includes developmental delay (26/28), autism (16/26), intellectual disability (14/25), epilepsy (11/27), movement disorders (6/26) and/ or genital anomalies (4/25) as presenting phenotypes. They were all identified with variants in UBR5 gene, of which 28 had monoallelic inheritance (24 with de novo, 1 with maternal, 1 with maternal mosaic and 2 with unknown inheritance), while one had recessive inheritance.

Of the 28 patients with monoallelic variants, 16 had global developmental delay, 13 had ID and 10 patients had epilepsy/ seizures. The single patient with biallelic variant had severe/ profound ID, developmental delay and epileptic encephalopathy.

Functional evidence is also available from C. elegans and in vitro ubiquitination assays.

This gene is associated with phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.19 CSF3R Arina Puzriakova Phenotypes for gene: CSF3R were changed from Neutropenia, severe congenital, 7, autosomal recessive, 617014; Neutropenia, severe congenital 7; Congenital neutropenia; N/A; Congenital defects of phagocyte number or function to Neutropenia, severe congenital, 7, autosomal recessive, OMIM:617014; Congenital defects of phagocyte number or function
Cytopenia - NOT Fanconi anaemia v4.21 CSF3R Arina Puzriakova Phenotypes for gene: CSF3R were changed from Neutropenia, severe congenital, 7, autosomal recessive, 617014; 617014 Neutropenia, severe congenital, 7; 617014 Neutropenia, severe congenital, 7, autosomal recessive; Severe congenital neutropenia to Neutropenia, severe congenital, 7, autosomal recessive, OMIM:617014
Mitochondrial disorders v9.19 GUK1 Hannah Knight gene: GUK1 was added
gene: GUK1 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GUK1 were set to PMID: 39230499
Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome 21
Review for gene: GUK1 was set to GREEN
Added comment: Four patients from three families reported with mitochondrial disorders and biallelic GUK1 variants. Different variants in all three families.
Key symptoms include ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy
Sources: Literature
Distal myopathies v6.8 NEB Achchuthan Shanmugasundram Tag dd_review tag was added to gene: NEB.
Intellectual disability v9.41 CRNKL1 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
Early onset or syndromic epilepsy v8.10 CRNKL1 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
Severe microcephaly v8.7 CRNKL1 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
Ataxia and cerebellar anomalies - narrow panel v8.12 CRNKL1 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
Intellectual disability v9.41 PDE1B Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
Intellectual disability v9.41 PDE1B Achchuthan Shanmugasundram Added comment: Comment on list classification: Intellectual disability was reported with the severity of moderate or above in only one patient and was either mild or severity not reported in others. Hence, this gene can only be rated amber with the current evidence.
Intellectual disability v9.41 PDE1B Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.6 NFIA Achchuthan Shanmugasundram Classified gene: NFIA as Amber List (moderate evidence)
Malformations of cortical development v7.6 NFIA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Malformations of cortical development v7.6 NFIA Achchuthan Shanmugasundram Gene: nfia has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.5 NFIA Achchuthan Shanmugasundram Phenotypes for gene: NFIA were changed from to Brain malformations with or without urinary tract defects, OMIM:613735
Malformations of cortical development v7.4 NFIA Achchuthan Shanmugasundram Publications for gene: NFIA were set to 36553517,
Malformations of cortical development v7.3 NFIA Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NFIA.
Malformations of cortical development v7.3 NFIA Achchuthan Shanmugasundram reviewed gene: NFIA: Rating: GREEN; Mode of pathogenicity: None; Publications: 27081522, 28452798, 33973697, 36553517; Phenotypes: Brain malformations with or without urinary tract defects, OMIM:613735; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v7.3 PDE1B Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v7.3 PDE1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with childhood onset dystonia. Hence, this gene can be promoted to green rating in the next GMS update.
Childhood onset dystonia, chorea or related movement disorder v7.3 PDE1B Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.2 PDE1B Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PDE1B.
Childhood onset dystonia, chorea or related movement disorder v7.2 PDE1B Achchuthan Shanmugasundram gene: PDE1B was added
gene: PDE1B was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE1B were set to 40492975
Phenotypes for gene: PDE1B were set to movement disorder, MONDO:0005395
Review for gene: PDE1B was set to GREEN
Added comment: As reviewed by Sarah Dixon, PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total.

They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability. Dystonia has been reported in five patients from four families. Functional evidence is also available for these variants.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.40 PDE1B Achchuthan Shanmugasundram changed review comment from: As reviewed by Sarah Dixon, PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total.

They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability (ID). ID was moderate in one patient, mild in three and severity not reported in one (ID noticed at the age of three years), while ID was not reported in two patients.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; to: As reviewed by Sarah Dixon, PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total.

They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability (ID). ID was moderate in one patient, mild in three and severity not reported in one patient (ID noticed at the age of three years).

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.
Ataxia and cerebellar anomalies - narrow panel v8.12 PDE1B Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.12 PDE1B Achchuthan Shanmugasundram Added comment: Comment on list classification: Ataxia has been reported in four unrelated families and hence this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.12 PDE1B Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.11 PDE1B Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PDE1B.
Tag Q3_25_NHS_review tag was added to gene: PDE1B.
Ataxia and cerebellar anomalies - narrow panel v8.11 PDE1B Achchuthan Shanmugasundram Phenotypes for gene: PDE1B were changed from hypotonia; ataxia; dystonia; developmental delay; intellectual disability to movement disorder, MONDO:0005395
Ataxia and cerebellar anomalies - narrow panel v8.10 PDE1B Achchuthan Shanmugasundram Publications for gene: PDE1B were set to PMID: 40492975
Ataxia and cerebellar anomalies - narrow panel v8.9 PDE1B Achchuthan Shanmugasundram reviewed gene: PDE1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 40492975; Phenotypes: movement disorder, MONDO:0005395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.40 PDE1B Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
Intellectual disability v9.40 PDE1B Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.39 PDE1B Achchuthan Shanmugasundram Phenotypes for gene: PDE1B were changed from hypotonia; ataxia; dystonia; developmental delay; intellectual disability to movement disorder, MONDO:0005395; intellectual disability, MONDO:0001071
Intellectual disability v9.38 PDE1B Achchuthan Shanmugasundram edited their review of gene: PDE1B: Changed phenotypes to: movement disorder, MONDO:0005395, intellectual disability, MONDO:0001071
Intellectual disability v9.38 PDE1B Achchuthan Shanmugasundram Publications for gene: PDE1B were set to PMID: 40492975
Intellectual disability v9.37 PDE1B Achchuthan Shanmugasundram reviewed gene: PDE1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 40492975; Phenotypes: movement disorder, MONDO:0005395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.9 RP1L1 Chris Campbell reviewed gene: RP1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Paediatric disorders - additional genes v7.1 CACHD1 Achchuthan Shanmugasundram changed review comment from: PMID:38158856 reported six affected individuals from four unrelated families with biallelic (either homozygous or compound heterozygous) CACHD1 variants (3 splice, 2 frameshift and 1 nonsense variant).

Excluding the two fatal cases from the fourth family, all others were affected by syndromic neurodevelopmental abnormalities, multiple organ systems featuring global impairment of psychomotor development, dysmorphic facial features, genitourinary abnormalities, oculo-auricular and congenital malformation. Cognitive impairment was reported to be mild in three cases from three different families, while the fourth case had no cognitive impairment. Psychomotor delay was reported in two unrelated cases and seizure was reported in one.

Functional evidence from human stem cell-derived neural models and zebrafish mutants are also available in support of the disease association.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:38158856 reported six affected individuals from four unrelated families with biallelic (either homozygous or compound heterozygous) CACHD1 variants (3 splice, 2 frameshift and 1 nonsense variant).

Excluding the two fetal cases from the fourth family, all others were affected by syndromic neurodevelopmental abnormalities, multiple organ systems featuring global impairment of psychomotor development, dysmorphic facial features, genitourinary abnormalities, oculo-auricular and congenital malformation. Cognitive impairment was reported to be mild in three cases from three different families, while the fourth case had no cognitive impairment. Psychomotor delay was reported in two unrelated cases and seizure was reported in one.

Functional evidence from human stem cell-derived neural models and zebrafish mutants are also available in support of the disease association.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Structural eye disease v4.16 NR6A1 Achchuthan Shanmugasundram Classified gene: NR6A1 as Amber List (moderate evidence)
Structural eye disease v4.16 NR6A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Structural eye disease v4.16 NR6A1 Achchuthan Shanmugasundram Gene: nr6a1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v4.15 NR6A1 Achchuthan Shanmugasundram Phenotypes for gene: NR6A1 were changed from microphthalmia, coloboma to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129
Structural eye disease v4.14 NR6A1 Achchuthan Shanmugasundram Publications for gene: NR6A1 were set to PMID: 40610405
Structural eye disease v4.13 NR6A1 Achchuthan Shanmugasundram Mode of inheritance for gene: NR6A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v4.12 NR6A1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NR6A1.
Tag Q3_25_NHS_review tag was added to gene: NR6A1.
Structural eye disease v4.12 NR6A1 Achchuthan Shanmugasundram reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40610405; Phenotypes: coloboma, MONDO:0001476, microphthalmia, MONDO:0021129; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v4.12 EFEMP1 Achchuthan Shanmugasundram Classified gene: EFEMP1 as Amber List (moderate evidence)
Structural eye disease v4.12 EFEMP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic EFEMP1 variants with glaucoma, which fits into the scope of this panel. Hence, this gene can be promoted to green rating in the next GMS update.
Structural eye disease v4.12 EFEMP1 Achchuthan Shanmugasundram Gene: efemp1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v4.11 EFEMP1 Achchuthan Shanmugasundram Phenotypes for gene: EFEMP1 were changed from Doyne honeycomb degeneration of retina, 126600; Eye Disorders to Glaucoma 1, open angle, H, OMIM:611276
Structural eye disease v4.10 EFEMP1 Achchuthan Shanmugasundram Publications for gene: EFEMP1 were set to
Structural eye disease v4.9 EFEMP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: EFEMP1.
Structural eye disease v4.9 EFEMP1 Achchuthan Shanmugasundram reviewed gene: EFEMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glaucoma 1, open angle, H, OMIM:611276; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Respiratory ciliopathies including non-CF bronchiectasis v4.44 CFAP74 Achchuthan Shanmugasundram commented on gene: CFAP74: The ClinGen Motile Ciliopathy expert panel has updated the classification for the association of CFAP74 gene to ciliary dyskinesia, primary, 49, without situs inversus (MONDO:0859353) from 'Limited' to 'Moderate' on 18/06/2025.

The reason for classification change is summarised in ClinGen (https://search.clinicalgenome.org/CCID:004429) as follows:
"Recurated and changed classification from Limited to Moderate. Additional proband from a ClinVar submission, and additional immunofluorescence data from patients previously reported."
Respiratory ciliopathies including non-CF bronchiectasis v4.44 TEKT1 Achchuthan Shanmugasundram Tag disputed tag was added to gene: TEKT1.
Respiratory ciliopathies including non-CF bronchiectasis v4.44 MNS1 Achchuthan Shanmugasundram Tag disputed tag was added to gene: MNS1.
Respiratory ciliopathies including non-CF bronchiectasis v4.44 DNAH14 Achchuthan Shanmugasundram Tag disputed was removed from gene: DNAH14.
Respiratory ciliopathies including non-CF bronchiectasis v4.44 DNAH14 Achchuthan Shanmugasundram Tag disputed tag was added to gene: DNAH14.
Respiratory ciliopathies including non-CF bronchiectasis v4.44 DNAH8 Achchuthan Shanmugasundram Tag disputed tag was added to gene: DNAH8.
Respiratory ciliopathies including non-CF bronchiectasis v4.44 DNAH6 Achchuthan Shanmugasundram Tag disputed tag was added to gene: DNAH6.
Respiratory ciliopathies including non-CF bronchiectasis v4.44 CFAP43 Achchuthan Shanmugasundram Tag disputed tag was added to gene: CFAP43.
Respiratory ciliopathies including non-CF bronchiectasis v4.44 AK7 Achchuthan Shanmugasundram Tag disputed tag was added to gene: AK7.
Respiratory ciliopathies including non-CF bronchiectasis v4.44 BRWD1 Achchuthan Shanmugasundram Classified gene: BRWD1 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.44 BRWD1 Achchuthan Shanmugasundram Gene: brwd1 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.43 BRWD1 Achchuthan Shanmugasundram Tag disputed tag was added to gene: BRWD1.
Respiratory ciliopathies including non-CF bronchiectasis v4.43 BRWD1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Ivone Leong below, biallelic BRWD1 variants have been reported in three unrelated patients displaying PCD-like phenotype recurring airway infections, bronchiectasis and rhinosinusitis. This gene is now associated with relevant phenotype in OMIM (MIM #620438).

However, the association of BRWD1 gene with primary ciliary dyskinesia (MONDO:0016575) has been classified as 'Disputed' by the Motile Ciliopathy expert panel in ClinGen. Detailed information on this classification can be found in https://search.clinicalgenome.org/CCID:004289.

The reason for their classification is as follows:
"Individuals with variants in BRWD1 and clinical features of PCD are reported in the literature. However, no functional data support the pathogenicity of the variants and their association with PCD. No valid experimental evidence remains to support this curation."; to: As reviewed by Ivone Leong below, biallelic BRWD1 variants have been reported in three unrelated patients displaying PCD-like phenotype including recurring airway infections, bronchiectasis and rhinosinusitis. This gene is now associated with relevant phenotype in OMIM (MIM #620438).

However, the association of BRWD1 gene with primary ciliary dyskinesia (MONDO:0016575) has been classified as 'Disputed' by the Motile Ciliopathy expert panel in ClinGen. Detailed information on this classification can be found in https://search.clinicalgenome.org/CCID:004289.

The reason for their classification is as follows:
"Individuals with variants in BRWD1 and clinical features of PCD are reported in the literature. However, no functional data support the pathogenicity of the variants and their association with PCD. No valid experimental evidence remains to support this curation."
Respiratory ciliopathies including non-CF bronchiectasis v4.43 DAW1 Achchuthan Shanmugasundram Classified gene: DAW1 as Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.43 DAW1 Achchuthan Shanmugasundram Added comment: Comment on list classification: The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient. Expert review is being sought from Genomic Laboratory Hubs on demotion of this gene from green to red.
Respiratory ciliopathies including non-CF bronchiectasis v4.43 DAW1 Achchuthan Shanmugasundram Gene: daw1 has been classified as Green List (High Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.42 DAW1 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has updated the classification for the association of DAW1 gene to ciliary dyskinesia, primary, 52 (MONDO:0957922) from 'Moderate' to 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008408.

ClinGen has provided the following summary as the reason(s) for change:
"The DAW1-PCD gene-disease relationship was changed to LIMITED pending more information on the respiratory and ultrastructural axoneme phenotypes of three sister patients carrying the p.Asn143Asp DAW1 variant OR the reporting of additional patients carrying biallelic DAW1 variants with laterality AND respiratory symptoms. The genetic evidence in this curation warranted scoring and the curation included strong experimental evidence from non-human model organisms, but the Motile Ciliopathy GCEP decided that this curation did not reach the level of a MODERATE classification."

Below is the summary of previously published cases:

PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients.

PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported.

The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient.; to: The ClinGen Motile Ciliopathy expert panel has updated the classification for the association of DAW1 gene to ciliary dyskinesia, primary, 52 (MONDO:0957922) from 'Moderate' to 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008408.

ClinGen has provided the following summary as the reason(s) for change:
"The DAW1-PCD gene-disease relationship was changed to LIMITED pending more information on the respiratory and ultrastructural axoneme phenotypes of three sister patients carrying the p.Asn143Asp DAW1 variant OR the reporting of additional patients carrying biallelic DAW1 variants with laterality AND respiratory symptoms. The genetic evidence in this curation warranted scoring and the curation included strong experimental evidence from non-human model organisms, but the Motile Ciliopathy GCEP decided that this curation did not reach the level of a MODERATE classification."

Below is the summary of previously published cases:

PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients.

PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported.
Respiratory ciliopathies including non-CF bronchiectasis v4.42 DAW1 Achchuthan Shanmugasundram changed review comment from: DAW1 has the gene-disease validity rating of 'Limited' in ClinGen. ClinGen has rated this gene with 'Limited' rating as there are no reported respiratory symptoms in the cases.

PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients.

PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported.

The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient.; to: The ClinGen Motile Ciliopathy expert panel has updated the classification for the association of DAW1 gene to ciliary dyskinesia, primary, 52 (MONDO:0957922) from 'Moderate' to 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008408.

ClinGen has provided the following summary as the reason(s) for change:
"The DAW1-PCD gene-disease relationship was changed to LIMITED pending more information on the respiratory and ultrastructural axoneme phenotypes of three sister patients carrying the p.Asn143Asp DAW1 variant OR the reporting of additional patients carrying biallelic DAW1 variants with laterality AND respiratory symptoms. The genetic evidence in this curation warranted scoring and the curation included strong experimental evidence from non-human model organisms, but the Motile Ciliopathy GCEP decided that this curation did not reach the level of a MODERATE classification."

Below is the summary of previously published cases:

PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients.

PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported.

The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient.
Respiratory ciliopathies including non-CF bronchiectasis v4.42 STK36 Achchuthan Shanmugasundram changed review comment from: STK36 has the gene-disease validity rating of 'Moderate' in ClinGen, based on evidence from a single reported human case and experiment evidence from both non-human models and patient cell line. Hence, the evidence is only sufficient for an amber rating.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of STK36 gene to ciliary dyskinesia, primary, 46 (MONDO:0030332) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008521. However, this 'moderate' rating in ClinGen was based on evidence from a single reported human case and experiment evidence from both non-human models and patient cell line.

This evidence is only sufficient for an amber rating, as per rating criteria used by PanelApp.
Respiratory ciliopathies including non-CF bronchiectasis v4.42 GAS2L2 Achchuthan Shanmugasundram commented on gene: GAS2L2: The ClinGen Motile Ciliopathy expert panel has classified the association of GAS2L2 gene to ciliary dyskinesia, primary, 41 (MONDO:0032757) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:004922.
Respiratory ciliopathies including non-CF bronchiectasis v4.42 DNAJB13 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877.

There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs*3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877.

There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs*3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.
Respiratory ciliopathies including non-CF bronchiectasis v4.42 DNAJB13 Achchuthan Shanmugasundram changed review comment from: DNAJB13 has the gene-disease validity rating of 'Moderate' in ClinGen.

There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs*3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877.

There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs*3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.
Respiratory ciliopathies including non-CF bronchiectasis v4.42 CFAP46 Achchuthan Shanmugasundram changed review comment from: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene.

PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus.

In addition, this gene-disease association is supported by Chlamydomonas reinhardtii null mutant model (PMID:22573824) and gene expression data (PMID:23715323). In addition, immunofluorescence microscopy analyses of respiratory epithelial cells show that CFAP46 localises along the entire ciliary axoneme in healthy individuals but is lost in the respiratory cells of a CFAP46-PCD patient (PMID:39362668).

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.; to: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene. As reviewed by Zornitza Stark below, the authors speculate that LEFTY1 variant might be responsible for the phenotype.

PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus.

In addition, this gene-disease association is supported by Chlamydomonas reinhardtii null mutant model (PMID:22573824) and gene expression data (PMID:23715323). In addition, immunofluorescence microscopy analyses of respiratory epithelial cells show that CFAP46 localises along the entire ciliary axoneme in healthy individuals but is lost in the respiratory cells of a CFAP46-PCD patient (PMID:39362668).

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Respiratory ciliopathies including non-CF bronchiectasis v4.42 CFAP46 Achchuthan Shanmugasundram Classified gene: CFAP46 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.42 CFAP46 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case reported with biallelic CFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. However, these are high frequency variants with homozygotes in gnomAD.

Hence, this gene is rated red with the current evidence.
Respiratory ciliopathies including non-CF bronchiectasis v4.42 CFAP46 Achchuthan Shanmugasundram Gene: cfap46 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.41 CFAP46 Achchuthan Shanmugasundram Deleted their comment
Respiratory ciliopathies including non-CF bronchiectasis v4.41 CFAP46 Achchuthan Shanmugasundram edited their review of gene: CFAP46: Changed rating: RED
Respiratory ciliopathies including non-CF bronchiectasis v4.41 CFAP221 Achchuthan Shanmugasundram changed review comment from: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen.

There are additional cases reported with primary ciliary dyskinesia now.

PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.

PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss.

This gene has also been associated with relevant phenotypes in OMIM (MIM #279000).; to: The ClinGen Motile Ciliopathy expert panel has classified the association of CFAP221 gene to primary ciliary dyskinesia (MONDO:0016575) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:004421.

There are additional cases reported with primary ciliary dyskinesia now.

PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.

PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss.

This gene has also been associated with relevant phenotypes in OMIM (MIM #279000).
Respiratory ciliopathies including non-CF bronchiectasis v4.41 TP73 Achchuthan Shanmugasundram changed review comment from: TP73 has the gene-disease validity rating of 'Strong' in ClinGen.

PMID:34077761 - Five different homozygous loss-of-function variants in TP73 gene have been reported in seven individuals from five unrelated families. They presented with a chronic airway disease, and brain malformation consistent with lissencephaly. Respiratory distress syndrome and recurrent respiratory infections have been reported in five and six patients respectively. There is also some experimental evidence available.

This gene has been associated with relevant phenotypes in both OMIM (MIM #619466) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature; to: The ClinGen Motile Ciliopathy expert panel has classified the association of TP73 gene to ciliary dyskinesia, primary, 47, and lissencephaly (MONDO:0030346) as 'Strong'. More information can be found in https://search.clinicalgenome.org/CCID:006420.

PMID:34077761 - Five different homozygous loss-of-function variants in TP73 gene have been reported in seven individuals from five unrelated families. They presented with a chronic airway disease, and brain malformation consistent with lissencephaly. Respiratory distress syndrome and recurrent respiratory infections have been reported in five and six patients respectively. There is also some experimental evidence available.

This gene has been associated with relevant phenotypes in both OMIM (MIM #619466) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature
Amelogenesis imperfecta v4.5 TP63 Claire Smith reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:not listed; Phenotypes: ectodermal dysplasia, split hand/foot malformation, orofacial defect, dry skin, wiry hair, fewer teeth, malformed teeth, amelogenesis imperfecta, dystrophic nails, reduced sweat glands, mammary gland and nipple hypoplasia, lacrimal duct defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Respiratory ciliopathies including non-CF bronchiectasis v4.41 NEK10 Achchuthan Shanmugasundram changed review comment from: NEK10 has the gene-disease validity rating of 'Strong' in ClinGen.

Additional cases reported with ciliopathy now.

PMID:32414360 - Two siblings were reported with a classical primary ciliary dyskinesia and were identified with a homozygous truncating variant (p.Tyr1134Ter) in the NEK10 gene. They both presented with bronchiectasis and chronic cough.

PMID:35728977 - Using the genetic data from severe bronchiectasis patients recruited to the Genomics England 100k Genomes Project, one patient was identified with compound heterozugous variants (c.1A>G & c.1028+1G>T).

This gene has been associated with relevant phenotypes in OMIM (MIM #618781).; to: The ClinGen Motile Ciliopathy expert panel has classified the association of NEK10 gene to ciliary dyskinesia, primary, 44 (MONDO:0032914) as 'Strong'. More information can be found in https://search.clinicalgenome.org/CCID:005617.

Additional cases reported with ciliopathy now.

PMID:32414360 - Two siblings were reported with a classical primary ciliary dyskinesia and were identified with a homozygous truncating variant (p.Tyr1134Ter) in the NEK10 gene. They both presented with bronchiectasis and chronic cough.

PMID:35728977 - Using the genetic data from severe bronchiectasis patients recruited to the Genomics England 100k Genomes Project, one patient was identified with compound heterozugous variants (c.1A>G & c.1028+1G>T).

This gene has been associated with relevant phenotypes in OMIM (MIM #618781).
Respiratory ciliopathies including non-CF bronchiectasis v4.41 EFCAB1 Achchuthan Shanmugasundram changed review comment from: EFCAB1 has the gene-disease validity rating of 'Strong' in ClinGen.

PMID:36727596 - Three individuals from three unrelated families were identified with three different homozygous variants in EFCAB1 gene (p.Arg98Ter, p.Glu123Ter & p.Glu40Trpfs*16). All three patients presented with situs inversus/ situs ambiguous, while chronic rhino-sinusitis was reported in one, and recurrent pneumonia and respiratory insufficiency were reported in another patient. There is also some functional evidence available.

This gene has also been associated with relevant phenotype in OMIM (MIM #620642).
Sources: Literature; to: The ClinGen Motile Ciliopathy expert panel has classified the association of EFCAB1 gene to ciliary dyskinesia, primary, 53 (MONDO:0957991) as 'Strong'. More information can be found in https://search.clinicalgenome.org/CCID:008800.

PMID:36727596 - Three individuals from three unrelated families were identified with three different homozygous variants in EFCAB1 gene (p.Arg98Ter, p.Glu123Ter & p.Glu40Trpfs*16). All three patients presented with situs inversus/ situs ambiguous, while chronic rhino-sinusitis was reported in one, and recurrent pneumonia and respiratory insufficiency were reported in another patient. There is also some functional evidence available.

This gene has also been associated with relevant phenotype in OMIM (MIM #620642).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v4.41 TUBB4B Achchuthan Shanmugasundram commented on gene: TUBB4B: The ClinGen Motile Ciliopathy expert panel has classified the association of TUBB4B gene to TUBB4B-related ciliopathy (MONDO:1060115) as 'Definitive'. More information can be found in https://search.clinicalgenome.org/CCID:006481.
Respiratory ciliopathies including non-CF bronchiectasis v4.41 TTC12 Achchuthan Shanmugasundram changed review comment from: TTC12 has the gene-disease validity rating of 'Definitive' in ClinGen.

PMID:36273201 - Five unrelated families with multisystem ciliopathy syndromes were studies, of which three were identified with biallelic variants in TTC12 gene. Two of them had respiratory phenotype.

PMID:37325566 - Three unrelated male patients from a large cohort of infertile Chinese males with asthenoteratozoospermia were identified with homozygous TTC12 variants. They also had a mild PCD-related nasosinusitis phenotype, which is a respiratory cilia impairment. However, they declined to undergo further investigation.

PMID:38992144 - A novel homozygous missense TTC12 variant was identified in an infertile Pakistani male with severe oligoasthenoteratozoospermia and primary ciliary dyskinesia. The patient also presented with sinusitis.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of TTC12 gene to ciliary dyskinesia, primary, 45 (MONDO:0032924) as 'Definitive'. More information can be found in https://search.clinicalgenome.org/CCID:008762.

PMID:36273201 - Five unrelated families with multisystem ciliopathy syndromes were studies, of which three were identified with biallelic variants in TTC12 gene. Two of them had respiratory phenotype.

PMID:37325566 - Three unrelated male patients from a large cohort of infertile Chinese males with asthenoteratozoospermia were identified with homozygous TTC12 variants. They also had a mild PCD-related nasosinusitis phenotype, which is a respiratory cilia impairment. However, they declined to undergo further investigation.

PMID:38992144 - A novel homozygous missense TTC12 variant was identified in an infertile Pakistani male with severe oligoasthenoteratozoospermia and primary ciliary dyskinesia. The patient also presented with sinusitis.
Respiratory ciliopathies including non-CF bronchiectasis v4.41 CEP164 Achchuthan Shanmugasundram changed review comment from: CEP164 has the gene-disease validity rating of 'Definitive' in ClinGen. As per ClinGen curation, seven different variants have been reported in 6 probands in four publications (PMIDs: 22863007, 34132027, 27708425, 36273371), of which 3 probands have been associated with non-CF bronchiectasis. Two of them also had cough, pneumonia, rhinitis and/ or recurrent infections.

PMID:22863007 - This study reported four different patients with biallelic CEP164 variants, of which one patient with homozygous variant (p.Arg576Ter) had cerebeller vermis hypoplasia, facial dysmorphism, obesity, bronchiectasis and polydactyly in addition to nephronophthisis.

PMID:34556108 - 21 probands from the PCD cohort and 52 probands from non-CF bronchiectasis cohort were recruited in Wessex Genome Medicine Centre (GMC) and their genomes sequenced as part of Genomics England 100k genomes project. Compound heterozygous variants in CEP164 (p.Gln1410Ter/ p.Arg576Ter) were reported in one of these probands from non-CF bronchiectasis cohort.

PMID:36273371 - A patient with bronchiectasis was reported with atypical motile ciliopathy phenotype and the same compound heterozygous CEP164 variants as above.
Sources: Literature; to: The ClinGen Kidney Cystic and Ciliopathy Disorders expert panel has classified the association of CEP164 gene to ciliopathy (MONDO:0005308) as 'Definitive'. More information can be found in https://search.clinicalgenome.org/CCID:004416.

As per ClinGen curation, seven different variants have been reported in 6 probands in four publications (PMIDs: 22863007, 34132027, 27708425, 36273371), of which 3 probands have been associated with non-CF bronchiectasis. Two of them also had cough, pneumonia, rhinitis and/ or recurrent infections.

PMID:22863007 - This study reported four different patients with biallelic CEP164 variants, of which one patient with homozygous variant (p.Arg576Ter) had cerebeller vermis hypoplasia, facial dysmorphism, obesity, bronchiectasis and polydactyly in addition to nephronophthisis.

PMID:34556108 - 21 probands from the PCD cohort and 52 probands from non-CF bronchiectasis cohort were recruited in Wessex Genome Medicine Centre (GMC) and their genomes sequenced as part of Genomics England 100k genomes project. Compound heterozygous variants in CEP164 (p.Gln1410Ter/ p.Arg576Ter) were reported in one of these probands from non-CF bronchiectasis cohort.

PMID:36273371 - A patient with bronchiectasis was reported with atypical motile ciliopathy phenotype and the same compound heterozygous CEP164 variants as above.
Sources: Literature
Amelogenesis imperfecta v4.5 SMARCD2 Claire Smith reviewed gene: SMARCD2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33279574, 28369036, 33025377, 36135322; Phenotypes: many including Amelogenesis imperfecta; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.41 CFAP54 Achchuthan Shanmugasundram commented on gene: CFAP54: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive CFAP54 variants to ciliary dyskinesia, primary, 54 (MONDO:0100607) as 'Strong'. More information can be found in https://search.clinicalgenome.org/
Amelogenesis imperfecta v4.5 NECTIN4 Claire Smith gene: NECTIN4 was added
gene: NECTIN4 was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: NECTIN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NECTIN4 were set to PMID: 34067522; 37183149
Phenotypes for gene: NECTIN4 were set to syndactyly of the toes and fingers; hair abnormalities; variable dental genesis; enamel hypoplasia (amelogenesis imperfecta?); variable nail dystrophy; variable palmoplantar keratoderma, hyperkeratosis, reduced sweating
Penetrance for gene: NECTIN4 were set to Complete
Review for gene: NECTIN4 was set to GREEN
Added comment: Evidence from literature is that loss of function variants in NECTIN4 lead to a syndromic phenotype which includes "enamel hypoplasia" a term often used when amelogenesis imperfecta occurs with other symptoms.

PMID:34067522 describes ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4. Nine other EDSS1 cases have been described prior to this report. 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in NECTIN4. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2–3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1.

PMID 37183149 reported a large Pakistani consanguineous family, the affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. NECTIN4 novel nonsense variant [c.163C>T; p.(Arg55*)]. Most likely Nectin-4 function will be lost.
Sources: Literature
Congenital myopathy v6.34 SRPK3 Anna Sarkozy reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 38429495, PMID: 39667923; Phenotypes: congenital myopathy; Mode of inheritance: Other
Respiratory ciliopathies including non-CF bronchiectasis v4.41 CFAP46 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is only one case reported with biallelic CFFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. Hence, this gene can be rated amber with the current evidence.; to: Comment on list classification: There is only one case reported with biallelic CFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. Hence, this gene can be rated amber with the current evidence.
Respiratory ciliopathies including non-CF bronchiectasis v4.41 DNAH8 Achchuthan Shanmugasundram Phenotypes for gene: DNAH8 were changed from Ciliopathies to Spermatogenic failure 46, OMIM:619095; primary ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v4.40 DNAH8 Achchuthan Shanmugasundram Classified gene: DNAH8 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.40 DNAH8 Achchuthan Shanmugasundram Gene: dnah8 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.39 DNAH8 Achchuthan Shanmugasundram Tag watchlist was removed from gene: DNAH8.
Respiratory ciliopathies including non-CF bronchiectasis v4.39 DNAH8 Achchuthan Shanmugasundram reviewed gene: DNAH8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 46, OMIM:619095, primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.39 DNAH6 Achchuthan Shanmugasundram Phenotypes for gene: DNAH6 were changed from to primary ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v4.38 DNAH6 Achchuthan Shanmugasundram Mode of inheritance for gene: DNAH6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.37 DNAH6 Achchuthan Shanmugasundram Classified gene: DNAH6 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.37 DNAH6 Achchuthan Shanmugasundram Gene: dnah6 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.36 DNAH6 Achchuthan Shanmugasundram reviewed gene: DNAH6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.36 TEKT1 Achchuthan Shanmugasundram Phenotypes for gene: TEKT1 were changed from to primary ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v4.35 TEKT1 Achchuthan Shanmugasundram edited their review of gene: TEKT1: Changed phenotypes to: primary ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v4.35 TEKT1 Achchuthan Shanmugasundram gene: TEKT1 was added
gene: TEKT1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen
Mode of inheritance for gene: TEKT1 was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: TEKT1 was set to RED
Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive TEKT1 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:008874.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.34 MNS1 Achchuthan Shanmugasundram gene: MNS1 was added
gene: MNS1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen
Mode of inheritance for gene: MNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MNS1 were set to Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM:618948
Review for gene: MNS1 was set to RED
Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive MNS1 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:005401.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.33 DNAH14 Achchuthan Shanmugasundram gene: DNAH14 was added
gene: DNAH14 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAH14 were set to primary ciliary dyskinesia, MONDO:0016575
Review for gene: DNAH14 was set to RED
Added comment: The ClinGen Motile Ciliopathy expert panel is currently reviewing the evidence for the association of DNAH14 gene to primary ciliary dyskinesia (MONDO:0016575). More information can be found in https://search.clinicalgenome.org/kb/genes/HGNC:2945.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.32 CFAP43 Achchuthan Shanmugasundram Source Literature was removed from CFAP43.
Source ClinGen was added to CFAP43.
Respiratory ciliopathies including non-CF bronchiectasis v4.31 CFAP43 Achchuthan Shanmugasundram gene: CFAP43 was added
gene: CFAP43 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: CFAP43 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CFAP43 were set to Spermatogenic failure 19, OMIM:617592; primary ciliary dyskinesia, MONDO:0016575
Review for gene: CFAP43 was set to RED
Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive CFAP43 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:004425.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v4.30 BRWD1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Ivone Leong below, biallelic BRWD1 variants have been reported in three unrelated patients displaying PCD-like phenotype recurring airway infections, bronchiectasis and rhinosinusitis. This gene is now associated with relevant phenotype in OMIM (MIM #620438).

However, the association of BRWD1 gene with primary ciliary dyskinesia (MONDO:0016575) has been classified as 'Disputed' by the Motile Ciliopathy expert panel in ClinGen. Detailed information on this classification can be found in https://search.clinicalgenome.org/CCID:004289.; to: As reviewed by Ivone Leong below, biallelic BRWD1 variants have been reported in three unrelated patients displaying PCD-like phenotype recurring airway infections, bronchiectasis and rhinosinusitis. This gene is now associated with relevant phenotype in OMIM (MIM #620438).

However, the association of BRWD1 gene with primary ciliary dyskinesia (MONDO:0016575) has been classified as 'Disputed' by the Motile Ciliopathy expert panel in ClinGen. Detailed information on this classification can be found in https://search.clinicalgenome.org/CCID:004289.

The reason for their classification is as follows:
"Individuals with variants in BRWD1 and clinical features of PCD are reported in the literature. However, no functional data support the pathogenicity of the variants and their association with PCD. No valid experimental evidence remains to support this curation."
Skeletal dysplasia v8.6 FGF4 Eleanor Williams Classified gene: FGF4 as Amber List (moderate evidence)
Skeletal dysplasia v8.6 FGF4 Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation of green rating following GMS review. 2 unrelated cases plus a supportive mouse model.
Skeletal dysplasia v8.6 FGF4 Eleanor Williams Gene: fgf4 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v8.5 FGF4 Eleanor Williams gene: FGF4 was added
gene: FGF4 was added to Skeletal dysplasia. Sources: Literature
Q3_25_promote_green tags were added to gene: FGF4.
Mode of inheritance for gene: FGF4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGF4 were set to 40259859; 33210601
Phenotypes for gene: FGF4 were set to Short-rib thoracic dysplasia 22 without polydactyly, OMIM:621260; Jeune syndrome, MONDO:0018770
Review for gene: FGF4 was set to GREEN
Added comment: Associated with Short-rib thoracic dysplasia 22 without polydactyly, OMIM:621260 (AR)

PMID: 40259859 - Watts et al 2025 report 2 unrelated families (1 in the 100,000 Genomes project) with a clinical diagnosis of thoracic dystrophy with associated respiratory insufficiency.

Family 1 - 2 affected boys clinically suspected to have Jeune syndrome, and 3 unaffected children born to healthy consanguineous 2nd cousin parents. Both affected individuals had narrow/small thorax and short ribs (11 pairs). 2nd child died at 3  months from respiratory infection. Both affected children were homozygous for a missense variant in FGF4 (c.256C>T p.(Leu86Phe)). Parents are confirmed carriers and 2 of the 3 unaffected siblings do not carry the variant.

Family 2 - 1 male with a chest shape suggesting thoracic dystrophy and a clinical suspicion of Jeune syndrome. A biallelic missense variant in FGF4 NM_002007.4:c.611C>A p.(Pro204His) was identified. Parents were both heterozygous carriers.

The variants are absent from gnomAD and UK Biobank and are predicted to be damaging by multiple in silico tools.

PMID: 33210601 - Anderson et al 2020 - Mouse mutants lacking Fgf4 Fgf4 show a variety of segmentation defects in the cervical and thoracic vertebrae with 100% penetrance.
Sources: Literature
Fetal anomalies v6.9 GPKOW Eleanor Williams reviewed gene: GPKOW: Rating: GREEN; Mode of pathogenicity: None; Publications: 28612833, 40221893; Phenotypes: syndromic disease, MONDO:0002254; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Childhood onset hereditary spastic paraplegia v8.6 FLVCR1 Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.6 FLVCR1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Childhood onset hereditary spastic paraplegia v8.6 FLVCR1 Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.10 FLVCR1 Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
Limb disorders v7.10 FLVCR1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Limb disorders v7.10 FLVCR1 Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.7 FLVCR1 Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
Severe microcephaly v8.7 FLVCR1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Severe microcephaly v8.7 FLVCR1 Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.9 FLVCR1 Eleanor Williams gene: FLVCR1 was added
gene: FLVCR1 was added to Limb disorders. Sources: Literature
Q3_25_promote_green tags were added to gene: FLVCR1.
Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR1 were set to 39306721
Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Review for gene: FLVCR1 was set to GREEN
Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.5 FLVCR1 Eleanor Williams gene: FLVCR1 was added
gene: FLVCR1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: FLVCR1.
Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR1 were set to 39306721
Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Review for gene: FLVCR1 was set to GREEN
Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.
Sources: Literature
Early onset or syndromic epilepsy v8.10 FLVCR1 Eleanor Williams gene: FLVCR1 was added
gene: FLVCR1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: FLVCR1.
Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR1 were set to 39306721
Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Review for gene: FLVCR1 was set to GREEN
Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.
Sources: Literature
Severe microcephaly v8.6 FLVCR1 Eleanor Williams gene: FLVCR1 was added
gene: FLVCR1 was added to Severe microcephaly. Sources: Literature
Q3_25_promote_green tags were added to gene: FLVCR1.
Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR1 were set to 39306721
Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Review for gene: FLVCR1 was set to GREEN
Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.
Sources: Literature
Fetal anomalies v6.9 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from ATAXIA, POSTERIOR COLUMN, WITH RETINITIS PIGMENTOSA to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Fetal anomalies v6.8 FLVCR1 Eleanor Williams Publications for gene: FLVCR1 were set to
Fetal anomalies v6.7 FLVCR1 Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
Fetal anomalies v6.7 FLVCR1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Fetal anomalies v6.7 FLVCR1 Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.6 FLVCR1 Eleanor Williams Tag Q3_25_promote_green tag was added to gene: FLVCR1.
Fetal anomalies v6.6 FLVCR1 Eleanor Williams reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39306721; Phenotypes: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060, neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.37 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126 to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Intellectual disability v9.36 FLVCR1 Eleanor Williams Publications for gene: FLVCR1 were set to 30656474; 22279524; 21267618; 21070897; 9409377; 30444160; 39306721
Intellectual disability v9.36 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from ATAXIA, POSTERIOR COLUMN, WITH RETINITIS PIGMENTOSA to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Intellectual disability v9.35 FLVCR1 Eleanor Williams Publications for gene: FLVCR1 were set to 21267618; 9409377; 21070897
Intellectual disability v9.35 FLVCR1 Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
Intellectual disability v9.35 FLVCR1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Intellectual disability v9.35 FLVCR1 Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.34 FLVCR1 Eleanor Williams Tag Q3_25_promote_green tag was added to gene: FLVCR1.
Intellectual disability v9.34 FLVCR1 Eleanor Williams edited their review of gene: FLVCR1: Changed rating: GREEN
Intellectual disability v9.34 FLVCR1 Eleanor Williams edited their review of gene: FLVCR1: Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.; Changed publications to: 30656474, 22279524, 21267618, 21070897, 9409377, 30444160, 39306721; Changed phenotypes to: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060, neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Respiratory ciliopathies including non-CF bronchiectasis v4.30 BRWD1 Achchuthan Shanmugasundram reviewed gene: BRWD1: Rating: RED; Mode of pathogenicity: None; Publications: 33389130; Phenotypes: Ciliary dyskinesia, primary, 51, OMIM:620438; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.30 AK7 Achchuthan Shanmugasundram gene: AK7 was added
gene: AK7 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen
Mode of inheritance for gene: AK7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AK7 were set to ?Spermatogenic failure 27, OMIM:617965; primary ciliary dyskinesia, MONDO:0016575
Review for gene: AK7 was set to RED
Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive AK7 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:004087.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.29 IFT74 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive IFT74 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008711.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive IFT74 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008711.
Respiratory ciliopathies including non-CF bronchiectasis v4.29 IFT74 Achchuthan Shanmugasundram Phenotypes for gene: IFT74 were changed from ciliary dyskinesia, MONDO:0016575 to primary ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v4.28 DNAH10 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008793.
Sources: ClinGen; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008793.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.28 IFT74 Achchuthan Shanmugasundram reviewed gene: IFT74: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.28 IFT74 Achchuthan Shanmugasundram Phenotypes for gene: IFT74 were changed from ciliary dyskinesia, MONDO:0016575) to ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v4.27 IFT74 Achchuthan Shanmugasundram gene: IFT74 was added
gene: IFT74 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen
Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IFT74 were set to ciliary dyskinesia, MONDO:0016575)
Respiratory ciliopathies including non-CF bronchiectasis v4.26 DNAH1 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified this association as 'Limited' for ciliary dyskinesia, primary, 37 (MONDO:0033204).

As per ClinGen, three unrelated patients have been reported with DNAH1 variants and bronchiectasis and other respiratory phenotypes including cough and respiratory distress. However, one of these patients has been reported with heterozygous variants.

PMID:25927852 - Two affected sisters with PCD were identified with homozygous missense p.Lys1154Gln variant. The variant segregated with the phenotypes and was not found in unaffected members of the family. The proband had a history of chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis. She also showed situs inversus and bronchiectasis, in addition to infertility.

PMID:31765523 - In a cohort of 265 patients with PCD, one patient was reported with heterozygous missense DNAH1 variant (p.Ala2599Ser).

PMID:34210339 - In a cohort of 26 individuals with PCD, one patient was reported with homozygous DNAH1 variant (p.P3909Rfs*33). The patient was infertile and presented with bronchiectasis, cough and sinusitis. As per ClinGen, this variant is recurrent in patients with isolated infertility and hence the association with PCD is doubtful.

Hence, this gene should be rated red with the current evidence.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH1 variants to ciliary dyskinesia, primary, 37 (MONDO:0033204) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:004667.

As per ClinGen, three unrelated patients have been reported with DNAH1 variants and bronchiectasis and other respiratory phenotypes including cough and respiratory distress. However, one of these patients has been reported with heterozygous variants.

PMID:25927852 - Two affected sisters with PCD were identified with homozygous missense p.Lys1154Gln variant. The variant segregated with the phenotypes and was not found in unaffected members of the family. The proband had a history of chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis. She also showed situs inversus and bronchiectasis, in addition to infertility.

PMID:31765523 - In a cohort of 265 patients with PCD, one patient was reported with heterozygous missense DNAH1 variant (p.Ala2599Ser).

PMID:34210339 - In a cohort of 26 individuals with PCD, one patient was reported with homozygous DNAH1 variant (p.P3909Rfs*33). The patient was infertile and presented with bronchiectasis, cough and sinusitis. As per ClinGen, this variant is recurrent in patients with isolated infertility and hence the association with PCD is doubtful.

Hence, this gene should be rated red with the current evidence.
Respiratory ciliopathies including non-CF bronchiectasis v4.26 DNAH7 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH7 variants to ciliary dyskinesia, primary, 50 (MONDO:0957252) as 'Limited'. Please see https://search.clinicalgenome.org/CCID:008791 for more information.
Sources: ClinGen; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH7 variants to ciliary dyskinesia, primary, 50 (MONDO:0957252) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008791.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.26 DNAH10 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. Please see https://search.clinicalgenome.org/CCID:008793 for more information.
Sources: ClinGen; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008793.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.26 DNAH7 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified this association as 'Limited' for ciliary dyskinesia, primary, 50 (MONDO:0957252).
Sources: ClinGen; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH7 variants to ciliary dyskinesia, primary, 50 (MONDO:0957252) as 'Limited'. Please see https://search.clinicalgenome.org/CCID:008791 for more information.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.26 DNAH10 Achchuthan Shanmugasundram gene: DNAH10 was added
gene: DNAH10 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen
Mode of inheritance for gene: DNAH10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAH10 were set to Spermatogenic failure 56, OMIM:619515; primary ciliary dyskinesia, MONDO:0016575
Review for gene: DNAH10 was set to RED
Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. Please see https://search.clinicalgenome.org/CCID:008793 for more information.
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.25 DNAH7 Achchuthan Shanmugasundram gene: DNAH7 was added
gene: DNAH7 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen
Mode of inheritance for gene: DNAH7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAH7 were set to Ciliary dyskinesia, primary, 50, OMIM:620356; ciliary dyskinesia, primary, 50, MONDO:0957252
Review for gene: DNAH7 was set to RED
Added comment: The ClinGen Motile Ciliopathy expert panel has classified this association as 'Limited' for ciliary dyskinesia, primary, 50 (MONDO:0957252).
Sources: ClinGen
Respiratory ciliopathies including non-CF bronchiectasis v4.24 DNAH1 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel have classified this association as 'Limited' for ciliary dyskinesia, primary, 37 (MONDO:0033204).

As per ClinGen, three unrelated patients have been reported with DNAH1 variants and bronchiectasis and other respiratory phenotypes including cough and respiratory distress. However, one of these patients has been reported with heterozygous variants.

PMID:25927852 - Two affected sisters with PCD were identified with homozygous missense p.Lys1154Gln variant. The variant segregated with the phenotypes and was not found in unaffected members of the family. The proband had a history of chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis. She also showed situs inversus and bronchiectasis, in addition to infertility.

PMID:31765523 - In a cohort of 265 patients with PCD, one patient was reported with heterozygous missense DNAH1 variant (p.Ala2599Ser).

PMID:34210339 - In a cohort of 26 individuals with PCD, one patient was reported with homozygous DNAH1 variant (p.P3909Rfs*33). The patient was infertile and presented with bronchiectasis, cough and sinusitis. As per ClinGen, this variant is recurrent in patients with isolated infertility and hence the association with PCD is doubtful.

Hence, this gene should be rated red with the current evidence.; to: The ClinGen Motile Ciliopathy expert panel has classified this association as 'Limited' for ciliary dyskinesia, primary, 37 (MONDO:0033204).

As per ClinGen, three unrelated patients have been reported with DNAH1 variants and bronchiectasis and other respiratory phenotypes including cough and respiratory distress. However, one of these patients has been reported with heterozygous variants.

PMID:25927852 - Two affected sisters with PCD were identified with homozygous missense p.Lys1154Gln variant. The variant segregated with the phenotypes and was not found in unaffected members of the family. The proband had a history of chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis. She also showed situs inversus and bronchiectasis, in addition to infertility.

PMID:31765523 - In a cohort of 265 patients with PCD, one patient was reported with heterozygous missense DNAH1 variant (p.Ala2599Ser).

PMID:34210339 - In a cohort of 26 individuals with PCD, one patient was reported with homozygous DNAH1 variant (p.P3909Rfs*33). The patient was infertile and presented with bronchiectasis, cough and sinusitis. As per ClinGen, this variant is recurrent in patients with isolated infertility and hence the association with PCD is doubtful.

Hence, this gene should be rated red with the current evidence.
Respiratory ciliopathies including non-CF bronchiectasis v4.24 DNAH1 Achchuthan Shanmugasundram Phenotypes for gene: DNAH1 were changed from Too new - not yet linked to the PCD mutations publication to Ciliary dyskinesia, primary, 37, OMIM:617577; ciliary dyskinesia, primary, 37, MONDO:0033204
Respiratory ciliopathies including non-CF bronchiectasis v4.23 DNAH1 Achchuthan Shanmugasundram Publications for gene: DNAH1 were set to
Respiratory ciliopathies including non-CF bronchiectasis v4.22 DNAH1 Achchuthan Shanmugasundram Classified gene: DNAH1 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.22 DNAH1 Achchuthan Shanmugasundram Gene: dnah1 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.21 DNAH1 Achchuthan Shanmugasundram reviewed gene: DNAH1: Rating: RED; Mode of pathogenicity: None; Publications: 25927852, 31765523, 34210339; Phenotypes: Ciliary dyskinesia, primary, 37, OMIM:617577, ciliary dyskinesia, primary, 37, MONDO:0033204; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.5 AIRE Claire Smith changed review comment from: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668).

Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F.

Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3  years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation.

This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1.

Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins.
Sources: Literature; to: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668).

Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F.

Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3  years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation.

This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1.

Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins.
Sources: Literature

Edit: I didn't add Amelogenesis imperfecta to the phenotype list. Can you please add this! I can't seem to add it in retrospect!
Amelogenesis imperfecta v4.5 AIRE Claire Smith gene: AIRE was added
gene: AIRE was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: AIRE was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AIRE were set to PMID: 37993717; 19393987; 27253668
Phenotypes for gene: AIRE were set to Addison disease; hypoparathyroidism; chronic mucocutaneous candidiasis
Penetrance for gene: AIRE were set to unknown
Review for gene: AIRE was set to GREEN
Added comment: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668).

Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F.

Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3  years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation.

This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1.

Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins.
Sources: Literature
Amelogenesis imperfecta v4.5 TUFT1 Claire Smith reviewed gene: TUFT1: Rating: RED; Mode of pathogenicity: None; Publications: 36689522; Phenotypes: woolly hair, skin fragility, keratosis pilaris; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.5 CLDN16 Claire Smith reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 32710267; Phenotypes: amelogenesis imperfecta, hyperparathyroidism, short stature, nephrocalcinosis, polyuria, polydipsia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Distal myopathies v6.8 NEB Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of monoallelic intragenic deletions in NEB gene with a milder distal myopathy phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.
Distal myopathies v6.8 NEB Achchuthan Shanmugasundram Mode of inheritance for gene: NEB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Distal myopathies v6.7 NEB Achchuthan Shanmugasundram Phenotypes for gene: NEB were changed from Nemaline myopathy 2, 256030 to Nemaline myopathy 2, OMIM:256030; distal myopathy, MONDO:0018949
Distal myopathies v6.6 NEB Achchuthan Shanmugasundram Publications for gene: NEB were set to 12207937; 30679003; 39474605
Distal myopathies v6.5 NEB Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: NEB.
Distal myopathies v6.5 NEB Achchuthan Shanmugasundram reviewed gene: NEB: Rating: GREEN; Mode of pathogenicity: None; Publications: 40517164; Phenotypes: distal myopathy, MONDO:0018949; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v2.1 KIF26A Anna Rybak changed review comment from: New patient with neurological impairment and paediatric intestinal pseudo-obstruction, has been found to be a carrier of KIF26A homozygous c.5111-2A>G LP variant.
Genetic diagnosis explains Abdullah's history of developmental delay, brain abnormalities, hypertonia, and bowel issues.
AR inheritance, both parents confirmed to be carriers.
Consanguineous parents.

Another three patients published in 2024:
Nosrati MSS, Doustmohammadi A, Severino M, Romano F, Zafari M, Nemati AH, Velmans C, Netzer C, Breuer J, Broekaert IJ, Joachim A, Almasri N, Kruer MC, Skidmore P, Bisarad P, Hoque J, Bakhtiari S, Torella A, Nigro V, Buffelli F, Fulcheri E, Müller A, Zara F, Capra V, Scala M. Novel KIF26A variants associated with pediatric intestinal pseudo-obstruction (PIPO) and brain developmental defects. Clin Genet. 2025 Jan;107(1):83-90. doi: 10.1111/cge.14621.; to: New patient with neurological impairment and paediatric intestinal pseudo-obstruction, has been found to be a carrier of KIF26A homozygous c.5111-2A>G LP variant.
Genetic diagnosis explains patient's history of developmental delay, brain abnormalities, hypertonia, and bowel issues.
AR inheritance, both parents confirmed to be carriers.
Consanguineous parents.

Another three patients published in 2024:
Nosrati MSS, Doustmohammadi A, Severino M, Romano F, Zafari M, Nemati AH, Velmans C, Netzer C, Breuer J, Broekaert IJ, Joachim A, Almasri N, Kruer MC, Skidmore P, Bisarad P, Hoque J, Bakhtiari S, Torella A, Nigro V, Buffelli F, Fulcheri E, Müller A, Zara F, Capra V, Scala M. Novel KIF26A variants associated with pediatric intestinal pseudo-obstruction (PIPO) and brain developmental defects. Clin Genet. 2025 Jan;107(1):83-90. doi: 10.1111/cge.14621.
Paediatric pseudo-obstruction syndrome v2.1 KIF26A Anna Rybak reviewed gene: KIF26A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: KIF26A homozygous c.5111-2A>G LP varian; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated and arrhythmogenic cardiomyopathy v3.1 MYLK3 Matthew Edwards Deleted their comment
Dilated and arrhythmogenic cardiomyopathy v3.1 MYLK3 Matthew Edwards edited their review of gene: MYLK3: Added comment: Several mouse models (and a zebrafish), one of which is heterozygous KO which recapitulates DCM (31244672). Good expression/protein interaction evidence 17885681, 18202317)

Rare cases in literature - PMID: 29235529 has two families: Family A - two early onset sibs and their affected mother (later onset) had heterozygous MYLK3 LOF variant - sibs also had a FLNC LOF variant (from unaffected father), likely explaining early onset. Family B two later onset sibs with heterozygous MYLK3 LOF variant. functional studies of both showed reduced protein expression. PMID: 30690923: has proband with heterozygous LOF variant. 3 consanguineous families with hom LOf (2 families) and hom missense (1 family).

We've seen 10 LOF variants in DCM patients (with 3 detected in control set of non-DCM cases ~5000 samples - one possibly too young for phenotype, 2 with variant in only one of two isforms expressed in heart), but currently classify as VUS due to limited haploinsufficiency evidence. (Clin~Gen curation still pending); Changed rating: GREEN
Retinal disorders v8.9 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177 to Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
Retinal disorders v8.8 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033 posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177 to Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
Hereditary ataxia with onset in adulthood v8.6 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Posterior Column Ataxia with Retinitis Pigmentosa; Posterior column ataxia with retinitis pigmentosa, 609033; Ataxia, posterior column, with retinitis pigmentosa, to Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
Ataxia and cerebellar anomalies - narrow panel v8.9 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177 to Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
Ataxia and cerebellar anomalies - narrow panel v8.8 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033 posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177 to Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
Ataxia and cerebellar anomalies - narrow panel v8.7 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Posterior Column Ataxia with Retinitis Pigmentosa; Ataxia, posterior column, with retinitis pigmentosa, to Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033 posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
Retinal disorders v8.7 FLVCR1 Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Eye Disorders; Posterior Column Ataxia with Retinitis Pigmentosa; Ataxia, posterior column, with retinitis pigmentosa, 609033; Retinitis pigmentosa to Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033 posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
Severe microcephaly v8.5 WARS Eleanor Williams changed review comment from: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review as there are 4 families with intellectual disability.; to: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review as there are 4 families with progressive microcephaly in the severe range.
Severe microcephaly v8.5 WARS Eleanor Williams Entity copied from Intellectual disability v9.34
Severe microcephaly v8.5 WARS Eleanor Williams gene: WARS was added
gene: WARS was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q3_25_promote_green tags were added to gene: WARS.
Mode of inheritance for gene: WARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WARS were set to 34585293; 35790048; 35815345
Phenotypes for gene: WARS were set to Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, OMIM:620317; neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, MONDO:0957218
Intellectual disability v9.34 WARS Eleanor Williams Classified gene: WARS as Amber List (moderate evidence)
Intellectual disability v9.34 WARS Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review as there are 4 families with intellectual disability.
Intellectual disability v9.34 WARS Eleanor Williams Gene: wars has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.33 WARS Eleanor Williams Tag Q3_25_promote_green tag was added to gene: WARS.
Intellectual disability v9.33 WARS Eleanor Williams changed review comment from: Sources: Literature; to: Associated with Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities OMIM:620317 (AR). Also associated with Neuronopathy, distal hereditary motor, autosomal dominant 9, OMIM:617721 (AD).

5 families reported with biallelic variants in WARS1 and phenotype of intellectual disability and progressive severe microcephaly in 4 families. Variable other phenotypes were also present such as hearing loss, skeletal and brain abnormalities and seizures.

PMID: 34585293 - Okamoto et al 2022 - 4 year old female Japanese proband with compound het variants in WARS1 (p.Arg448Trp and p.Ala333Thr). Parents were heterozygous. Variants are rare. She presented with hypotonia, developmental delay, delayed myelination in the cerebral white matter. She had a seizure age 2. Severe intellectual disability at age 4, did not walk independently. Head circumference was -0.4 SD at birth and -3.4 SD by age 4.

PMID: 35815345 - Lin et al 2022 - 3 probands from 2 consanguineous Pakistani families. In family 1, one proband at age 20 had developmental delay, mild ID, mild microcephaly, mild sensorineural hearing loss. The second proband at age 16 had severe delayed developmental milestones/intellectual disability, hypotonia, severe microcephaly (-7.8 SD), severe hearing impairment and skeletal abnormalities of the legs. In family 2, the 5 year male had global developmental delay, complex partial epilepsy, a history of central adrenal insufficiency, cortical blindness, and multiple brain abnormalities. He has a history of seizures. A homozygous, rare, start loss variant (c.1A>G, p.Met1?) in exon 2 of WARS1 was identified in family 1 with parents as carriers. A homozygous c.1255G>A, p.(Asp419Asn) variant was identified in WARS1 in family 2, with parents as carriers. This variant is present in population databases with a MAF ~ 0.003 but not in the homozygous state. Zebrafish wars1 knockout displayed microcephaly, hearing loss, and musculoskeletal abnormalities, and the homozygous animals do not survive past Day 10

PMID: 35790048 - Bögershausen et al 2022 - 4 individuals from 2 families all with the same missense variant in WARS1 (c.397C>T, p.(R133C)). All 4 had progressive microcephaly with OFC at (-4.2, -4.3, -3.8 and −3.5) at assessment at ages 5, 13, 8 and 7 years. the proband from family 1 had mild ID, the three from family 2 had severe ID and two from family 2 had hypotonia. No seizures or hearing loss was reported. The WARS1 variant negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model.

Intellectual disability v9.33 WARS Eleanor Williams gene: WARS was added
gene: WARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WARS were set to 34585293; 35790048; 35815345
Phenotypes for gene: WARS were set to Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, OMIM:620317; neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, MONDO:0957218
Review for gene: WARS was set to GREEN
Added comment: Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.6 CRNKL1 Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.6 CRNKL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are nine unrelated patients reported with pontocerebellar hypoplasia, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.6 CRNKL1 Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.5 CRNKL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
Severe microcephaly v8.4 CRNKL1 Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
Severe microcephaly v8.4 CRNKL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Severe microcephaly v8.4 CRNKL1 Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.3 CRNKL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
Early onset or syndromic epilepsy v8.9 CRNKL1 Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.9 CRNKL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.9 CRNKL1 Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.8 CRNKL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
Intellectual disability v9.32 CRNKL1 Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
Intellectual disability v9.32 CRNKL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.32 CRNKL1 Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.31 CRNKL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
Severe microcephaly v8.3 CRNKL1 Achchuthan Shanmugasundram gene: CRNKL1 was added
gene: CRNKL1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: CRNKL1 was set to GREEN
Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients).

Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.5 CRNKL1 Achchuthan Shanmugasundram gene: CRNKL1 was added
gene: CRNKL1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: CRNKL1 was set to GREEN
Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients).

Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v8.8 CRNKL1 Achchuthan Shanmugasundram gene: CRNKL1 was added
gene: CRNKL1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: CRNKL1 was set to GREEN
Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients).

Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.31 CRNKL1 Achchuthan Shanmugasundram gene: CRNKL1 was added
gene: CRNKL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: CRNKL1 was set to GREEN
Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients).

Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v4.21 CFAP46 Achchuthan Shanmugasundram Classified gene: CFAP46 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.21 CFAP46 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case reported with biallelic CFFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. Hence, this gene can be rated amber with the current evidence.
Respiratory ciliopathies including non-CF bronchiectasis v4.21 CFAP46 Achchuthan Shanmugasundram Gene: cfap46 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.20 CFAP46 Achchuthan Shanmugasundram Publications for gene: CFAP46 were set to 29843777; 39362668
Respiratory ciliopathies including non-CF bronchiectasis v4.19 CFAP46 Achchuthan Shanmugasundram edited their review of gene: CFAP46: Changed rating: AMBER; Changed publications to: 22573824, 23715323, 29843777, 39362668
Respiratory ciliopathies including non-CF bronchiectasis v4.19 CFAP46 Achchuthan Shanmugasundram changed review comment from: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene.

PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.; to: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene.

PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus.

In addition, this gene-disease association is supported by Chlamydomonas reinhardtii null mutant model (PMID:22573824) and gene expression data (PMID:23715323). In addition, immunofluorescence microscopy analyses of respiratory epithelial cells show that CFAP46 localises along the entire ciliary axoneme in healthy individuals but is lost in the respiratory cells of a CFAP46-PCD patient (PMID:39362668).

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Respiratory ciliopathies including non-CF bronchiectasis v4.19 CFAP46 Achchuthan Shanmugasundram edited their review of gene: CFAP46: Changed publications to: 22573824, 29843777, 39362668
Respiratory ciliopathies including non-CF bronchiectasis v4.19 DAW1 Achchuthan Shanmugasundram edited their review of gene: DAW1: Changed rating: RED; Changed publications to: 28991257, 36074124; Changed phenotypes to: Ciliary dyskinesia, primary, 52, OMIM:620570
Respiratory ciliopathies including non-CF bronchiectasis v4.19 DAW1 Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: DAW1.
Respiratory ciliopathies including non-CF bronchiectasis v4.19 DAW1 Achchuthan Shanmugasundram Tag Q2_25_ demote_red tag was added to gene: DAW1.
Respiratory ciliopathies including non-CF bronchiectasis v4.19 DAW1 Achchuthan Shanmugasundram changed review comment from: DAW1 has the gene-disease validity rating of 'Limited' in ClinGen. There are no reported respiratory symptoms in the cases, and only had situs inversus.; to: DAW1 has the gene-disease validity rating of 'Limited' in ClinGen. ClinGen has rated this gene with 'Limited' rating as there are no reported respiratory symptoms in the cases.

PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients.

PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported.

The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient.
Respiratory ciliopathies including non-CF bronchiectasis v4.19 DAW1 Achchuthan Shanmugasundram edited their review of gene: DAW1: Added comment: DAW1 has the gene-disease validity rating of 'Limited' in ClinGen. There are no reported respiratory symptoms in the cases, and only had situs inversus.; Changed rating: AMBER
Respiratory ciliopathies including non-CF bronchiectasis v4.19 STK36 Achchuthan Shanmugasundram reviewed gene: STK36: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Ciliary dyskinesia, primary, 41, OMIM:618449; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.19 GAS2L2 Achchuthan Shanmugasundram Tag watchlist was removed from gene: GAS2L2.
Respiratory ciliopathies including non-CF bronchiectasis v4.19 DNAJB13 Achchuthan Shanmugasundram Classified gene: DNAJB13 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.19 DNAJB13 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases from two different publications) for the promotion of this gene to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.19 DNAJB13 Achchuthan Shanmugasundram Gene: dnajb13 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.18 DNAJB13 Achchuthan Shanmugasundram Tag watchlist was removed from gene: DNAJB13.
Tag Q2_25_ promote_green tag was added to gene: DNAJB13.
Respiratory ciliopathies including non-CF bronchiectasis v4.18 DNAJB13 Achchuthan Shanmugasundram Publications for gene: DNAJB13 were set to 27486783
Respiratory ciliopathies including non-CF bronchiectasis v4.17 DNAJB13 Achchuthan Shanmugasundram reviewed gene: DNAJB13: Rating: GREEN; Mode of pathogenicity: None; Publications: 35166991; Phenotypes: Ciliary dyskinesia, primary, 34, OMIM:617091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.17 CFAP221 Achchuthan Shanmugasundram Classified gene: CFAP221 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.17 CFAP221 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available now for the promotion of this gene to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.17 CFAP221 Achchuthan Shanmugasundram Gene: cfap221 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.16 CFAP221 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: CFAP221.
Respiratory ciliopathies including non-CF bronchiectasis v4.16 CFAP221 Achchuthan Shanmugasundram changed review comment from: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen.

There are additional cases reported with primary ciliary dyskinesia now.

PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.

PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss.; to: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen.

There are additional cases reported with primary ciliary dyskinesia now.

PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.

PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss.

This gene has also been associated with relevant phenotypes in OMIM (MIM #279000).
Respiratory ciliopathies including non-CF bronchiectasis v4.16 CFAP221 Achchuthan Shanmugasundram Phenotypes for gene: CFAP221 were changed from Primary ciliary dyskinesia, MONDO:0016575 to Ciliary dyskinesia, primary, 55, OMIM:279000
Respiratory ciliopathies including non-CF bronchiectasis v4.15 CFAP221 Achchuthan Shanmugasundram Publications for gene: CFAP221 were set to 31636325; 39362668
Respiratory ciliopathies including non-CF bronchiectasis v4.14 CFAP221 Achchuthan Shanmugasundram changed review comment from: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen.

There are additional cases reported with primary ciliary dyskinesia now.

PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.; to: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen.

There are additional cases reported with primary ciliary dyskinesia now.

PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.

PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss.
Respiratory ciliopathies including non-CF bronchiectasis v4.14 CFAP221 Achchuthan Shanmugasundram edited their review of gene: CFAP221: Changed publications to: 31636325, 38960684, 39362668, 40250778
Respiratory ciliopathies including non-CF bronchiectasis v4.14 CFAP221 Achchuthan Shanmugasundram edited their review of gene: CFAP221: Added comment: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen.

There are additional cases reported with primary ciliary dyskinesia now.

PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.; Changed rating: GREEN; Changed publications to: 31636325, 38960684, 39362668; Changed phenotypes to: Ciliary dyskinesia, primary, 55, OMIM:279000
Respiratory ciliopathies including non-CF bronchiectasis v4.14 CFAP221 Achchuthan Shanmugasundram Deleted their comment
Respiratory ciliopathies including non-CF bronchiectasis v4.14 TP73 Achchuthan Shanmugasundram Classified gene: TP73 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.14 TP73 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.14 TP73 Achchuthan Shanmugasundram Gene: tp73 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.13 TP73 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: TP73.
Respiratory ciliopathies including non-CF bronchiectasis v4.13 TP73 Achchuthan Shanmugasundram gene: TP73 was added
gene: TP73 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: TP73 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TP73 were set to 34077761
Phenotypes for gene: TP73 were set to Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466
Review for gene: TP73 was set to GREEN
Added comment: TP73 has the gene-disease validity rating of 'Strong' in ClinGen.

PMID:34077761 - Five different homozygous loss-of-function variants in TP73 gene have been reported in seven individuals from five unrelated families. They presented with a chronic airway disease, and brain malformation consistent with lissencephaly. Respiratory distress syndrome and recurrent respiratory infections have been reported in five and six patients respectively. There is also some experimental evidence available.

This gene has been associated with relevant phenotypes in both OMIM (MIM #619466) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v4.12 NEK10 Achchuthan Shanmugasundram Classified gene: NEK10 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.12 NEK10 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available now from three different studies for the association of biallelic variants in NEK10 gene with this panel. Hence, this gene can be promoted to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.12 NEK10 Achchuthan Shanmugasundram Gene: nek10 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.11 NEK10 Achchuthan Shanmugasundram Publications for gene: NEK10 were set to 31959991; 32414360
Respiratory ciliopathies including non-CF bronchiectasis v4.10 NEK10 Achchuthan Shanmugasundram Tag watchlist was removed from gene: NEK10.
Tag Q2_25_ promote_green tag was added to gene: NEK10.
Respiratory ciliopathies including non-CF bronchiectasis v4.10 NEK10 Achchuthan Shanmugasundram reviewed gene: NEK10: Rating: GREEN; Mode of pathogenicity: None; Publications: 32414360, 35728977; Phenotypes: Ciliary dyskinesia, primary, 44, OMIM:618781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.10 EFCAB1 Achchuthan Shanmugasundram Classified gene: EFCAB1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.10 EFCAB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases and some experimental evidence) for the promotion of this gene to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.10 EFCAB1 Achchuthan Shanmugasundram Gene: efcab1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.9 EFCAB1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: EFCAB1.
Respiratory ciliopathies including non-CF bronchiectasis v4.9 EFCAB1 Achchuthan Shanmugasundram commented on gene: EFCAB1: The 'new-gene-name' tag has been added as the official HGNC gene symbol for EFCAB1 is CLXN.
Respiratory ciliopathies including non-CF bronchiectasis v4.9 EFCAB1 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: EFCAB1.
Respiratory ciliopathies including non-CF bronchiectasis v4.9 EFCAB1 Achchuthan Shanmugasundram gene: EFCAB1 was added
gene: EFCAB1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to 36727596
Phenotypes for gene: EFCAB1 were set to Ciliary dyskinesia, primary, 53, OMIM:620642
Review for gene: EFCAB1 was set to GREEN
Added comment: EFCAB1 has the gene-disease validity rating of 'Strong' in ClinGen.

PMID:36727596 - Three individuals from three unrelated families were identified with three different homozygous variants in EFCAB1 gene (p.Arg98Ter, p.Glu123Ter & p.Glu40Trpfs*16). All three patients presented with situs inversus/ situs ambiguous, while chronic rhino-sinusitis was reported in one, and recurrent pneumonia and respiratory insufficiency were reported in another patient. There is also some functional evidence available.

This gene has also been associated with relevant phenotype in OMIM (MIM #620642).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v4.8 TTC12 Achchuthan Shanmugasundram Classified gene: TTC12 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.8 TTC12 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (10 unrelated cases) for the association of biallelic TTC12 patients with respiratory ciliopathy. Hence, this gene can be promoted to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.8 TTC12 Achchuthan Shanmugasundram Gene: ttc12 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.7 TTC12 Achchuthan Shanmugasundram Tag watchlist was removed from gene: TTC12.
Tag Q2_25_ promote_green tag was added to gene: TTC12.
Respiratory ciliopathies including non-CF bronchiectasis v4.7 TTC12 Achchuthan Shanmugasundram Publications for gene: TTC12 were set to 31978331
Respiratory ciliopathies including non-CF bronchiectasis v4.6 TTC12 Achchuthan Shanmugasundram reviewed gene: TTC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 36273201, 37325566, 38992144; Phenotypes: Ciliary dyskinesia, primary, 45, OMIM:618801; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.6 CEP164 Achchuthan Shanmugasundram Classified gene: CEP164 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.6 CEP164 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated probands reported with biallelic CEP164 variants and non-CF bronchiectasis. Hence, this gene can be promoted to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.6 CEP164 Achchuthan Shanmugasundram Gene: cep164 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v4.5 CEP164 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: CEP164.
Respiratory ciliopathies including non-CF bronchiectasis v4.5 CEP164 Achchuthan Shanmugasundram gene: CEP164 was added
gene: CEP164 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: CEP164 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP164 were set to 22863007; 34556108; 36273371
Phenotypes for gene: CEP164 were set to Nephronophthisis 15, OMIM:614845; Bronchiectasis, HP:0002110
Review for gene: CEP164 was set to GREEN
Added comment: CEP164 has the gene-disease validity rating of 'Definitive' in ClinGen. As per ClinGen curation, seven different variants have been reported in 6 probands in four publications (PMIDs: 22863007, 34132027, 27708425, 36273371), of which 3 probands have been associated with non-CF bronchiectasis. Two of them also had cough, pneumonia, rhinitis and/ or recurrent infections.

PMID:22863007 - This study reported four different patients with biallelic CEP164 variants, of which one patient with homozygous variant (p.Arg576Ter) had cerebeller vermis hypoplasia, facial dysmorphism, obesity, bronchiectasis and polydactyly in addition to nephronophthisis.

PMID:34556108 - 21 probands from the PCD cohort and 52 probands from non-CF bronchiectasis cohort were recruited in Wessex Genome Medicine Centre (GMC) and their genomes sequenced as part of Genomics England 100k genomes project. Compound heterozygous variants in CEP164 (p.Gln1410Ter/ p.Arg576Ter) were reported in one of these probands from non-CF bronchiectasis cohort.

PMID:36273371 - A patient with bronchiectasis was reported with atypical motile ciliopathy phenotype and the same compound heterozygous CEP164 variants as above.
Sources: Literature
Structural eye disease v4.9 NR6A1 Siying Lin gene: NR6A1 was added
gene: NR6A1 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: NR6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NR6A1 were set to PMID: 40610405
Phenotypes for gene: NR6A1 were set to microphthalmia, coloboma
Penetrance for gene: NR6A1 were set to Incomplete
Mode of pathogenicity for gene: NR6A1 was set to Other
Review for gene: NR6A1 was set to GREEN
Added comment: PMID 40610405: 6 unrelated families with autosomal dominant syndromic form of colobomatous microphthalmia and missing vertebrae with or without congenital kidney abnormalities
Sources: Literature
Cerebral vascular malformations v4.5 ANO1 Eleanor Williams Tag Q2_25_expert_review tag was added to gene: ANO1.
Monogenic hearing loss v5.22 MRPL49 Arina Puzriakova Tag Q2_25_expert_review was removed from gene: MRPL49.
Thrombocythaemia v1.6 SH2B3 Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: SH2B3.
Thrombocythaemia v1.6 SH2B3 Arina Puzriakova commented on gene: SH2B3: Tagging for GMS expert review to determine whether this gene should be included and the MOI that should be set on this panel. Both germline and somatic variants have been reported - MOI currently set to Other to capture somatic origin.

Terri McVeigh states that this gene should be included on the panel, although thrombocythaemia typically presents alongside myeloproliferative neoplasm. Testing criteria for this panel states that secondary causes such as myeloproliferative neoplasm should be excluded.
Hereditary Erythrocytosis v2.13 SH2B3 Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: SH2B3.
Hereditary Erythrocytosis v2.13 SH2B3 Arina Puzriakova edited their review of gene: SH2B3: Added comment: Tagging for GMS expert review to determine whether this gene should be included and the MOI that should be set on this panel. Erythrocytosis is thought to be caused by somatic variants (for somatic variants MOI is set to Other) and testing criteria for this panel states that secondary causes such as myeloproliferative neoplasm should be excluded. However, Terri McVeigh states that germline variants should be included, although these are typically linked to myeloproliferative neoplasms.

Cases of erythrocytosis due to germline variants are rare, and most studies reporting SH2B3 variants have not determined germline or somatic status (PMID: 20843259; 23812944; 27651169; 34349782). In the literature, there is only one report of idiopathic erythrocytosis, without signs of myeloproliferative neoplasms, associated with a confirmed germline heterozygous SH2B3 variant. The mother was also a carrier but had no signs of erythrocytosis (PMID: 38024597).; Changed publications to: 20843259, 23812944, 27651169, 34349782, 38024597
Acute intermittent porphyria v1.3 HMBS Arina Puzriakova Tag Q2_25_expert_review was removed from gene: HMBS.
Non-acute porphyrias v1.26 HMBS Arina Puzriakova commented on gene: HMBS
Retinal disorders v8.6 POC5 Siying Lin reviewed gene: POC5: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 29272404, 40590205; Phenotypes: Retinal dystrophy, diabetes mellitus, lipodystrophy, renal failure, abnormal muscle physiology; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v6.4 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic cysteine-involving missense variants of NOTCH3 gene with early-adult-onset leukodystrophy. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Adult onset leukodystrophy v6.4 NOTCH3 Achchuthan Shanmugasundram Mode of inheritance for gene: NOTCH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset leukodystrophy v6.3 NOTCH3 Achchuthan Shanmugasundram Publications for gene: NOTCH3 were set to 27159321; 25527826; 28334938; 20301621; 24357685
Adult onset leukodystrophy v6.2 NOTCH3 Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310 to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310; neurodevelopmental disorder, MONDO:0700092; leukodystrophy, MONDO:0019046
Adult onset leukodystrophy v6.1 NOTCH3 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: NOTCH3.
Adult onset leukodystrophy v6.1 NOTCH3 Achchuthan Shanmugasundram edited their review of gene: NOTCH3: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, leukodystrophy, MONDO:0019046
Adult onset leukodystrophy v6.1 NOTCH3 Achchuthan Shanmugasundram reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram changed review comment from: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. 19 of these patients from 11 different families were reported with spasticity.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Spasticity and ataxia were reported in three and four patients respectively.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.; to: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia.

19 of these patients from 11 different families were reported with spasticity. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Spasticity and ataxia were reported in three and four patients respectively.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available for the association of biallelic LoF variants from NOTCH3 gene with childhood-onset spastic paraplegia. Hence, this gene can be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.3 NOTCH3 Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Spasticity, stroke, periatrial white matter volume loss to neurodevelopmental disorder, MONDO:0700092
Childhood onset hereditary spastic paraplegia v8.2 NOTCH3 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NOTCH3.
Tag Q3_25_NHS_review tag was added to gene: NOTCH3.
Childhood onset hereditary spastic paraplegia v8.2 NOTCH3 Achchuthan Shanmugasundram reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v7.8 NOTCH3 Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v7.8 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available for the association of biallelic LoF variants from NOTCH3 gene with childhood-onset leukoencephalopathy. Hence, this gene can be promoted to green rating in the next GMS update.
White matter disorders and cerebral calcification - narrow panel v7.8 NOTCH3 Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v7.7 NOTCH3 Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310 to neurodevelopmental disorder, MONDO:0700092; leukodystrophy, MONDO:0019046
White matter disorders and cerebral calcification - narrow panel v7.6 NOTCH3 Achchuthan Shanmugasundram Publications for gene: NOTCH3 were set to
White matter disorders and cerebral calcification - narrow panel v7.5 NOTCH3 Achchuthan Shanmugasundram Mode of inheritance for gene: NOTCH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v7.4 NOTCH3 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NOTCH3.
Tag Q3_25_NHS_review tag was added to gene: NOTCH3.
White matter disorders and cerebral calcification - narrow panel v7.4 NOTCH3 Achchuthan Shanmugasundram reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: neurodevelopmental disorder, MONDO:0700092, leukodystrophy, MONDO:0019046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autosomal recessive primary hypertrophic osteoarthropathy v1.14 SLCO2A1 Arina Puzriakova Tag Q2_25_expert_review was removed from gene: SLCO2A1.
Early onset or syndromic epilepsy v8.7 NOTCH3 Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.7 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic LoF variants in NOTCH3 gene with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.7 NOTCH3 Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.6 NOTCH3 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: NOTCH3.
Tag Q3_25_promote_green tag was added to gene: NOTCH3.
Intellectual disability v9.30 NOTCH3 Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
Intellectual disability v9.30 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic LoF variants in NOTCH3 gene with intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.30 NOTCH3 Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.29 NOTCH3 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: NOTCH3.
Tag Q3_25_promote_green tag was added to gene: NOTCH3.
Early onset or syndromic epilepsy v8.6 NOTCH3 Achchuthan Shanmugasundram gene: NOTCH3 was added
gene: NOTCH3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOTCH3 were set to 39191170
Phenotypes for gene: NOTCH3 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: NOTCH3 was set to GREEN
Added comment: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia.

Of these 24 patients from 15 families had developmental delay, ranging from mild or only motor delay in 7 patients to global developmental impairment in 17 patients. 21 patents from 13 families had predominantly severe intellectual disability, of which five had mild ID. Seizures were reported in 10 patients from seven different families.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.29 NOTCH3 Achchuthan Shanmugasundram gene: NOTCH3 was added
gene: NOTCH3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOTCH3 were set to 39191170
Phenotypes for gene: NOTCH3 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: NOTCH3 was set to GREEN
Added comment: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia.

Of these 24 patients from 15 families had developmental delay, ranging from mild or only motor delay in 7 patients to global developmental impairment in 17 patients. 21 patents from 13 families had predominantly severe intellectual disability, of which five had mild ID. Seizures were reported in 10 patients from seven different families.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Hereditary Erythrocytosis v2.13 JAK2 Arina Puzriakova Tag Q1_25_ MOI was removed from gene: JAK2.
Thrombocythaemia v1.6 SH2B3 Arina Puzriakova Tag Q2_25_ MOI was removed from gene: SH2B3.
Haematological malignancies cancer susceptibility v4.25 SH2B3 Arina Puzriakova Tag Q2_25_ MOI was removed from gene: SH2B3.
Hereditary Erythrocytosis v2.13 SH2B3 Achchuthan Shanmugasundram Tag Q2_25_ MOI was removed from gene: SH2B3.
Intellectual disability v9.28 KDM5B Arina Puzriakova commented on gene: KDM5B
Intellectual disability v9.28 KDM5B Arina Puzriakova Tag Q2_25_ demote_red was removed from gene: KDM5B.
Tag Q2_25_ MOI tag was added to gene: KDM5B.
Intellectual disability v9.28 KDM5B Arina Puzriakova Tag Q2_25_ demote_amber was removed from gene: KDM5B.
Tag Q2_25_ demote_red tag was added to gene: KDM5B.
Intellectual disability v9.28 KDM5B Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: KDM5B.
Tag Q2_25_ demote_amber tag was added to gene: KDM5B.
Tag Q2_25_ NHS_review tag was added to gene: KDM5B.
Dilated and arrhythmogenic cardiomyopathy v3.1 MYLK3 Arina Puzriakova commented on gene: MYLK3: Tagged for GMS review to determine whether this gene should remain Amber or be promoted to Green. As stated by Matthew Edwards, the evidence is borderline - several unrelated cases and supportive mouse model but MOI varies, one family also had variants in another DCM gene and there are unaffected carriers. MYLK3 is green on the R135 Paediatric or syndromic cardiomyopathy panel based on the same evidence.
Monogenic hearing loss v5.22 PLCG1 Arina Puzriakova Tag watchlist tag was added to gene: PLCG1.
Dilated and arrhythmogenic cardiomyopathy v3.1 MYLK3 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MYLK3.
Tag Q2_25_expert_review tag was added to gene: MYLK3.
Tag Q2_25_ NHS_review tag was added to gene: MYLK3.
Congenital myopathy v6.34 MT-TP Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TP.
Congenital myopathy v6.34 MT-TE Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TE.
Congenital myopathy v6.34 MT-TG Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TG.
Congenital myopathy v6.34 MT-TN Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TN.
Congenital myopathy v6.34 MT-TA Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TA.
Congenital myopathy v6.34 MT-TW Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TW.
Paediatric or syndromic cardiomyopathy v7.6 MT-TV Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TV.
Hypertrophic cardiomyopathy v5.12 MT-TV Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TV.
Monogenic hearing loss v5.22 MT-TK Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TK.
Congenital myopathy v6.34 MT-TK Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TK.
Optic neuropathy v5.23 MT-TK Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TK.
Monogenic hearing loss v5.22 MT-TS2 Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TS2.
Optic neuropathy v5.23 MT-TS2 Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TS2.
Congenital myopathy v6.34 MT-TP Achchuthan Shanmugasundram Classified gene: MT-TP as Amber List (moderate evidence)
Congenital myopathy v6.34 MT-TP Achchuthan Shanmugasundram Gene: mt-tp has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.33 MT-TP Achchuthan Shanmugasundram Phenotypes for gene: MT-TP were changed from to inborn mitochondrial myopathy, MONDO:0009637
Congenital myopathy v6.32 MT-TP Achchuthan Shanmugasundram Publications for gene: MT-TP were set to
Congenital myopathy v6.31 MT-TP Achchuthan Shanmugasundram edited their review of gene: MT-TP: Changed phenotypes to: inborn mitochondrial myopathy, MONDO:0009637
Congenital myopathy v6.31 MT-TP Achchuthan Shanmugasundram reviewed gene: MT-TP: Rating: AMBER; Mode of pathogenicity: None; Publications: 7689388, 32305257; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.31 MT-TA Achchuthan Shanmugasundram changed review comment from: PMID:17825557 - One family reported with predominantly proximal myopathy, with the onset of symptoms around five years, six years and 53 years in three affected individuals. They were identified with m.5650G>A pathogenic variant in MT-TA gene.

MitoPhen (https://www.mitophen.org) also reported patients from PMID:11715067 and PMID:14569122 with myopathy.

PMID:11715067 - A 53 year old patient was reported with CADASIL and myopathy. He was identified with a NOTCH3 variant, responsible for CADASIL. He was also identified with m.5650G>A variant. This variant was also present to a lower extent in the unaffected sister of the patient.

PMID:14569122 - A 38-year-old patient was first reported with weakness during regular exercise at 14 years of age, and then with slowly progressive proximal muscle weakness and atrophy of the lower limbs. He was also identified with the same m.5650G>A variant.; to: PMID:17825557 - One family reported with predominantly proximal myopathy, with the onset of symptoms around five years, six years and 53 years in three affected individuals. They were identified with m.5650G>A pathogenic variant in MT-TA gene.

MitoPhen (https://www.mitophen.org) also reported patients from PMID:11715067 and PMID:14569122 with myopathy.

PMID:11715067 - A 53 year old patient was reported with CADASIL and myopathy. He was identified with a NOTCH3 variant, responsible for CADASIL. He was also identified with m.5650G>A variant. This variant was also present to a lower extent in the unaffected sister of the patient.

PMID:14569122 - A 38-year-old patient was first reported with weakness during regular exercise at 14 years of age, and then with slowly progressive proximal muscle weakness and atrophy of the lower limbs. He was also identified with the same m.5650G>A variant.

In summary, there are no cases reported with onset of myopathy in infancy. However, it appears that there is one family with myopathy since early childhood. The other reported cases developed myopathy later in life.
Congenital myopathy v6.31 MT-TA Achchuthan Shanmugasundram Classified gene: MT-TA as Amber List (moderate evidence)
Congenital myopathy v6.31 MT-TA Achchuthan Shanmugasundram Gene: mt-ta has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.30 MT-TA Achchuthan Shanmugasundram Phenotypes for gene: MT-TA were changed from to inborn mitochondrial myopathy, MONDO:0009637
Congenital myopathy v6.29 MT-TA Achchuthan Shanmugasundram Publications for gene: MT-TA were set to
Congenital myopathy v6.28 MT-TA Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TA.
Tag Q2_25_expert_review was removed from gene: MT-TA.
Tag Q2_25_ NHS_review was removed from gene: MT-TA.
Congenital myopathy v6.28 MT-TA Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TA.
Tag Q2_25_expert_review tag was added to gene: MT-TA.
Tag Q2_25_ NHS_review tag was added to gene: MT-TA.
Congenital myopathy v6.28 MT-TA Achchuthan Shanmugasundram edited their review of gene: MT-TA: Changed publications to: 11715067, 14569122, 17825557
Congenital myopathy v6.28 MT-TA Achchuthan Shanmugasundram changed review comment from: PMID:17825557 - One family reported with predominantly proximal myopathy, with the onset of symptoms around five years, six years and 53 years in three affected individuals. They were identified with m.5650G>A pathogenic variant in MT-TA gene.

MitoPhen (https://www.mitophen.org) also reported patients from PMID:11715067 and PMID:14569122 with myopathy.

PMID:11715067 - A 53 year old patient was reported with CADASIL and myopathy. He was identified with a NOTCH3 variant, responsible for CADASIL. He was also identified with m.5650G>A variant.

PMID:14569122 - A 38-year-old patient was first reported with weakness during regular exercise at 14 years of age, and then with slowly progressive proximal muscle weakness and atrophy of the lower limbs. He was also identified with the same m.5650G>A variant.; to: PMID:17825557 - One family reported with predominantly proximal myopathy, with the onset of symptoms around five years, six years and 53 years in three affected individuals. They were identified with m.5650G>A pathogenic variant in MT-TA gene.

MitoPhen (https://www.mitophen.org) also reported patients from PMID:11715067 and PMID:14569122 with myopathy.

PMID:11715067 - A 53 year old patient was reported with CADASIL and myopathy. He was identified with a NOTCH3 variant, responsible for CADASIL. He was also identified with m.5650G>A variant. This variant was also present to a lower extent in the unaffected sister of the patient.

PMID:14569122 - A 38-year-old patient was first reported with weakness during regular exercise at 14 years of age, and then with slowly progressive proximal muscle weakness and atrophy of the lower limbs. He was also identified with the same m.5650G>A variant.
Congenital myopathy v6.28 MT-TA Achchuthan Shanmugasundram reviewed gene: MT-TA: Rating: AMBER; Mode of pathogenicity: None; Publications: 17825557; Phenotypes: inborn mitochondrial myopathy, MONDO:0009637; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.23 MT-TS2 Achchuthan Shanmugasundram Classified gene: MT-TS2 as Amber List (moderate evidence)
Optic neuropathy v5.23 MT-TS2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Katherine Schon has reviewed this gene green on this panel. However, the ophthalmological phenotypes reported in the families identified with m.12258C>A variant are retinitis pigmentosa and cataracts. Hence, expert review is sought from the Genomic Medicine Service on the rating of MT-TS2 gene on this panel.
Optic neuropathy v5.23 MT-TS2 Achchuthan Shanmugasundram Gene: mt-ts2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.22 MT-TS2 Achchuthan Shanmugasundram changed review comment from: PMIDs: 8432539;9135384;10090882 - A large Irish kindred was reported with progressive sensorineural hearing loss and retinitis pigmentosa. The patient also had optic disc pallor and progressive visual loss. They were identified with pathogenic m.12258C>A variant in MT-TS2 gene.

PMID:9792552 - A 61-year-old mother and 30-year old daughter were reported with maternally inherited syndrome consisting of cerebellar ataxia, cataracts, deafness and diabetes. They were identified with m.12258C>A variant.

PMID:12086967 - This study reported 28 patients that had maternally inherited diabetes with or without one or more additional features of mitochondrial disease, including bilateral sensorineural deafness and neuromuscular disease. One of these patients with additional features (cerebellar ataxia, bilateral nerve deafness and cataracts) harboured m.12258C>A variant.; to: PMIDs: 8432539;9135384;10090882 - A large Irish kindred was reported with progressive sensorineural hearing loss and retinitis pigmentosa. The patients also had optic disc pallor and progressive visual loss. They were identified with pathogenic m.12258C>A variant in MT-TS2 gene.

PMID:9792552 - A 61-year-old mother and 30-year old daughter were reported with maternally inherited syndrome consisting of cerebellar ataxia, cataracts, deafness and diabetes. They were identified with m.12258C>A variant.

PMID:12086967 - This study reported 28 patients that had maternally inherited diabetes with or without one or more additional features of mitochondrial disease, including bilateral sensorineural deafness and neuromuscular disease. One of these patients with additional features (cerebellar ataxia, bilateral nerve deafness and cataracts) harboured m.12258C>A variant.
Optic neuropathy v5.22 MT-TS2 Achchuthan Shanmugasundram Publications for gene: MT-TS2 were set to
Optic neuropathy v5.21 MT-TS2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TS2.
Tag Q2_25_expert_review tag was added to gene: MT-TS2.
Tag Q2_25_ NHS_review tag was added to gene: MT-TS2.
Optic neuropathy v5.21 MT-TS2 Achchuthan Shanmugasundram reviewed gene: MT-TS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 8432539, 9135384, 9792552, 10090882, 12086967; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Monogenic hearing loss v5.22 MT-TS2 Achchuthan Shanmugasundram Classified gene: MT-TS2 as Amber List (moderate evidence)
Monogenic hearing loss v5.22 MT-TS2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available (three unrelated families) for the association of m.12258C>A variant in MT-TS2 gene with sensorineural hearing loss. Hence, this gene can be promoted to green rating in the next GMS update.
Monogenic hearing loss v5.22 MT-TS2 Achchuthan Shanmugasundram Gene: mt-ts2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.21 MT-TS2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TS2.
Tag Q2_25_expert_review tag was added to gene: MT-TS2.
Tag Q2_25_ NHS_review tag was added to gene: MT-TS2.
Monogenic hearing loss v5.21 MT-TS2 Achchuthan Shanmugasundram Phenotypes for gene: MT-TS2 were changed from to Sensorineural hearing impairment, HP:0000407
Monogenic hearing loss v5.20 MT-TS2 Achchuthan Shanmugasundram Publications for gene: MT-TS2 were set to
Monogenic hearing loss v5.19 MT-TS2 Achchuthan Shanmugasundram edited their review of gene: MT-TS2: Changed phenotypes to: Sensorineural hearing impairment, HP:0000407
Monogenic hearing loss v5.19 MT-TS2 Achchuthan Shanmugasundram reviewed gene: MT-TS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9792552, 10090882, 12086967; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.28 MT-TE Achchuthan Shanmugasundram edited their review of gene: MT-TE: Changed rating: GREEN
Congenital myopathy v6.28 MT-TE Achchuthan Shanmugasundram Classified gene: MT-TE as Amber List (moderate evidence)
Congenital myopathy v6.28 MT-TE Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed below, patients with MT-TE variants are reported with either congenital myopathy or adult-onset myopathy. As there are >3 unrelated cases with congenital myopathy, this gene can be considered for promotion to green rating in the next GMS update.
Congenital myopathy v6.28 MT-TE Achchuthan Shanmugasundram Gene: mt-te has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.27 MT-TE Achchuthan Shanmugasundram Phenotypes for gene: MT-TE were changed from to inborn mitochondrial myopathy, MONDO:0009637; congenital myopathy, MONDO:0019952
Congenital myopathy v6.26 MT-TE Achchuthan Shanmugasundram Publications for gene: MT-TE were set to
Congenital myopathy v6.25 MT-TE Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TE.
Tag Q2_25_expert_review tag was added to gene: MT-TE.
Tag Q2_25_ NHS_review tag was added to gene: MT-TE.
Congenital myopathy v6.25 MT-TE Achchuthan Shanmugasundram edited their review of gene: MT-TE: Changed phenotypes to: inborn mitochondrial myopathy, MONDO:0009637, congenital myopathy, MONDO:0019952
Congenital myopathy v6.25 MT-TE Achchuthan Shanmugasundram reviewed gene: MT-TE: Rating: AMBER; Mode of pathogenicity: None; Publications: 7726155, 10392369, 15607216, 21194154; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Pigmentary skin disorders v4.4 BLM Eleanor Williams Tag Q2_25_ promote_green tag was added to gene: BLM.
Pigmentary skin disorders v4.4 BLM Eleanor Williams Classified gene: BLM as Amber List (moderate evidence)
Pigmentary skin disorders v4.4 BLM Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for a green rating following NHS GMS review. After consultation with the Genomics England clinical team, their recommendation is for green as there are management implications (including avoiding exposures / ionising radiation) so the view is that is reasonable to include on this panel.
Pigmentary skin disorders v4.4 BLM Eleanor Williams Gene: blm has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.25 MT-TG Achchuthan Shanmugasundram Classified gene: MT-TG as Amber List (moderate evidence)
Congenital myopathy v6.25 MT-TG Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients reported with m.10010T>C variant and with myopathy as part of the presenting phenotype. Hence, this gene is rated amber.
Congenital myopathy v6.25 MT-TG Achchuthan Shanmugasundram Gene: mt-tg has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.24 MT-TG Achchuthan Shanmugasundram Phenotypes for gene: MT-TG were changed from to mitochondrial encephalomyopathy, MONDO:0004675
Congenital myopathy v6.23 MT-TG Achchuthan Shanmugasundram Publications for gene: MT-TG were set to
Congenital myopathy v6.22 MT-TG Achchuthan Shanmugasundram reviewed gene: MT-TG: Rating: AMBER; Mode of pathogenicity: None; Publications: 11971101, 16120360; Phenotypes: mitochondrial encephalomyopathy, MONDO:0004675; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.22 MT-TN Achchuthan Shanmugasundram Classified gene: MT-TN as Amber List (moderate evidence)
Congenital myopathy v6.22 MT-TN Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, pathogenic variants in MT-TN have been reported to cause mitochondrial myopathy. However, there is no clear evidence to suggest that the reported patients had onset of myopathy during infancy/ early childhood. Hence, expert review is sought on whether this gene can be promoted to green rating in the next GMS update.
Congenital myopathy v6.22 MT-TN Achchuthan Shanmugasundram Gene: mt-tn has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.21 MT-TN Achchuthan Shanmugasundram Phenotypes for gene: MT-TN were changed from to inborn mitochondrial myopathy, MONDO:0009637
Congenital myopathy v6.20 MT-TN Achchuthan Shanmugasundram Publications for gene: MT-TN were set to
Congenital myopathy v6.19 MT-TN Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TN.
Tag Q2_25_expert_review tag was added to gene: MT-TN.
Tag Q2_25_ NHS_review tag was added to gene: MT-TN.
Congenital myopathy v6.19 MT-TN Achchuthan Shanmugasundram edited their review of gene: MT-TN: Changed publications to: 8254046, 16908752, 23696415, 31026515
Congenital myopathy v6.19 MT-TN Achchuthan Shanmugasundram changed review comment from: PMID:8254046 - Two patients were reported with identification of pathogenic variants in two different mitochondrial tRNA genes. One of them had m.5703G>A variant in MT-TN gene and it was associated with isolated ophthalmoplegia. Electromyography tests taken at 27 years of age were compatible with myopathy. However, the actual age of onset of myopathy was not reported.

PMID:16908752 - A 13-year-old male patient with multi organ failure was identified with m.5728C>T variant in MT-TN gene. The patient had initial symptoms since 2 years of age and muscle weakness was first reported at 10 years.

PMID:23696415 - This study identified nine different mt-tRNA variants in nine families, of which one was m.5690A>G variant from MT-TN gene. The patient had the onset of disease at 13 years and presented with chronic progressive external ophthalmoplegia (CPEO), ptosis and proximal myopathy.

PMID:31026515 - A nine-year old female was identified with m.5728C>T variant and has a milder clinical phenotype with isolated ptosis and ophthalmoplegia. She She was reported to have the onset of ptosis at around 8 years of age.; to: PMID:8254046 - Two patients were reported with identification of pathogenic variants in two different mitochondrial tRNA genes. One of them had m.5703G>A variant in MT-TN gene and it was associated with isolated ophthalmoplegia. Electromyography tests taken at 27 years of age were compatible with myopathy. However, the actual age of onset of myopathy was not reported.

PMID:16908752 - A 13-year-old male patient with multi organ failure was identified with m.5728C>T variant in MT-TN gene. The patient had initial symptoms since 2 years of age and muscle weakness was first reported at 10 years.

PMID:23696415 - This study identified nine different mt-tRNA variants in nine families, of which one was m.5690A>G variant from MT-TN gene. The patient had the onset of disease at 13 years and presented with chronic progressive external ophthalmoplegia (CPEO), ptosis and proximal myopathy.

PMID:31026515 - A nine-year old female was identified with m.5728C>T variant and has a milder clinical phenotype with isolated ptosis and ophthalmoplegia. She was reported to have the onset of ptosis at around 8 years of age.
Congenital myopathy v6.19 MT-TN Achchuthan Shanmugasundram reviewed gene: MT-TN: Rating: GREEN; Mode of pathogenicity: None; Publications: 8254046, 16908752, 23696415; Phenotypes: inborn mitochondrial myopathy, MONDO:0009637; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.19 MT-TW Achchuthan Shanmugasundram Classified gene: MT-TW as Amber List (moderate evidence)
Congenital myopathy v6.19 MT-TW Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, myopathy has been reported in patients with m.5521G>A variant in MT-TW. However, there is no clear evidence for the onset of myopathy in infancy or early childhood. Hence, expert review is being sought on whether to promote this gene to green rating on this panel.
Congenital myopathy v6.19 MT-TW Achchuthan Shanmugasundram Gene: mt-tw has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.18 MT-TW Achchuthan Shanmugasundram Phenotypes for gene: MT-TW were changed from to inborn mitochondrial myopathy, MONDO:0009637
Congenital myopathy v6.17 MT-TW Achchuthan Shanmugasundram Publications for gene: MT-TW were set to
Congenital myopathy v6.16 MT-TW Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TW.
Tag Q2_25_expert_review tag was added to gene: MT-TW.
Tag Q2_25_ NHS_review tag was added to gene: MT-TW.
Congenital myopathy v6.16 MT-TW Achchuthan Shanmugasundram edited their review of gene: MT-TW: Changed publications to: 9673981, 20360171, 23841600; Changed phenotypes to: inborn mitochondrial myopathy, MONDO:0009637
Congenital myopathy v6.16 MT-TW Achchuthan Shanmugasundram changed review comment from: PMID:9673981 - The m.5521G>A variant in MT-TW gene was identified in a patient with late-onset mitochondrial myopathy.

PMID:23841600 - Three Tunisian patients were reported with mitochondrial myopathy. One of these patients was detected with m.5521G>A variant in MT-TW and with m.8682A>G variant in MT-ATP6 gene.; to: PMID:9673981 - The m.5521G>A variant in MT-TW gene was identified in a patient with late-onset mitochondrial myopathy.

PMID:20360171 - A female patient was reported with m.5521G>A variant, who initially developed sensorineural hearing loss at 24 years of age. She was diagnosed with overlapped MERRF/ MELAS phenotype.

PMID:23841600 - Three Tunisian patients were reported with mitochondrial myopathy. One of these patients was detected with m.5521G>A variant in MT-TW and with m.8682A>G variant in MT-ATP6 gene. This patient had the onset of the disorder at 11 months of age with neurodevelopmental and psychomotor delay, mental retardation, axial hypotonia, paraplegia, seizures and lactic acidosis. It is not clear when this patient started showing myopathic features.
Congenital myopathy v6.16 MT-TW Achchuthan Shanmugasundram reviewed gene: MT-TW: Rating: AMBER; Mode of pathogenicity: None; Publications: 9673981, 23841600; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Monogenic hearing loss v5.19 MT-CO1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: MT-CO1.
Tag Q2_25_ NHS_review tag was added to gene: MT-CO1.
Monogenic hearing loss v5.19 MT-CO1 Achchuthan Shanmugasundram Classified gene: MT-CO1 as Amber List (moderate evidence)
Monogenic hearing loss v5.19 MT-CO1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon and Sarah Leigh, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Monogenic hearing loss v5.19 MT-CO1 Achchuthan Shanmugasundram Gene: mt-co1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.18 MT-CO1 Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: MT-CO1.
Paediatric or syndromic cardiomyopathy v7.6 MT-TV Achchuthan Shanmugasundram Classified gene: MT-TV as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.6 MT-TV Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in at least three unrelated patients with variants in MT-TV gene. This gene can therefore be promoted to green rating on the next GMS update.
Paediatric or syndromic cardiomyopathy v7.6 MT-TV Achchuthan Shanmugasundram Gene: mt-tv has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.5 MT-TV Achchuthan Shanmugasundram Deleted their comment
Paediatric or syndromic cardiomyopathy v7.5 MT-TV Achchuthan Shanmugasundram edited their review of gene: MT-TV: Changed rating: GREEN
Paediatric or syndromic cardiomyopathy v7.5 MT-TV Achchuthan Shanmugasundram Tag Q2_25_ NHS_review was removed from gene: MT-TV.
Paediatric or syndromic cardiomyopathy v7.5 MT-TV Achchuthan Shanmugasundram Tag Q2_25_expert_review was removed from gene: MT-TV.
Paediatric or syndromic cardiomyopathy v7.5 MT-TV Achchuthan Shanmugasundram Entity copied from Hypertrophic cardiomyopathy v5.12
Paediatric or syndromic cardiomyopathy v7.5 MT-TV Achchuthan Shanmugasundram gene: MT-TV was added
gene: MT-TV was added to Paediatric or syndromic cardiomyopathy. Sources: Literature,Expert Review Amber
Q2_25_ promote_green, Q2_25_expert_review, Q2_25_ NHS_review tags were added to gene: MT-TV.
Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL
Publications for gene: MT-TV were set to 15320572; 21986556; 34298071
Phenotypes for gene: MT-TV were set to MELAS syndrome, MONDO:0010789; hypertrophic cardiomyopathy, MONDO:000504
Mode of pathogenicity for gene: MT-TV was set to Other
Hypertrophic cardiomyopathy v5.12 MT-TV Achchuthan Shanmugasundram Classified gene: MT-TV as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v5.12 MT-TV Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least three unrelated cases reported with MT-TV variants and with hypertrophic cardiomyopathy. However, HCM is part of a syndromic phenotype.

R131 is only intended for genes associated with isolated HCM and not for syndromic genes. Hence, expert review is sought on whether this gene can be promoted to green rating on this panel.

This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
Hypertrophic cardiomyopathy v5.12 MT-TV Achchuthan Shanmugasundram Gene: mt-tv has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v5.11 MT-TV Achchuthan Shanmugasundram Phenotypes for gene: MT-TV were changed from to MELAS syndrome, MONDO:0010789; hypertrophic cardiomyopathy, MONDO:000504
Hypertrophic cardiomyopathy v5.10 MT-TV Achchuthan Shanmugasundram Publications for gene: MT-TV were set to
Hypertrophic cardiomyopathy v5.9 MT-TV Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TV.
Tag Q2_25_expert_review tag was added to gene: MT-TV.
Tag Q2_25_ NHS_review tag was added to gene: MT-TV.
Hypertrophic cardiomyopathy v5.9 MT-TV Achchuthan Shanmugasundram reviewed gene: MT-TV: Rating: AMBER; Mode of pathogenicity: None; Publications: 15320572, 21986556, 34298071; Phenotypes: MELAS syndrome, MONDO:0010789, hypertrophic cardiomyopathy, MONDO:0005045; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.16 MT-TK Achchuthan Shanmugasundram Classified gene: MT-TK as Amber List (moderate evidence)
Congenital myopathy v6.16 MT-TK Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, myopathy is one of the clinical presentations of MERFF syndrome caused by m.8344A>G variant in MT-TK gene. However, it should be noted that the onset of myopathic features is not during infancy or first few years of life in the reported patients. Hence, expert review is sought from the Genomic Medicine Service on upgrading this gene to green rating on this panel.
Congenital myopathy v6.16 MT-TK Achchuthan Shanmugasundram Gene: mt-tk has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.1 FLG Ronnie Wright reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:16444271; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Congenital myopathy v6.15 MT-TK Achchuthan Shanmugasundram Publications for gene: MT-TK were set to
Congenital myopathy v6.14 MT-TK Achchuthan Shanmugasundram Phenotypes for gene: MT-TK were changed from to MERRF syndrome, MONDO:0010790; inborn mitochondrial myopathy, MONDO:0009637
Congenital myopathy v6.13 MT-TK Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TK.
Tag Q2_25_expert_review tag was added to gene: MT-TK.
Tag Q2_25_ NHS_review tag was added to gene: MT-TK.
Congenital myopathy v6.13 MT-TK Achchuthan Shanmugasundram reviewed gene: MT-TK: Rating: AMBER; Mode of pathogenicity: None; Publications: 1463006, 8228033; Phenotypes: MERRF syndrome, MONDO:0010790, inborn mitochondrial myopathy, MONDO:0009637; Mode of inheritance: MITOCHONDRIAL
Monogenic hearing loss v5.18 MT-TK Achchuthan Shanmugasundram Classified gene: MT-TK as Amber List (moderate evidence)
Monogenic hearing loss v5.18 MT-TK Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of variants in MT-TK gene with sensorineural hearing loss. Hence, this gene can be promoted to green rating in the next GMS update.
Monogenic hearing loss v5.18 MT-TK Achchuthan Shanmugasundram Gene: mt-tk has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.17 MT-TK Achchuthan Shanmugasundram Publications for gene: MT-TK were set to 8651277; 1899320; 23224446
Monogenic hearing loss v5.16 MT-TK Achchuthan Shanmugasundram Phenotypes for gene: MT-TK were changed from to MERRF syndrome, MONDO:0010790; Sensorineural hearing impairment, HP:0000407
Monogenic hearing loss v5.16 MT-TK Achchuthan Shanmugasundram Publications for gene: MT-TK were set to
Monogenic hearing loss v5.15 MT-TK Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TK.
Tag Q2_25_expert_review tag was added to gene: MT-TK.
Tag Q2_25_ NHS_review tag was added to gene: MT-TK.
Monogenic hearing loss v5.15 MT-TK Achchuthan Shanmugasundram edited their review of gene: MT-TK: Changed phenotypes to: MERRF syndrome, MONDO:0010790, Sensorineural hearing impairment, HP:0000407
Monogenic hearing loss v5.15 MT-TK Achchuthan Shanmugasundram reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8651277, 1899320, 23224446; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.21 MT-TK Achchuthan Shanmugasundram Classified gene: MT-TK as Amber List (moderate evidence)
Optic neuropathy v5.21 MT-TK Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.8344A>G variant in MT-TK gene with optic atrophy. Hence, this gene can be promoted to green rating in the next GMS update.
Optic neuropathy v5.21 MT-TK Achchuthan Shanmugasundram Gene: mt-tk has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.20 MT-TK Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TK.
Tag Q2_25_expert_review tag was added to gene: MT-TK.
Tag Q2_25_ NHS_review tag was added to gene: MT-TK.
Optic neuropathy v5.20 MT-TK Achchuthan Shanmugasundram Phenotypes for gene: MT-TK were changed from to MERRF syndrome, MONDO:0010790; optic atrophy, MONDO:0003608
Optic neuropathy v5.19 MT-TK Achchuthan Shanmugasundram Publications for gene: MT-TK were set to
Optic neuropathy v5.18 MT-TK Achchuthan Shanmugasundram reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: None; Publications: 1463006, 8228033, 33766967; Phenotypes: MERRF syndrome, MONDO:0010790, optic atrophy, MONDO:0003608; Mode of inheritance: MITOCHONDRIAL
Pulmonary fibrosis familial v1.7 MUC5B Matthew Edwards reviewed gene: MUC5B: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Risk allele for Pulmonary Fibrosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Paediatric or syndromic cardiomyopathy v7.4 MT-ND5 Achchuthan Shanmugasundram Classified gene: MT-ND5 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.4 MT-ND5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with variants in MT-ND5 gene.

This gene can therefore be promoted to green rating on the next GMS update.
Paediatric or syndromic cardiomyopathy v7.4 MT-ND5 Achchuthan Shanmugasundram Gene: mt-nd5 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.3 MT-ND5 Achchuthan Shanmugasundram Tag Q2_25_ NHS_review was removed from gene: MT-ND5.
Paediatric or syndromic cardiomyopathy v7.3 MT-ND5 Achchuthan Shanmugasundram edited their review of gene: MT-ND5: Changed rating: GREEN
Paediatric or syndromic cardiomyopathy v7.3 MT-ND5 Achchuthan Shanmugasundram Deleted their comment
Paediatric or syndromic cardiomyopathy v7.3 MT-ND5 Achchuthan Shanmugasundram Tag Q2_25_expert_review was removed from gene: MT-ND5.
Paediatric or syndromic cardiomyopathy v7.3 MT-ND5 Achchuthan Shanmugasundram Entity copied from Hypertrophic cardiomyopathy v5.9
Paediatric or syndromic cardiomyopathy v7.3 MT-ND5 Achchuthan Shanmugasundram gene: MT-ND5 was added
gene: MT-ND5 was added to Paediatric or syndromic cardiomyopathy. Sources: Expert Review Amber,Literature
Q2_25_ promote_green, Q2_25_expert_review, Q2_25_ NHS_review tags were added to gene: MT-ND5.
Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL
Publications for gene: MT-ND5 were set to 14520659; 22759514; 23847141; 30587702
Phenotypes for gene: MT-ND5 were set to hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v5.9 MT-ND5 Achchuthan Shanmugasundram Classified gene: MT-ND5 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v5.9 MT-ND5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with variants in MT-ND5. The only case of isolated HCM was the family reported in PMID:22759514.

However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, expert review from the NHS Genomic Medicine Service is sought with regard to rating this gene green on this panel.

This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
Hypertrophic cardiomyopathy v5.9 MT-ND5 Achchuthan Shanmugasundram Gene: mt-nd5 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v5.8 MT-ND5 Achchuthan Shanmugasundram Phenotypes for gene: MT-ND5 were changed from to hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v5.7 MT-ND5 Achchuthan Shanmugasundram Publications for gene: MT-ND5 were set to
Hypertrophic cardiomyopathy v5.6 MT-ND5 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND5.
Tag Q2_25_expert_review tag was added to gene: MT-ND5.
Tag Q2_25_ NHS_review tag was added to gene: MT-ND5.
Hypertrophic cardiomyopathy v5.6 MT-ND5 Achchuthan Shanmugasundram edited their review of gene: MT-ND5: Changed rating: AMBER
Hypertrophic cardiomyopathy v5.6 MT-ND5 Achchuthan Shanmugasundram reviewed gene: MT-ND5: Rating: GREEN; Mode of pathogenicity: None; Publications: 14520659, 22759514, 23847141, 30587702; Phenotypes: hypertrophic cardiomyopathy, MONDO:0005045; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.18 MT-ND5 Achchuthan Shanmugasundram Classified gene: MT-ND5 as Amber List (moderate evidence)
Optic neuropathy v5.18 MT-ND5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of MT-ND5 gene with LHON. Hence, this gene can be promoted to green rating in the next GMS update.
Optic neuropathy v5.18 MT-ND5 Achchuthan Shanmugasundram Gene: mt-nd5 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.17 MT-ND5 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND5.
Tag Q2_25_expert_review tag was added to gene: MT-ND5.
Tag Q2_25_ NHS_review tag was added to gene: MT-ND5.
Optic neuropathy v5.17 MT-ND5 Achchuthan Shanmugasundram Phenotypes for gene: MT-ND5 were changed from to Leber hereditary optic neuropathy, MONDO:0010788
Optic neuropathy v5.16 MT-ND5 Achchuthan Shanmugasundram Publications for gene: MT-ND5 were set to
Optic neuropathy v5.15 MT-ND5 Achchuthan Shanmugasundram reviewed gene: MT-ND5: Rating: GREEN; Mode of pathogenicity: None; Publications: 12509858, 12736867, 27164671, 38357617; Phenotypes: Leber hereditary optic neuropathy, MONDO:0010788; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.15 MT-ND4L Achchuthan Shanmugasundram Classified gene: MT-ND4L as Amber List (moderate evidence)
Optic neuropathy v5.15 MT-ND4L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.10663T>C variant from MT-ND4L gene with LHON. Hence, this gene can be promoted to green rating in the next GMS update.
Optic neuropathy v5.15 MT-ND4L Achchuthan Shanmugasundram Gene: mt-nd4l has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.14 MT-ND4L Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND4L.
Tag Q2_25_expert_review tag was added to gene: MT-ND4L.
Tag Q2_25_ NHS_review tag was added to gene: MT-ND4L.
Optic neuropathy v5.14 MT-ND4L Achchuthan Shanmugasundram Phenotypes for gene: MT-ND4L were changed from to Leber hereditary optic neuropathy, MONDO:0010788
Optic neuropathy v5.13 MT-ND4L Achchuthan Shanmugasundram Publications for gene: MT-ND4L were set to
Optic neuropathy v5.12 MT-ND4L Achchuthan Shanmugasundram edited their review of gene: MT-ND4L: Changed phenotypes to: Leber hereditary optic neuropathy, MONDO:0010788
Optic neuropathy v5.12 MT-ND4L Achchuthan Shanmugasundram reviewed gene: MT-ND4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 11935318, 22879922, 29210930, 36381806; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.12 MT-ND3 Achchuthan Shanmugasundram Classified gene: MT-ND3 as Amber List (moderate evidence)
Optic neuropathy v5.12 MT-ND3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.10197G>A variant from MT-ND3 gene with LHON/ LDYT. Hence, this gene can be promoted to green rating in the next GMS update.
Optic neuropathy v5.12 MT-ND3 Achchuthan Shanmugasundram Gene: mt-nd3 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.11 MT-ND3 Achchuthan Shanmugasundram Phenotypes for gene: MT-ND3 were changed from to Leber hereditary optic neuropathy, MONDO:0010788; Leber optic atrophy and dystonia, MONDO:0010772
Optic neuropathy v5.10 MT-ND3 Achchuthan Shanmugasundram edited their review of gene: MT-ND3: Changed phenotypes to: Leber hereditary optic neuropathy, MONDO:0010788, Leber optic atrophy and dystonia, MONDO:0010772
Optic neuropathy v5.10 MT-ND2 Achchuthan Shanmugasundram Publications for gene: MT-ND2 were set to
Optic neuropathy v5.9 MT-ND2 Achchuthan Shanmugasundram Phenotypes for gene: MT-ND2 were changed from to Leber hereditary optic neuropathy, MONDO:0010788
Optic neuropathy v5.8 MT-ND3 Achchuthan Shanmugasundram Publications for gene: MT-ND3 were set to
Optic neuropathy v5.7 MT-ND3 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND3.
Tag Q2_25_expert_review tag was added to gene: MT-ND3.
Tag Q2_25_ NHS_review tag was added to gene: MT-ND3.
Optic neuropathy v5.7 MT-ND3 Achchuthan Shanmugasundram changed review comment from: PMID:19458970 - Leber hereditary optic neuropathy and dystonia (LDYT) was reported in 18 patients from a Chinese family. They were identified with m.10197G>A variant (p.Ala47Thr).

PMID:30199507 - A mother and daughter were reported with Leber hereditary optic neuropathy (LHON) and were identified with m.10197G>A variant.

PMID:39923090 - A patient was reported with adult-onset Leigh syndrome (LS) and Leber hereditary optic neuropathy and dystonia (LDYT) and was identified with m.10197G>A variant. His mother also developed vision disturbance, epilepsy, and abnormal gait in her second decade and harboured the same variant.; to: PMID:19458970 - Leber hereditary optic neuropathy and dystonia (LDYT) was reported in 18 patients from a Chinese family. They were identified with m.10197G>A variant (p.Ala47Thr).

PMID:30199507 - A mother and daughter were reported with Leber hereditary optic neuropathy (LHON) and were identified with m.10197G>A variant.

PMID:39923090 - A patient was reported with adult-onset Leigh syndrome (LS) and Leber hereditary optic neuropathy and dystonia (LDYT) and was identified with m.10197G>A variant. His mother also developed vision disturbance, epilepsy, and abnormal gait in her second decade and harboured the same variant. This publication also reviewed previously published cases, and reported a total of 84 participants (78 patients and 6 asymptomatic carriers) harbouring the m.10197G>A variant. LHON and LDYT were reported in 18 and six patients each.
Optic neuropathy v5.7 MT-ND3 Achchuthan Shanmugasundram reviewed gene: MT-ND3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19458970, 30199507, 39923090; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.7 MT-ND2 Achchuthan Shanmugasundram Classified gene: MT-ND2 as Amber List (moderate evidence)
Optic neuropathy v5.7 MT-ND2 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has been reviewed green by Katherine Schon on this panel. Expert review from the Genomic Medicine Service is being sought on the inclusion of this gene with green rating on this panel.
Optic neuropathy v5.7 MT-ND2 Achchuthan Shanmugasundram Gene: mt-nd2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.6 MT-ND2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND2.
Tag Q2_25_expert_review tag was added to gene: MT-ND2.
Tag Q2_25_ NHS_review tag was added to gene: MT-ND2.
Optic neuropathy v5.6 MT-ND2 Achchuthan Shanmugasundram reviewed gene: MT-ND2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8680405, 11479733, 21145289, 20454697; Phenotypes: Leber hereditary optic neuropathy, MONDO:0010788; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.13 MT-TL1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As the myopathy phenotype has predominantly been reported to be relatively late-onset, expert review is sought from the Genomic Medicine Service on promotion of this gene to green rating.; to: Comment on list classification: As the myopathy phenotype has predominantly been reported to be relatively late-onset, expert review is sought from the Genomic Medicine Service on promotion of this gene to green rating on this panel.
Congenital myopathy v6.13 MT-TL1 Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
Congenital myopathy v6.13 MT-TL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As the myopathy phenotype has predominantly been reported to be relatively late-onset, expert review is sought from the Genomic Medicine Service on promotion of this gene to green rating.
Congenital myopathy v6.13 MT-TL1 Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.12 MT-TL1 Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from MELAS syndrome, MONDO:0010789 to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; inborn mitochondrial myopathy, MONDO:0009637
Congenital myopathy v6.11 MT-TL1 Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
Congenital myopathy v6.10 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1.
Tag Q2_25_expert_review tag was added to gene: MT-TL1.
Tag Q2_25_ NHS_review tag was added to gene: MT-TL1.
Congenital myopathy v6.10 MT-TL1 Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 8122892, 8559168, 18391161; Phenotypes: MELAS syndrome caused by mutation in MTTL1, MONDO:0800032, inborn mitochondrial myopathy, MONDO:0009637; Mode of inheritance: MITOCHONDRIAL
Hypertrophic cardiomyopathy v5.6 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1.
Tag Q2_25_expert_review tag was added to gene: MT-TL1.
Tag Q2_25_ NHS_review tag was added to gene: MT-TL1.
Hypertrophic cardiomyopathy v5.6 MT-TL1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, expert review from the NHS Genomic Medicine Service is sought with regard to rating this gene green on this panel.

This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.; to: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, expert review from the NHS Genomic Medicine Service is sought with regard to rating this gene green on this panel.

This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
Hypertrophic cardiomyopathy v5.6 MT-TL1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, the rating should remain amber on this panel.

This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.; to: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, expert review from the NHS Genomic Medicine Service is sought with regard to rating this gene green on this panel.

This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
Monogenic hearing loss v5.15 MT-TL1 Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
Monogenic hearing loss v5.15 MT-TL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.3243A>G variant with sensorineural hearing loss. Hence, this gene can be promoted to green rating in the next GMS update.
Monogenic hearing loss v5.15 MT-TL1 Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.14 MT-TL1 Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; maternally-inherited diabetes and deafness, MONDO:0010785; Sensorineural hearing impairment, HP:0000407 to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; maternally-inherited diabetes and deafness, MONDO:0010785; Sensorineural hearing impairment, HP:0000407
Monogenic hearing loss v5.13 MT-TL1 Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; maternally-inherited diabetes and deafness, MONDO:0010785; Sensorineural hearing impairment, HP:0000407
Monogenic hearing loss v5.12 MT-TL1 Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
Monogenic hearing loss v5.11 MT-TL1 Achchuthan Shanmugasundram Mode of inheritance for gene: MT-TL1 was changed from to MITOCHONDRIAL
Monogenic hearing loss v5.10 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1.
Tag Q2_25_expert_review tag was added to gene: MT-TL1.
Tag Q2_25_ NHS_review tag was added to gene: MT-TL1.
Monogenic hearing loss v5.10 MT-TL1 Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22403016, 23355809, 35455034; Phenotypes: MELAS syndrome caused by mutation in MTTL1, MONDO:0800032, maternally-inherited diabetes and deafness, MONDO:0010785, Sensorineural hearing impairment, HP:0000407; Mode of inheritance: MITOCHONDRIAL
Paediatric or syndromic cardiomyopathy v7.2 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1.