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Fetal anomalies v1.195 RSPH9 Rhiannon Mellis reviewed gene: RSPH9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 12; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v2.33 TCTEX1D2 Arina Puzriakova Phenotypes for gene: TCTEX1D2 were changed from Polydactyly; Short-rib thoracic dysplasia 17 with or without polydactyly, 617405; Brachydactyly to Short-rib thoracic dysplasia 17 with or without polydactyly, OMIM:617405; Short-rib thoracic dysplasia 17 with or without polydactyly, MONDO:0054565; Polydactyly; Brachydactyly
Childhood onset dystonia, chorea or related movement disorder v1.74 CACNB4 Sarah Leigh commented on gene: CACNB4: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional data.
Limb disorders v2.32 TCTEX1D2 Arina Puzriakova Tag watchlist was removed from gene: TCTEX1D2.
Limb disorders v2.32 TCTEX1D2 Arina Puzriakova commented on gene: TCTEX1D2
Childhood onset dystonia, chorea or related movement disorder v1.74 CACNB4 Sarah Leigh reviewed gene: CACNB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 32176688; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.195 SCLT1 Rhiannon Mellis gene: SCLT1 was added
gene: SCLT1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SCLT1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SCLT1 were set to No OMIM phenotype; Oro-facio-digital syndrome type IX; Senior-Løken Syndrome
Review for gene: SCLT1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Rare multisystem ciliopathy Super panel


Copied from rare multisystem ciliopathies panel:
PMID: 24285566 - Adly et al 2014 - 1 case with index patient with consanguineous Saudi parents and a severe ciliopathy phenotype. He had severe midline cleft lip and palate, microcephaly and choanal atresia. He also had significant eye involvement in the form of severe coloboma, and congenital heart disease (ASD and VSD). He had micropenis. Brain imaging revealed pachygyria and absent corpus callosum. He had abnormal inner ear structures. A splicing mutation was identified in SCLT1 (, NM_144643.2:exon5:c.290+2T>C). This mutation completely abolishes the consensus donor site of exon 5 as confirmed by RTPCR, which showed complete skipping of exon 5 resulting in a frameshift and introduction of a premature stop codon (p.Lys79Valfs*4),

PMID: 28005958 - de Castro-Miró et al 2016 - A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. 1 case with compound heterozygosity (one missense and one splicing altering mutations) in SCLT1 that segregates with the condition in the family (2 affected siblings). Proposed to be causative of early-onset Retinitis Pigmentosa. SCLT1 is a member of the centrosomal/ciliary protein family.

PMID: 28486600 - Li et al 2017 - report a mouse model with mutated Sclt1 gene. The Sclt1-/- mice exhibit typical ciliopathy phenotypes, including cystic kidney, cleft palate and polydactyly.

PMID: 30425282 - Katagiri et al 2018 - a patient with Senior Løken syndrome and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218 + 3insT and c.1631A > G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218 + 3insT variant leads to exon 14 skipping (p.V383_M406del), while the other variant (c.1631A > G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts. Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein.

= 3 cases plus a mouse model and functional evidence that the protein is a ciliary protein.
Sources: Literature
Fetal anomalies v1.195 TCTEX1D2 Arina Puzriakova Phenotypes for gene: TCTEX1D2 were changed from Short-rib thoracic dysplasia 17 with or without polydactyly to Short-rib thoracic dysplasia 17 with or without polydactyly, OMIM:617405; Short-rib thoracic dysplasia 17 with or without polydactyly, MONDO:0054565
Fetal anomalies v1.194 SDR9C7 Rhiannon Mellis gene: SDR9C7 was added
gene: SDR9C7 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: SDR9C7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SDR9C7 were set to Ichthyosis, congenital, autosomal recessive 13
Review for gene: SDR9C7 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Autosomal recessive congenital ichthyosis
Sources: Expert list
Fetal anomalies v1.194 TCTEX1D2 Arina Puzriakova Classified gene: TCTEX1D2 as Amber List (moderate evidence)
Fetal anomalies v1.194 TCTEX1D2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.194 TCTEX1D2 Arina Puzriakova Gene: tctex1d2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.193 SEC24D Rhiannon Mellis reviewed gene: SEC24D: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25683121; Phenotypes: Cole-Carpenter syndrome 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.193 TCTEX1D2 Arina Puzriakova Tag for-review tag was added to gene: TCTEX1D2.
Fetal anomalies v1.193 SERPINF1 Rhiannon Mellis gene: SERPINF1 was added
gene: SERPINF1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: SERPINF1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SERPINF1 were set to Osteogenesis imperfecta, type VI
Review for gene: SERPINF1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Osteogenesis imperfecta; Skeletal dysplasia
Sources: Expert list
Fetal anomalies v1.193 SERPINH1 Rhiannon Mellis gene: SERPINH1 was added
gene: SERPINH1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: SERPINH1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SERPINH1 were set to Osteogenesis imperfecta, type X
Review for gene: SERPINH1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Osteogenesis imperfecta; Skeletal dysplasia
Sources: Expert list
Fetal anomalies v1.193 SGCG Rhiannon Mellis gene: SGCG was added
gene: SGCG was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: SGCG was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SGCG were set to Muscular dystrophy, limb-girdle, autosomal recessive 5
Review for gene: SGCG was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Neuromuscular disorders
Sources: Expert list
Autosomal recessive congenital ichthyosis v1.10 SULT2B1 Arina Puzriakova Phenotypes for gene: SULT2B1 were changed from Ichthyosis, congenital, autosomal recessive 14 617571 to Ichthyosis, congenital, autosomal recessive 14, OMIM:617571; Ichthyosis, congenital, autosomal recessive 14, MONDO:0033091
Fetal anomalies v1.193 SULT2B1 Arina Puzriakova Publications for gene: SULT2B1 were set to
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh Tag for-review tag was added to gene: CPA6.
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh commented on gene: CPA6: After consultation Helen Lord, recommend change of MOI to BIALLELIC, autosomal or pseudosomal
Fetal anomalies v1.192 SHANK3 Rhiannon Mellis reviewed gene: SHANK3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: PHELAN-MCDERMID SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh edited their review of gene: CPA6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.192 SIX6 Rhiannon Mellis gene: SIX6 was added
gene: SIX6 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SIX6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SIX6 were set to Optic disc anomalies with retinal and/or macular dystrophy
Review for gene: SIX6 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Anophthalmia and microphthalmia
Sources: Literature
Palmoplantar keratodermas v1.7 SULT2B1 Arina Puzriakova Phenotypes for gene: SULT2B1 were changed from Ichthyosis, congenital, autosomal recessive 14; 617571 to Ichthyosis, congenital, autosomal recessive 14, OMIM:617571; Ichthyosis, congenital, autosomal recessive 14, MONDO:0033091
Ichthyosis and erythrokeratoderma v1.5 SULT2B1 Arina Puzriakova Phenotypes for gene: SULT2B1 were changed from Ichthyosis, congenital, autosomal recessive 14 617571 to Ichthyosis, congenital, autosomal recessive 14, OMIM:617571; Ichthyosis, congenital, autosomal recessive 14, MONDO:0033091
Fetal anomalies v1.192 SLC18A3 Rhiannon Mellis gene: SLC18A3 was added
gene: SLC18A3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC18A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC18A3 were set to PMID: 31059209
Phenotypes for gene: SLC18A3 were set to Myasthenic syndrome, congenital, 21, presynaptic
Review for gene: SLC18A3 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Neuromuscular disorders
Sources: Literature
Fetal anomalies v1.192 SULT2B1 Arina Puzriakova Phenotypes for gene: SULT2B1 were changed from Ichthyosis, congenital, autosomal recessive 14 to Ichthyosis, congenital, autosomal recessive 14, OMIM:617571; Ichthyosis, congenital, autosomal recessive 14, MONDO:0033091
Fetal anomalies v1.191 SULT2B1 Arina Puzriakova Classified gene: SULT2B1 as Amber List (moderate evidence)
Fetal anomalies v1.191 SULT2B1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.191 SULT2B1 Arina Puzriakova Gene: sult2b1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.190 SULT2B1 Arina Puzriakova Tag for-review tag was added to gene: SULT2B1.
Fetal anomalies v1.190 SLC25A19 Rhiannon Mellis reviewed gene: SLC25A19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly, Amish type, 607196; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v2.8 ADAMTS3 Arina Puzriakova Phenotypes for gene: ADAMTS3 were changed from Hennekam syndrome; Hennekam lymphangiectasia-lymphedema syndrome 3 to Hennekam lymphangiectasia-lymphedema syndrome 3, OMIM:618154; Hennekam lymphangiectasia-lymphedema syndrome 3, MONDO:0032564
Fetal anomalies v1.190 ADAMTS3 Arina Puzriakova Publications for gene: ADAMTS3 were set to
Fetal anomalies v1.189 SLC29A3 Rhiannon Mellis gene: SLC29A3 was added
gene: SLC29A3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC29A3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC29A3 were set to Histiocytosis-lymphadenopathy plus syndrome
Review for gene: SLC29A3 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Skeletal dysplasia
Sources: Literature
Fetal anomalies v1.189 SLC5A7 Rhiannon Mellis reviewed gene: SLC5A7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27569547, 31299140; Phenotypes: Myasthenic syndrome, congenital, 20, presynaptic; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.189 ADAMTS3 Arina Puzriakova Phenotypes for gene: ADAMTS3 were changed from Hennekam lymphangiectasia-lymphedema syndrome 3 to Hennekam lymphangiectasia-lymphedema syndrome 3, OMIM:618154; Hennekam lymphangiectasia-lymphedema syndrome 3, MONDO:0032564
Fetal anomalies v1.188 ADAMTS3 Arina Puzriakova Tag for-review tag was added to gene: ADAMTS3.
Fetal anomalies v1.188 ADAMTS3 Arina Puzriakova Classified gene: ADAMTS3 as Amber List (moderate evidence)
Fetal anomalies v1.188 ADAMTS3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.188 ADAMTS3 Arina Puzriakova Gene: adamts3 has been classified as Amber List (Moderate Evidence).
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.11 DLST Ivone Leong Classified gene: DLST as Amber List (moderate evidence)
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.11 DLST Ivone Leong Gene: dlst has been classified as Amber List (Moderate Evidence).
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.10 DLST Ivone Leong gene: DLST was added
gene: DLST was added to Inherited phaeochromocytoma and paraganglioma excluding NF1. Sources: Expert Review
for-review tags were added to gene: DLST.
Mode of inheritance for gene: DLST was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLST were set to 30929736; 33180916
Phenotypes for gene: DLST were set to Paragangliomas 7, OMIM:618475
Review for gene: DLST was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. Therefore, this gene should be rated Green at the next review.

This gene was suggested to be added and given a Green rating by Ruth Casey (Cambridge University Hospital). Sources: Expert Review
Sources: Expert Review
Fetal anomalies v1.187 SMPD4 Rhiannon Mellis gene: SMPD4 was added
gene: SMPD4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SMPD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPD4 were set to PMID: 31495489
Phenotypes for gene: SMPD4 were set to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
Review for gene: SMPD4 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Arthrogryposis; Cerebellar hypoplasia

Additional comment: Documented fetal phenotype with IUGR, microcephaly, arthrogryposis, and structural brain anomalies in some. (32 reported cases from 12 families) PMID: 31495489
Sources: Literature
Fetal anomalies v1.187 SMS Rhiannon Mellis reviewed gene: SMS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: SNYDER-ROBINSON SYNDROME; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.187 SNX10 Rhiannon Mellis gene: SNX10 was added
gene: SNX10 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: SNX10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SNX10 were set to Osteopetrosis, autosomal recessive 8
Review for gene: SNX10 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Hydrocephalus; Osteopetrosis; Skeletal dysplasia
Sources: Expert list
Fetal anomalies v1.187 SOX18 Rhiannon Mellis gene: SOX18 was added
gene: SOX18 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: SOX18 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SOX18 were set to Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome; Hypotrichosis-lymphedema-telangiectasia syndrome
Review for gene: SOX18 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Primary lymphoedema
Sources: Literature, Expert list
Fetal anomalies v1.187 SOX6 Rhiannon Mellis gene: SOX6 was added
gene: SOX6 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SOX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SOX6 were set to Tolchin-Le Caignec syndrome
Review for gene: SOX6 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Craniosynostosis
Sources: Literature
Fetal anomalies v1.187 SP7 Rhiannon Mellis gene: SP7 was added
gene: SP7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SP7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SP7 were set to Osteogenesis imperfecta, type XII
Review for gene: SP7 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Green on related panel(s): Osteogenesis imperfecta; Skeletal dysplasia
Sources: Literature
Fetal anomalies v1.187 SPARC Rhiannon Mellis reviewed gene: SPARC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteogenesis imperfecta, type XVII; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.187 SPECC1L Rhiannon Mellis reviewed gene: SPECC1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Facial clefting, oblique, 1, Hypertelorism, Teebi type, Opitz GBBB syndrome, type II; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.187 ST14 Rhiannon Mellis reviewed gene: ST14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis, congenital, autosomal recessive 11; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.187 STAC3 Rhiannon Mellis gene: STAC3 was added
gene: STAC3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: STAC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAC3 were set to PMID: 30168660
Phenotypes for gene: STAC3 were set to Myopathy, congenital, Baily-Bloch
Review for gene: STAC3 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Additional comment: Documented arthrogryposis, also cleft palate, polyhydramnios and reduced fetal movements. PMID: 30168660
Sources: Literature
Fetal anomalies v1.187 STIL Rhiannon Mellis reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: 29230157; Phenotypes: Microcephaly 7, primary, autosomal recessive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.187 STRADA Rhiannon Mellis gene: STRADA was added
gene: STRADA was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: STRADA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STRADA were set to Polyhydramnios, megalencephaly, and symptomatic epilepsy
Review for gene: STRADA was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Hydrocephalus). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.9 SLC25A11 Ivone Leong Classified gene: SLC25A11 as Amber List (moderate evidence)
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.9 SLC25A11 Ivone Leong Gene: slc25a11 has been classified as Amber List (Moderate Evidence).
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.8 SLC25A11 Ivone Leong gene: SLC25A11 was added
gene: SLC25A11 was added to Inherited phaeochromocytoma and paraganglioma excluding NF1. Sources: Expert Review
for-review tags were added to gene: SLC25A11.
Mode of inheritance for gene: SLC25A11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC25A11 were set to 29431636
Phenotypes for gene: SLC25A11 were set to Paragangliomas 6, OMIM:618464
Review for gene: SLC25A11 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not on Gene2Phenotype. There are >3 unrelated cases and therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

This gene was suggested to be added and given a Green rating by Ruth Casey (Cambridge University Hospital).
Sources: Expert Review
Fetal anomalies v1.187 SUFU Rhiannon Mellis reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 33024317, 21289193; Phenotypes: Joubert syndrome 32; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.277 CPA6 Helen Lord reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.277 ALG14 Sarah Leigh edited their review of gene: ALG14: Changed rating: GREEN
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.7 MDH2 Ivone Leong Classified gene: MDH2 as Amber List (moderate evidence)
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.7 MDH2 Ivone Leong Gene: mdh2 has been classified as Amber List (Moderate Evidence).
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.6 MDH2 Ivone Leong gene: MDH2 was added
gene: MDH2 was added to Inherited phaeochromocytoma and paraganglioma excluding NF1. Sources: Expert Review
for-review tags were added to gene: MDH2.
Mode of inheritance for gene: MDH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDH2 were set to 30008476; 25766404
Phenotypes for gene: MDH2 were set to PPGL
Review for gene: MDH2 was set to GREEN
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. There are >3 cases and therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

This gene was suggested to be added and given a Green rating by Ruth Casey (Cambridge University Hospital).
Sources: Expert Review
Congenital adrenal hypoplasia v2.6 POLE Ivone Leong Classified gene: POLE as Amber List (moderate evidence)
Congenital adrenal hypoplasia v2.6 POLE Ivone Leong Gene: pole has been classified as Amber List (Moderate Evidence).
Congenital adrenal hypoplasia v2.5 POLE Ivone Leong gene: POLE was added
gene: POLE was added to Congenital adrenal hypoplasia. Sources: Expert Review
for-review tags were added to gene: POLE.
Mode of inheritance for gene: POLE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLE were set to 14760276; 30503519
Phenotypes for gene: POLE were set to IMAGE-I syndrome, OMIM:618336
Review for gene: POLE was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases and therefore, enough evidence to support a gene-disease association. This gene should be Green at the next review.

This gene was also proposed to be added and given Green status by Soo-Mi Park (East Anglian Medical Genetics Service).
Sources: Expert Review
Respiratory ciliopathies including non-CF bronchiectasis v1.42 RPGR Gabrielle Wheway changed review comment from: Although few cases of PCD associated with RPGR variants have been published, the PCD diagnostic centre at University Hospital Southampton has diagnosed 5 cases of PCD where RPGR missense variants have been judged to be the cause of disease. 4 cases have stop gains in RPGR, 3 of whom had PCD diagnosed before eye disease and 1 of whom is an adult whose wet cough and rhinitis started in very early childhood before eye symptoms, but was diagnosed with RP before PCD (due to late referral for PCD rather than lack of symptoms). i.e. in all cases lung disease preceded eye disease. 1 case has a pathogenic missense mutation and is an adult who only has PCD, no eye disease. I am submitting this review as a researcher who works closely with the diagnostic service at UHS and Wessex Clinical Genetics Lab. The fact that RPGR has been downgraded to Amber was raised at our recent PCD genetics MDT and Prof Jane Lucas, who leads the diagnostic service at UHS asked me to submit a review to provide support for this gene being a 'Green' gene.
; to: Although few cases of PCD associated with RPGR variants have been published, the PCD diagnostic centre at University Hospital Southampton has diagnosed 5 cases of PCD where RPGR variants have been judged to be the cause of disease. 4 cases have stop gains in RPGR, 3 of whom had PCD diagnosed before eye disease and 1 of whom is an adult whose wet cough and rhinitis started in very early childhood before eye symptoms, but was diagnosed with RP before PCD (due to late referral for PCD rather than lack of symptoms). i.e. in all cases lung disease preceded eye disease. 1 case has a pathogenic missense mutation and is an adult who only has PCD, no eye disease. I am submitting this review as a researcher who works closely with the diagnostic service at UHS and Wessex Clinical Genetics Lab. The fact that RPGR has been downgraded to Amber was raised at our recent PCD genetics MDT and Prof Jane Lucas, who leads the diagnostic service at UHS asked me to submit a review to provide support for this gene being a 'Green' gene.
Respiratory ciliopathies including non-CF bronchiectasis v1.42 RPGR Gabrielle Wheway changed review comment from: Although few cases of PCD have been reported associated with RPGR variants, the PCD diagnostic centre at University Hospital Southampton has diagnosed a number of PCD cases where RPGR missense variants have been judged to be the cause of disease. At least one of these cases is isolated PCD, with no evidence of RP (the patient has been seen by the eye clinic). I am submitting this review as a researcher who works closely with the diagnostic service at UHS and Wessex Clinical Genetics Lab. The fact that RPGR has been downgraded to Amber was raised at our recent PCD genetics MDT and Prof Jane Lucas, who leads the diagnostic service at UHS asked me to submit a review to provide support for this gene being a 'Green' gene. Prof Lucas will register as a PanelApp reviewer to add additional detail.; to: Although few cases of PCD associated with RPGR variants have been published, the PCD diagnostic centre at University Hospital Southampton has diagnosed 5 cases of PCD where RPGR missense variants have been judged to be the cause of disease. 4 cases have stop gains in RPGR, 3 of whom had PCD diagnosed before eye disease and 1 of whom is an adult whose wet cough and rhinitis started in very early childhood before eye symptoms, but was diagnosed with RP before PCD (due to late referral for PCD rather than lack of symptoms). i.e. in all cases lung disease preceded eye disease. 1 case has a pathogenic missense mutation and is an adult who only has PCD, no eye disease. I am submitting this review as a researcher who works closely with the diagnostic service at UHS and Wessex Clinical Genetics Lab. The fact that RPGR has been downgraded to Amber was raised at our recent PCD genetics MDT and Prof Jane Lucas, who leads the diagnostic service at UHS asked me to submit a review to provide support for this gene being a 'Green' gene.
Fetal anomalies v1.187 ERCC5 Arina Puzriakova Publications for gene: ERCC5 were set to
Fetal anomalies v1.186 ERCC5 Arina Puzriakova Phenotypes for gene: ERCC5 were changed from XERODERMA PIGMENTOSUM COMPLEMENTATION GROUP G to Cerebrooculofacioskeletal syndrome 3, OMIM:616570; Cerebrooculofacioskeletal syndrome 3, MONDO:0014696
Severe microcephaly v2.91 ERCC5 Arina Puzriakova Publications for gene: ERCC5 were set to 24700531; 9096355 (Retracted)
Fetal anomalies v1.185 SULT2B1 Rhiannon Mellis gene: SULT2B1 was added
gene: SULT2B1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SULT2B1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SULT2B1 were set to Ichthyosis, congenital, autosomal recessive 14
Review for gene: SULT2B1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Autosomal recessive congenital ichthyosis). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Severe microcephaly v2.90 ERCC5 Arina Puzriakova Classified gene: ERCC5 as Amber List (moderate evidence)
Severe microcephaly v2.90 ERCC5 Arina Puzriakova Added comment: Comment on list classification: Gene reassessed in view of recent expert review. Upgraded from Red to Amber as there are at least 9 fetuses from 4 unrelated families with cerebrooculofacioskeletal syndrome due to biallelic variants in this gene (PMIDs: 24700531; 32052936; 32557569). Microcephaly is reported in all affected cases; however, as extent of this presentation is not specified ERCC5 cannot be promoted to Green on this panel at present.

Nonetheless, we would expect this phenotype to be picked up via the Fetal anomalies panel, for which this gene is already Green (v.1.92).
Severe microcephaly v2.90 ERCC5 Arina Puzriakova Gene: ercc5 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.185 TBC1D32 Rhiannon Mellis gene: TBC1D32 was added
gene: TBC1D32 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to PMID: 32573025; 31130284; 32060556
Phenotypes for gene: TBC1D32 were set to OFD IX
Review for gene: TBC1D32 was set to GREEN
Added comment: Now 5 families reported:

The same group who reported the first individual with a ciliopathy phenotype (Adly et al 2014) now report two further unrelated fetal cases (Alsahan 2020, Monies et al 2019) with OFD/ciliopathy phenotype:

- One had polyhydramnios, hydrocephaly with enlarged biparietal diameter and dilated lateral ventricles, single nostril, anophthalmia, short long bones and echogenic lungs
- The other had holoprosencephaly, cyclops, cleft lip, ventricular septal defect, agenesis of corpus callosum, and club feet

- There are also two sib pairs (one Finnish, one Pakistani) reported by Hietamaki et al 2020 with TBC1D32 variants and a variable phenotype of pituitary hypoplasia +/- other midline defects, hydrocephalus, short limbs, polydactyly
Sources: Literature
Fetal anomalies v1.185 TCTEX1D2 Rhiannon Mellis gene: TCTEX1D2 was added
gene: TCTEX1D2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TCTEX1D2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TCTEX1D2 were set to Short-rib thoracic dysplasia 17 with or without polydactyly
Review for gene: TCTEX1D2 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Rare multisystem ciliopathy Super panel; Skeletal dysplasia; Thoracic dystrophies). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Arthrogryposis v3.55 ERCC5 Arina Puzriakova Phenotypes for gene: ERCC5 were changed from Cerebrooculofacioskeletal syndrome 3, 616570 to Cerebrooculofacioskeletal syndrome 3, OMIM:616570; Cerebrooculofacioskeletal syndrome 3, MONDO:0014696
Arthrogryposis v3.54 ERCC5 Arina Puzriakova Publications for gene: ERCC5 were set to 9096355; 24700531
Arthrogryposis v3.53 ERCC5 Arina Puzriakova Classified gene: ERCC5 as Amber List (moderate evidence)
Arthrogryposis v3.53 ERCC5 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient unrelated families (4) with multiple fetuses affected by COFS3, including arthrogryposis.
Arthrogryposis v3.53 ERCC5 Arina Puzriakova Gene: ercc5 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.185 TELO2 Rhiannon Mellis reviewed gene: TELO2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: You-Hoover-Fong syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.52 ERCC5 Arina Puzriakova Tag for-review tag was added to gene: ERCC5.
Fetal anomalies v1.185 TENM3 Rhiannon Mellis gene: TENM3 was added
gene: TENM3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TENM3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TENM3 were set to Microphthalmia, syndromic 15; ?Microphthalmia, isolated, with coloboma 9
Review for gene: TENM3 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Anophthalmia and microphthalmia). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Arthrogryposis v3.52 ERCC5 Arina Puzriakova reviewed gene: ERCC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24700531, 32052936, 32557569; Phenotypes: Cerebrooculofacioskeletal syndrome 3, OMIM:616570; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 TMEM38B Rhiannon Mellis gene: TMEM38B was added
gene: TMEM38B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TMEM38B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TMEM38B were set to Osteogenesis imperfecta, type XIV
Review for gene: TMEM38B was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Osteogenesis imperfecta; Skeletal dysplasia). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Fetal anomalies v1.185 TMEM98 Rhiannon Mellis gene: TMEM98 was added
gene: TMEM98 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TMEM98 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TMEM98 were set to Nanophthalmos 4
Review for gene: TMEM98 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Anophthalmia and microphthalmia). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Fetal anomalies v1.185 TMX2 Rhiannon Mellis gene: TMX2 was added
gene: TMX2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TMX2 were set to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity
Review for gene: TMX2 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Cerebral malformations; Malformations of cortical development; Severe microcephaly). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Fetal anomalies v1.185 TNNT3 Rhiannon Mellis gene: TNNT3 was added
gene: TNNT3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TNNT3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNNT3 were set to 32779773
Phenotypes for gene: TNNT3 were set to Arthrogryposis, distal, type 2B2
Mode of pathogenicity for gene: TNNT3 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: TNNT3 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Additional comment: Clearly documented phenotype of distal arthrogryposis. Also, recent paper in Prenatal Diagnosis reporting a het pathogenic variant in TNNT3 in a fetus with FADS; that variant has previously only been described in a family with much milder distal arthrogryposis phenotype. PMID: 32779773

(copied from OMIM): In in vitro studies, Robinson et al. (2007) demonstrated that the TNNI2 R174Q (191043.0001) and R156X (191043.0002) mutations and the TNNT3 mutation R63H (600692.0001) resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. In patients, Robinson et al. (2007) concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA2B.
Sources: Literature
Fetal anomalies v1.185 TOE1 Rhiannon Mellis changed review comment from: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.; to: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (cerebellar hypoplasia). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Fetal anomalies v1.185 TOE1 Rhiannon Mellis reviewed gene: TOE1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia, type 7; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 TOR1A Rhiannon Mellis gene: TOR1A was added
gene: TOR1A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TOR1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOR1A were set to 30244176; 29053766; 28516161
Phenotypes for gene: TOR1A were set to Arthrogryposis multiplex congenita 5
Review for gene: TOR1A was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Additional comment: documented phenotype of severe arthrogryposis multiplex congenital with prenatal onset
Sources: Literature
Fetal anomalies v1.185 TRAF3IP1 Rhiannon Mellis gene: TRAF3IP1 was added
gene: TRAF3IP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TRAF3IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRAF3IP1 were set to Senior-Loken syndrome 9
Review for gene: TRAF3IP1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Cystic renal disease (super panel); Rare multisystem ciliopathy Super panel). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Fetal anomalies v1.185 TRAIP Rhiannon Mellis reviewed gene: TRAIP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Seckel syndrome 9; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 TRAP1 Rhiannon Mellis gene: TRAP1 was added
gene: TRAP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TRAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRAP1 were set to CAKUT; VACTERL
Review for gene: TRAP1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Early onset or syndromic epilepsy v2.277 ADAM22 Sarah Leigh Publications for gene: ADAM22 were set to 27066583; 30237576; 15876356
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Classified gene: SCN9A as Red List (low evidence)
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Added comment: Comment on list classification: Evidence presented by PMID 33216760 disputes the association between SCN9A and epilepsy, inparticular the serendipitous identification of the SCN9A p.(Asn641Tyr) variant within the Wisconsin Amish community with no epilepsy in their phenotypes. The authors report this lack of gene disease association was also evident in the UK Biobank.
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Gene: scn9a has been classified as Red List (Low Evidence).
Fetal anomalies v1.185 TRMT10A Rhiannon Mellis gene: TRMT10A was added
gene: TRMT10A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TRMT10A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRMT10A were set to Microcephaly, short stature, and impaired glucose metabolism 1
Review for gene: TRMT10A was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Severe microcephaly). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Fetal anomalies v1.185 TSEN2 Rhiannon Mellis reviewed gene: TSEN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia type 2B; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 TSEN34 Rhiannon Mellis reviewed gene: TSEN34: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia type 2C; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 TSFM Rhiannon Mellis gene: TSFM was added
gene: TSFM was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TSFM was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TSFM were set to Combined oxidative phosphorylation deficiency 3
Review for gene: TSFM was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Neuromuscular disorders). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Additional comment: IUGR, decreased fetal movements, reduced brain gyri
Sources: Literature
Fetal anomalies v1.185 TUBB3 Rhiannon Mellis reviewed gene: TUBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.185 TUBG1 Rhiannon Mellis reviewed gene: TUBG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 4; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.185 TUBGCP4 Rhiannon Mellis reviewed gene: TUBGCP4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 TXNDC15 Rhiannon Mellis gene: TXNDC15 was added
gene: TXNDC15 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TXNDC15 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TXNDC15 were set to Meckel Gruber syndrome
Review for gene: TXNDC15 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel (Cystic renal disease (super panel); Limb disorders; Rare multisystem ciliopathy Super panel). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Comment from copied from skeletal ciliopathies panel:
Shaheen et al. 2016 (PMID:27894351) report TXNDC15 variants in two consanguineous Saudi families that share the features of Meckel-Gruber syndrome (a ciliopathy phenotype). Phenotypes of both patients included polydactyly; one patients was still born, and one survived till 11 hours old. Furthermore, through an international collaboration, they were able to identify an additional Meckel-Gruber syndrome patient (Pakistani origin) with a homozygous truncating variant in this gene. The patient also had polydactyly, although a sibling presented similarly but with no polydactyl. Patient fibroblasts had aberrant ciliogenesis.
Sources: Other
Sources: Literature
Fetal anomalies v1.185 UBE2T Rhiannon Mellis reviewed gene: UBE2T: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anemia, complementation group T; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 USP9X Rhiannon Mellis reviewed gene: USP9X: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: MENTAL RETARDATION, X-LINKED 99, MRX99; 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 v2.275 SCN9A Sarah Leigh Publications for gene: SCN9A were set to 19763161; 29500686; 30834459; 23895530
Adult onset hereditary spastic paraplegia v1.16 AP4S1 Arina Puzriakova Tag for-review tag was added to gene: AP4S1.
Adult onset hereditary spastic paraplegia v1.16 AP4S1 Arina Puzriakova commented on gene: AP4S1
Fetal anomalies v1.185 VAMP1 Rhiannon Mellis changed review comment from: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature; to: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Additional comment: Phenotype = congenital myasthenic syndrome. Reported patients present with severe hypotonia from birth, some have contractures, unclear if present at birth but decreased fetal movements reported so could present prenatally. PubMed: 28600779, 28253535, 28168212

Sources: Literature
Endocrine neoplasia v1.10 VHL Ivone Leong changed review comment from: This gene was proposed to be added to this panel with Green by Soo-Mi Park (East Anglian Medical Genetics Service).

This gene is Green on the Multiple endocrine tumours (Version 1.9) panel.

This gene has been added as an Amber gene and will be given Green status pending decision by the GMS review panel.
Sources: Expert Review; to: This gene was proposed to be added to this panel with Green status by Soo-Mi Park (East Anglian Medical Genetics Service).

This gene is Green on the Multiple endocrine tumours (Version 1.9) panel.

This gene has been added as an Amber gene and will be given Green status pending decision by the GMS review panel.
Sources: Expert Review
Endocrine neoplasia v1.10 TP53 Ivone Leong Classified gene: TP53 as Amber List (moderate evidence)
Endocrine neoplasia v1.10 TP53 Ivone Leong Gene: tp53 has been classified as Amber List (Moderate Evidence).
Endocrine neoplasia v1.9 PRKAR1A Ivone Leong changed review comment from: This gene was proposed to be added to this panel with Green by Soo-Mi Park (East Anglian Medical Genetics Service).

This gene is Green on the Multiple endocrine tumours (Version 1.9) panel.

This gene has been added as an Amber gene and will be given Green status pending decision by the GMS review panel.
Sources: Expert Review; to: This gene was proposed to be added to this panel with Green status by Soo-Mi Park (East Anglian Medical Genetics Service).

This gene is Green on the Multiple endocrine tumours (Version 1.9) panel.

This gene has been added as an Amber gene and will be given Green status pending decision by the GMS review panel.
Sources: Expert Review
Endocrine neoplasia v1.9 TP53 Ivone Leong gene: TP53 was added
gene: TP53 was added to Endocrine neoplasms. Sources: Expert Review
for-review tags were added to gene: TP53.
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TP53 were set to Endocrine Cancer; Paragangliomas 1, with or without deafness, 168000; Pheochromocytoma, 171300; Carcinoid tumors, intestinal, 114900; Merkel cell carcinoma, somatic; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 3, 615106
Review for gene: TP53 was set to AMBER
Added comment: This gene was proposed to be added to this panel with Green status by Soo-Mi Park (East Anglian Medical Genetics Service).

This gene is Green on the Multiple endocrine tumours (Version 1.9) panel.

This gene has been added as an Amber gene and will be given Green status pending decision by the GMS review panel.
Sources: Expert Review
Fetal anomalies v1.185 VAMP1 Rhiannon Mellis gene: VAMP1 was added
gene: VAMP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: VAMP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VAMP1 were set to Myasthenic syndrome, congenital, 25
Review for gene: VAMP1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Endocrine neoplasia v1.8 VHL Ivone Leong Classified gene: VHL as Amber List (moderate evidence)
Endocrine neoplasia v1.8 VHL Ivone Leong Gene: vhl has been classified as Amber List (Moderate Evidence).
Endocrine neoplasia v1.7 VHL Ivone Leong gene: VHL was added
gene: VHL was added to Endocrine neoplasms. Sources: Expert Review
for-review tags were added to gene: VHL.
Mode of inheritance for gene: VHL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: VHL were set to Endocrine Cancer; Paragangliomas 1, with or without deafness, 168000; Pheochromocytoma, 171300; Carcinoid tumors, intestinal, 114900; Merkel cell carcinoma, somatic; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 3, 615106
Review for gene: VHL was set to AMBER
Added comment: This gene was proposed to be added to this panel with Green by Soo-Mi Park (East Anglian Medical Genetics Service).

This gene is Green on the Multiple endocrine tumours (Version 1.9) panel.

This gene has been added as an Amber gene and will be given Green status pending decision by the GMS review panel.
Sources: Expert Review
Fetal anomalies v1.185 VEGFC Rhiannon Mellis gene: VEGFC was added
gene: VEGFC was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: VEGFC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: VEGFC were set to Lymphatic malformation 4
Review for gene: VEGFC was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Fetal anomalies v1.185 VRK1 Rhiannon Mellis reviewed gene: VRK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia type 1A; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Endocrine neoplasia v1.6 PRKAR1A Ivone Leong Classified gene: PRKAR1A as Amber List (moderate evidence)
Endocrine neoplasia v1.6 PRKAR1A Ivone Leong Gene: prkar1a has been classified as Amber List (Moderate Evidence).
Endocrine neoplasia v1.5 PRKAR1A Ivone Leong Tag for-review tag was added to gene: PRKAR1A.
Endocrine neoplasia v1.5 PRKAR1A Ivone Leong gene: PRKAR1A was added
gene: PRKAR1A was added to Endocrine neoplasms. Sources: Expert Review
Mode of inheritance for gene: PRKAR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PRKAR1A were set to Endocrine Cancer
Review for gene: PRKAR1A was set to AMBER
Added comment: This gene was proposed to be added to this panel with Green by Soo-Mi Park (East Anglian Medical Genetics Service).

This gene is Green on the Multiple endocrine tumours (Version 1.9) panel.

This gene has been added as an Amber gene and will be given Green status pending decision by the GMS review panel.
Sources: Expert Review
Fetal anomalies v1.185 WDR73 Rhiannon Mellis reviewed gene: WDR73: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Galloway-Mowat syndrome 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v2.6 GCM2 Ivone Leong changed review comment from: PMID 31671402 is an additional paper report on the same variant that was detected previously by Guan et al 2016 and 2017. This gene is recommended to be promoted to Green at the next review.; to: Looking at the available evidence, there is an additional paper (PMID 31671402) reporting on the same variant that was detected previously by Guan et al 2016 and 2017. This gene is recommended to be promoted to Green at the next review.

This gene was proposed to be given Green status by Soo-Mi Park (East Anglian Medical Genetics Service).
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v2.6 GCM2 Ivone Leong Tag for-review tag was added to gene: GCM2.
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v2.6 GCM2 Ivone Leong edited their review of gene: GCM2: Added comment: PMID 31671402 is an additional paper report on the same variant that was detected previously by Guan et al 2016 and 2017. This gene is recommended to be promoted to Green at the next review.; Changed publications: 31671402
Fetal anomalies v1.185 WDR81 Rhiannon Mellis gene: WDR81 was added
gene: WDR81 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WDR81 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WDR81 were set to Hydrocephalus, congenital, 3, with brain anomalies
Review for gene: WDR81 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other PanelApp panel (Cerebellar hypoplasia). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v2.6 GCM2 Ivone Leong Publications for gene: GCM2 were set to 27745835; 29264504; 14715834; 29199197
Fetal anomalies v1.185 XYLT2 Rhiannon Mellis reviewed gene: XYLT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloocular syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 ZMYND10 Rhiannon Mellis reviewed gene: ZMYND10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 22; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.185 ZSWIM6 Rhiannon Mellis reviewed gene: ZSWIM6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Acromelic frontonasal dysostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.185 AKT2 Rhiannon Mellis gene: AKT2 was added
gene: AKT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: AKT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: AKT2 were set to Hypoinsulinemic hypoglycemia with hemihypertrophy
Review for gene: AKT2 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other PanelApp panel (BWS and Overgrowth panel). Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Fetal anomalies v1.185 ADAMTS3 Rhiannon Mellis gene: ADAMTS3 was added
gene: ADAMTS3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ADAMTS3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ADAMTS3 were set to Hennekam lymphangiectasia-lymphedema syndrome 3
Review for gene: ADAMTS3 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Literature
Fetal anomalies v1.185 ABL1 Rhiannon Mellis reviewed gene: ABL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects and skeletal malformations syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy or pain disorder v1.23 SORD Ivone Leong Tag for-review tag was added to gene: SORD.
Hereditary neuropathy or pain disorder v1.23 SORD Ivone Leong Classified gene: SORD as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.23 SORD Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics) and recommended to be Green by David Hunt (Wessex Clinical Genetics Service).

"Given that this is a potentially treatable neuropathy (https://www.ucl.ac.uk/ion/news/2020/may/sord-neuropathy-accelerated-journey-gene-identification-effective-treatment-patients), I think that SORD should be included in the ‘Hereditary neuropathy NOT PMP22 copy number’ gene panel."

There is enough evidence to support a gene-disease association and this gene should be Green at the next review.
Hereditary neuropathy or pain disorder v1.23 SORD Ivone Leong Gene: sord has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.22 SORD Ivone Leong Publications for gene: SORD were set to 32367058
Severe microcephaly v2.89 AP4S1 Arina Puzriakova Phenotypes for gene: AP4S1 were changed from Spastic paraplegia 52, autosomal recessive (MIM#614067) to Spastic paraplegia 52, autosomal recessive, OMIM:614067; Hereditary spastic paraplegia 52, MONDO:0013552
Early onset or syndromic epilepsy v2.274 CEP85L Helen Lord reviewed gene: CEP85L: Rating: GREEN; Mode of pathogenicity: None; Publications: 32097630; Phenotypes: Lissencephaly 10; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.88 AP4S1 Arina Puzriakova changed review comment from: Literature search revealed at least 23 individuals from 17 unrelated families reported in literature with biallelic variants in this gene (PMID: 21620353; 25552650; 27444738; 30283821; 32216065; 32979048). Microcephaly was observed in 15/21 cases but precise details regarding head circumference were mostly omitted or presentation was too mild relative to the scope of this panel. However, at least 2 individuals (2 families) did have microcephaly of relevant severity (OFC ≤ -3 SD) (see PMIDs: 21620353 and 25552650).

This disorder may be better represented by other panels (e.g. HSP, ID) for which this gene is already Green.; to: Literature search revealed at least 23 individuals from 17 unrelated families reported in literature with biallelic variants in this gene (PMID: 21620353; 25552650; 27444738; 30283821; 32216065; 32979048). Microcephaly was observed in 15/21 cases but precise details regarding head circumference were mostly omitted or presentation was too mild relative to the scope of this panel. However, at least 2 individuals (2 families) did have microcephaly of relevant severity (OFC ≤ -3 SD) (see PMIDs: 21620353 and 25552650).

This disorder may be better represented by other panels (e.g. HSP, ID) for which this gene is already Green.

- PMID: 32216065 (2020) - Zebrafish model recapitulates several human phenotypes, including decreased head size.
Early onset or syndromic epilepsy v2.274 CDK19 Helen Lord changed review comment from: Chung et al 2020 - 3 iunrealrted indicuduals with de novo missense variants in CDK19 - presented with hypotonia, global developmental delay, epileptic encephalopathy and dysmorphic features. Two patients had the Thr196Ala variant and the other Tyr32His - predicted to be likely pathogenic. Fuinctional work suggests dominant loss of function variants.; to: Chung et al 2020 - 3 unrelated indiviuduals with de novo missense variants in CDK19 - presented with hypotonia, global developmental delay, epileptic encephalopathy and dysmorphic features. Two patients had the Thr196Ala variant and the other Tyr32His - predicted to be likely pathogenic. Fuinctional work suggests dominant loss of function variants.
Early onset or syndromic epilepsy v2.274 CDK19 Helen Lord reviewed gene: CDK19: Rating: AMBER; Mode of pathogenicity: None; Publications: 32330417; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.88 AP4S1 Arina Puzriakova Classified gene: AP4S1 as Amber List (moderate evidence)
Severe microcephaly v2.88 AP4S1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber with recommendation of review by the GMS team to assess whether there is sufficient evidence to support a Green rating (added 'for-review' tag)
Severe microcephaly v2.88 AP4S1 Arina Puzriakova Gene: ap4s1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.87 AP4S1 Arina Puzriakova Tag for-review tag was added to gene: AP4S1.
Severe microcephaly v2.87 AP4S1 Arina Puzriakova reviewed gene: AP4S1: Rating: ; Mode of pathogenicity: None; Publications: 21620353, 25552650, 27444738, 30283821, 32216065, 32979048; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.78 RINT1 Eleanor Williams Classified gene: RINT1 as Amber List (moderate evidence)
Cholestasis v1.78 RINT1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, but with recommendation for green rating, pending review of whether the phenotype is within the scope of this panel.
Cholestasis v1.78 RINT1 Eleanor Williams Gene: rint1 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.77 RINT1 Eleanor Williams Tag for-review tag was added to gene: RINT1.
Cholestasis v1.77 RINT1 Eleanor Williams gene: RINT1 was added
gene: RINT1 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RINT1 were set to 31204009
Phenotypes for gene: RINT1 were set to Infantile liver failure syndrome 3 OMIM:618641; infantile liver failure syndrome 3 MONDO:0032844
Review for gene: RINT1 was set to GREEN
Added comment: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. Probable association with Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities in Gene2Phenotype.

PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.
Sources: Literature
Retinal disorders v2.163 TUBGCP4 Ivone Leong commented on gene: TUBGCP4: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Retinal disorders v2.163 TUBGCP4 Ivone Leong Tag for-review tag was added to gene: TUBGCP4.
Retinal disorders v2.163 TUBGCP4 Ivone Leong Added comment: Comment on publications: PMID: 33137195 extra case
Retinal disorders v2.163 TUBGCP4 Ivone Leong Publications for gene: TUBGCP4 were set to 25817018; 32270730
Paediatric disorders - additional genes v1.78 RINT1 Eleanor Williams Classified gene: RINT1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.78 RINT1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, but with a recommendation for green rating following GMS review. Liver failure could lead to paediatric ITU admission and so thought appropriate for this panel.
Paediatric disorders - additional genes v1.78 RINT1 Eleanor Williams Gene: rint1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.77 RINT1 Eleanor Williams Tag for-review tag was added to gene: RINT1.
Paediatric disorders - additional genes v1.77 RINT1 Eleanor Williams gene: RINT1 was added
gene: RINT1 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RINT1 were set to 31204009
Phenotypes for gene: RINT1 were set to Infantile liver failure syndrome 3 OMIM:618641; infantile liver failure syndrome 3 MONDO:0032844
Review for gene: RINT1 was set to GREEN
Added comment: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. Probable association with Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities in Gene2Phenotype.

PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.
Sources: Literature
Skeletal dysplasia v2.76 RINT1 Eleanor Williams changed review comment from: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM.

PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.; to: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. Probable association with Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities in Gene2Phenotype.

PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.
Retinal disorders v2.162 TUBGCP4 Ivone Leong Phenotypes for gene: TUBGCP4 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 3, OMIM:616335
Retinal disorders v2.161 TUBGCP4 Ivone Leong Publications for gene: TUBGCP4 were set to
Retinal disorders v2.160 TUBGCP4 Ivone Leong Mode of inheritance for gene: TUBGCP4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.76 RINT1 Eleanor Williams changed review comment from: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM.

PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF_ and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.; to: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM.

PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.
Retinal disorders v2.159 TUBB4B Ivone Leong Phenotypes for gene: TUBB4B were changed from Leber congenital amaurosis with early-onset deafness MIM#617879 to Leber congenital amaurosis with early-onset deafness, OMIM:617879
Paediatric disorders - additional genes v1.76 HYAL2 Eleanor Williams Classified gene: HYAL2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.76 HYAL2 Eleanor Williams Gene: hyal2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.75 HYAL2 Eleanor Williams Classified gene: HYAL2 as Red List (low evidence)
Paediatric disorders - additional genes v1.75 HYAL2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. Checking with Genomics England clinical team as to whether a green rating would be appropriate.
Paediatric disorders - additional genes v1.75 HYAL2 Eleanor Williams Gene: hyal2 has been classified as Red List (Low Evidence).
Paediatric disorders - additional genes v1.74 HYAL2 Eleanor Williams gene: HYAL2 was added
gene: HYAL2 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYAL2 were set to 28081210; 23172227; 26515055
Phenotypes for gene: HYAL2 were set to cor triatriatum; congenital cardiac malformations
Review for gene: HYAL2 was set to AMBER
Added comment: PMID: 28081210 (Muggenthaler et al 2017) report 2 unrelated consanguineous extended families (Amish and Arab) who have an orofacial clefting phenotype with cardiac anomalies are also reported.

In pedigree 1 (Amish) 5/5 analysed individuals had cleft lip and palate. 3/5 had congenital cardiac malformations including left cor triatriatum and dilated coronary sinus consistent with persistent left superior vena cava. All had a homzogyous c.443A>G, p.K148R variant which segregated with the disorder in the pedigree. It was found in a heterozygous state at a frequency of 0.013 in the Amish population, but was not found in 1000 Genomes or ExAC databases.

In pedigree 2 (Arab) 1/2 analysed individuals had cleft lip and palate and 1/2 had an abnormal mitral valve with accessory tissue. Both were found to have a homozygous c.749C>T; p.P250L variant following whole genome SNP mapping. This variant was found in 2 individuals in the ExAC database in heterozygous state. Transient expression of the patient variants in mouse embryonic fibroblasts showed a large decrease in protein levels compared to wild type.

They report that valvular thickening and atrial dilatation are found in all Hyal2-/- mice (PMID: 23172227) and that Cor triatriatum sinister has been detected in 50% of Hyal2-/- mice (PMID: 26515055).
Sources: Literature
Early onset or syndromic epilepsy v2.274 CACNB4 Helen Lord reviewed gene: CACNB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 32176688; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial non syndromic congenital heart disease v1.56 HYAL2 Eleanor Williams Classified gene: HYAL2 as Amber List (moderate evidence)
Familial non syndromic congenital heart disease v1.56 HYAL2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 2 cases reported with supporting data from mouse. Cardiac phenotype is not fully penetrant. Awaiting confirmation of further cases before promoting to green.
Familial non syndromic congenital heart disease v1.56 HYAL2 Eleanor Williams Gene: hyal2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.158 TRNT1 Ivone Leong commented on gene: TRNT1: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Familial non syndromic congenital heart disease v1.55 HYAL2 Eleanor Williams changed review comment from: PMID: 28081210 (Muggenthaler et al 2017) report 2 unrelated consanguineous extended families (Amish and Arab) who have an orofacial clefting phenotype but cardiac anomalies are also reported. In pedigree 1 (Amish) 5/5 analysed individuals had cleft lip and palate. 3/5 had congenital cardiac malformations including left cor triatriatum and dilated coronary sinus consistent with persistent left superior vena cava. All had a homzogyous c.443A>G, p.K148R variant which segregated with the disorder in the pedigree. It was found in a heterozygous state at a frequency of 0.013 in the Amish population, but was not found in 1000 Genomes or ExAC databases. In pedigree 2 (Arab) 1/2 analysed individuals had cleft lip and palate and 1/2 had an abnormal mitral valve with accessory tissue. Both were found to have a homozygous c.749C>T; p.P250L variant following whole genome SNP mapping. This variant was found in 2 individuals in the ExAC database in heterozygous state. Transient expression of the patient variants in mouse embryonic fibroblasts showed a large decrease in protein levels compared to wild type. They report that valvular thickening and atrial dilatation are found in all Hyal2-/- mice (PMID: 23172227) and that Cor triatriatum sinister has been detected in 50% of Hyal2-/- mice (PMID: 26515055).
Sources: Literature; to: PMID: 28081210 (Muggenthaler et al 2017) report 2 unrelated consanguineous extended families (Amish and Arab) who have an orofacial clefting phenotype with cardiac anomalies are also reported.

In pedigree 1 (Amish) 5/5 analysed individuals had cleft lip and palate. 3/5 had congenital cardiac malformations including left cor triatriatum and dilated coronary sinus consistent with persistent left superior vena cava. All had a homzogyous c.443A>G, p.K148R variant which segregated with the disorder in the pedigree. It was found in a heterozygous state at a frequency of 0.013 in the Amish population, but was not found in 1000 Genomes or ExAC databases.

In pedigree 2 (Arab) 1/2 analysed individuals had cleft lip and palate and 1/2 had an abnormal mitral valve with accessory tissue. Both were found to have a homozygous c.749C>T; p.P250L variant following whole genome SNP mapping. This variant was found in 2 individuals in the ExAC database in heterozygous state. Transient expression of the patient variants in mouse embryonic fibroblasts showed a large decrease in protein levels compared to wild type.

They report that valvular thickening and atrial dilatation are found in all Hyal2-/- mice (PMID: 23172227) and that Cor triatriatum sinister has been detected in 50% of Hyal2-/- mice (PMID: 26515055).
Sources: Literature
Familial non syndromic congenital heart disease v1.55 HYAL2 Eleanor Williams gene: HYAL2 was added
gene: HYAL2 was added to Familial non syndromic congenital heart disease. Sources: Literature
Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYAL2 were set to 28081210; 23172227; 26515055
Phenotypes for gene: HYAL2 were set to cor triatriatum; congenital cardiac malformations
Review for gene: HYAL2 was set to AMBER
Added comment: PMID: 28081210 (Muggenthaler et al 2017) report 2 unrelated consanguineous extended families (Amish and Arab) who have an orofacial clefting phenotype but cardiac anomalies are also reported. In pedigree 1 (Amish) 5/5 analysed individuals had cleft lip and palate. 3/5 had congenital cardiac malformations including left cor triatriatum and dilated coronary sinus consistent with persistent left superior vena cava. All had a homzogyous c.443A>G, p.K148R variant which segregated with the disorder in the pedigree. It was found in a heterozygous state at a frequency of 0.013 in the Amish population, but was not found in 1000 Genomes or ExAC databases. In pedigree 2 (Arab) 1/2 analysed individuals had cleft lip and palate and 1/2 had an abnormal mitral valve with accessory tissue. Both were found to have a homozygous c.749C>T; p.P250L variant following whole genome SNP mapping. This variant was found in 2 individuals in the ExAC database in heterozygous state. Transient expression of the patient variants in mouse embryonic fibroblasts showed a large decrease in protein levels compared to wild type. They report that valvular thickening and atrial dilatation are found in all Hyal2-/- mice (PMID: 23172227) and that Cor triatriatum sinister has been detected in 50% of Hyal2-/- mice (PMID: 26515055).
Sources: Literature
Retinal disorders v2.158 TRNT1 Ivone Leong Tag for-review tag was added to gene: TRNT1.
Retinal disorders v2.158 TRNT1 Ivone Leong Mode of inheritance for gene: TRNT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.157 TRNT1 Ivone Leong Phenotypes for gene: TRNT1 were changed from to Retinitis pigmentosa and erythrocytic microcytosis, OMIM:616959; Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay, OMIM:616084
Retinal disorders v2.156 TRNT1 Ivone Leong Publications for gene: TRNT1 were set to
Retinal disorders v2.155 TRIM32 Ivone Leong reviewed gene: TRIM32: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.274 SCN9A Helen Lord reviewed gene: SCN9A: Rating: RED; Mode of pathogenicity: None; Publications: 33216760; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.274 ANKRD11 Helen Lord reviewed gene: ANKRD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33476899; Phenotypes: KBG syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.155 TRIM32 Ivone Leong Tag for-review tag was added to gene: TRIM32.
Retinal disorders v2.155 TRIM32 Ivone Leong Phenotypes for gene: TRIM32 were changed from Eye Disorders to Bardet-Biedl syndrome 11, OMIM:615988
Retinal disorders v2.154 TRIM32 Ivone Leong Publications for gene: TRIM32 were set to
Retinal disorders v2.153 TREX1 Ivone Leong commented on gene: TREX1: This gene is associated with the relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.153 TREX1 Ivone Leong Tag for-review tag was added to gene: TREX1.
Early onset or syndromic epilepsy v2.274 ALG14 Helen Lord reviewed gene: ALG14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28733338, 30221345; Phenotypes: epilepsy, behavioural problems, severe developmental delay, mild dysmorphic features, severe neurodegeneration with myopathic and myasthenic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.87 AP4E1 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but details regarding head circumference were mostly unavailable. At least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).; to: Comment on list classification: New gene added by Zornitza Stark. Rating Amber with recommendation of review by the GMS team to assess whether there is sufficient evidence to support a Green rating (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but precise details regarding head circumference were mostly omitted (no relevant info was provided for the remaining 5 patients). However, at least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).
Retinal disorders v2.153 TREX1 Ivone Leong Publications for gene: TREX1 were set to
Retinal disorders v2.152 TREX1 Ivone Leong Mode of inheritance for gene: TREX1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.151 TREX1 Ivone Leong Phenotypes for gene: TREX1 were changed from to Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations, OMIM:192315
Early onset or syndromic epilepsy v2.274 ADAM22 Helen Lord reviewed gene: ADAM22: Rating: AMBER; Mode of pathogenicity: None; Publications: 31432233, 33397806; Phenotypes: Developmental and epileptic encephalopathy 61; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.150 TRAF3IP1 Ivone Leong Classified gene: TRAF3IP1 as Amber List (moderate evidence)
Retinal disorders v2.150 TRAF3IP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.150 TRAF3IP1 Ivone Leong Gene: traf3ip1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.149 TRAF3IP1 Ivone Leong Tag for-review tag was added to gene: TRAF3IP1.
Retinal disorders v2.149 TRAF3IP1 Ivone Leong Phenotypes for gene: TRAF3IP1 were changed from Senior-Loken syndrome 9, MIM#616629 to Senior-Loken syndrome 9, OMIM:616629
Early onset or syndromic epilepsy v2.274 ABCA2 Helen Lord reviewed gene: ABCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29302074, 31047799, 30237576; Phenotypes: intellectual delay, poor growth, ataxia, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset hereditary spastic paraplegia v1.16 AP4M1 Arina Puzriakova Tag for-review tag was added to gene: AP4M1.
Adult onset hereditary spastic paraplegia v1.16 AP4M1 Arina Puzriakova commented on gene: AP4M1
Retinal disorders v2.148 TMEM231 Ivone Leong Classified gene: TMEM231 as Amber List (moderate evidence)
Retinal disorders v2.148 TMEM231 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.148 TMEM231 Ivone Leong Gene: tmem231 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.147 TMEM231 Ivone Leong Tag for-review tag was added to gene: TMEM231.
Retinal disorders v2.147 TMEM231 Ivone Leong Phenotypes for gene: TMEM231 were changed from Joubert syndrome 20 MIM#614970 to Joubert syndrome 20, OMIM:614970
Retinal disorders v2.146 TMEM216 Ivone Leong Classified gene: TMEM216 as Amber List (moderate evidence)
Retinal disorders v2.146 TMEM216 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at the next review.
Retinal disorders v2.146 TMEM216 Ivone Leong Gene: tmem216 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.145 TMEM216 Ivone Leong Tag for-review tag was added to gene: TMEM216.
Leber hereditary optic neuropathy v1.7 DNAJC30 Ivone Leong Phenotypes for gene: DNAJC30 were changed from Leber hereditary optic neuropathy to Leber hereditary optic neuropathy; LHON-like
Leber hereditary optic neuropathy v1.6 DNAJC30 Ivone Leong Publications for gene: DNAJC30 were set to
Severe microcephaly v2.87 AP4M1 Arina Puzriakova Phenotypes for gene: AP4M1 were changed from Spastic paraplegia 50, autosomal recessive (MIM#612936) to Spastic paraplegia 50, autosomal recessive, OMIM:612936; Hereditary spastic paraplegia 50, MONDO:0013048
Severe microcephaly v2.86 AP4M1 Arina Puzriakova Classified gene: AP4M1 as Amber List (moderate evidence)
Severe microcephaly v2.86 AP4M1 Arina Puzriakova Added comment: Comment on list classification: Microcephaly is a variable feature of the disease presentation - often too mild relative to the scope of this panel, or absent altogether. However, there are at least 3 unrelated cases with sufficiently severe microcephaly. Although the overall disorder may be better represented by other panels (e.g. HSP, ID) for which this gene is already Green, microcephaly can be an early manifestation that may be evident prior to other AP4M1-related phenotypes. Therefore, there may be value in inclusion on this panel.

Rating Amber, with recommendation of review by the GMS team to assess whether there is sufficient evidence to support a Green rating on this panel (added 'for-review' tag)
Severe microcephaly v2.86 AP4M1 Arina Puzriakova Gene: ap4m1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.85 AP4M1 Arina Puzriakova Tag for-review tag was added to gene: AP4M1.
Severe microcephaly v2.85 AP4M1 Arina Puzriakova reviewed gene: AP4M1: Rating: ; Mode of pathogenicity: None; Publications: 19559397, 21937992, 24700674, 25496299, 28464862, 29473051, 32337850; Phenotypes: Spastic paraplegia 50, autosomal recessive, OMIM:612936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.145 TMEM216 Ivone Leong Phenotypes for gene: TMEM216 were changed from Eye Disorders to Joubert syndrome 2, OMIM:608091, MONDO:0011963; Meckel syndrome 2, OMIM:603194, MONDO:0011296
Retinal disorders v2.144 SSBP1 Ivone Leong Classified gene: SSBP1 as Amber List (moderate evidence)
Retinal disorders v2.144 SSBP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be reviewed by the GMS specialist group to see whether the phenotype is appropriate to be included in this panel.

This gene is Green on the Optic neuropathy panel (Version 2.29).
Retinal disorders v2.144 SSBP1 Ivone Leong Gene: ssbp1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.143 SSBP1 Ivone Leong Tag for-review tag was added to gene: SSBP1.
Severe microcephaly v2.85 ANKLE2 Arina Puzriakova Tag for-review tag was added to gene: ANKLE2.
Severe microcephaly v2.85 ANKLE2 Arina Puzriakova Phenotypes for gene: ANKLE2 were changed from ?Microcephaly 16, primary, autosomal recessive, 616681 to Microcephaly 16, primary, autosomal recessive, OMIM:616681; Microcephaly 16, primary, autosomal recessive, MONDO:0014730
Severe microcephaly v2.84 ANKLE2 Arina Puzriakova Publications for gene: ANKLE2 were set to 25259927
Severe microcephaly v2.83 ANKLE2 Arina Puzriakova Classified gene: ANKLE2 as Amber List (moderate evidence)
Severe microcephaly v2.83 ANKLE2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is enough evidence to rate Green at the next GMS panel update (added 'for-review' tag).

At least 5 individuals from 4 unrelated families with primary microcephaly (HC -4.33 to -16.30 SD) and biallelic variants in ANKLE2 (PMIDs: 25259927 and 30214071). Several lines of supporting evidence using Drosophila Ankle2 mutants, including reduced brain size which could be rescued by expression of wildtype human ANKLE2.

This gene-disease association is also listed in OMIM (MIM# 616681).
Severe microcephaly v2.83 ANKLE2 Arina Puzriakova Gene: ankle2 has been classified as Amber List (Moderate Evidence).
Leber hereditary optic neuropathy v1.5 DNAJC30 Neringa Jurkute reviewed gene: DNAJC30: Rating: RED; Mode of pathogenicity: Other; Publications: PMID: 33465056; Phenotypes: LHON-like; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.143 SSBP1 Ivone Leong Phenotypes for gene: SSBP1 were changed from Optic atrophy-13 with retinal and foveal abnormalities, MIM#165510 to Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510
Retinal disorders v2.142 RIMS2 Ivone Leong Tag for-review tag was added to gene: RIMS2.
Retinal disorders v2.142 RIMS2 Ivone Leong Classified gene: RIMS2 as Amber List (moderate evidence)
Retinal disorders v2.142 RIMS2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.142 RIMS2 Ivone Leong Gene: rims2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.141 RIMS2 Ivone Leong Phenotypes for gene: RIMS2 were changed from Cone-rod synaptic disorder syndrome, congenital nonprogressive, MIM# 618970 to Cone-rod synaptic disorder syndrome, congenital nonprogressive, OMIM:618970
Retinal disorders v2.140 RDH11 Ivone Leong Mode of inheritance for gene: RDH11 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.139 RDH11 Ivone Leong Phenotypes for gene: RDH11 were changed from to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108
Retinal disorders v2.138 RDH11 Ivone Leong Publications for gene: RDH11 were set to
Retinal disorders v2.137 PRDM13 Ivone Leong commented on gene: PRDM13: This gene is associated with a relevant phenotype in Gene2Phenotype but not in OMIM. There is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Retinal disorders v2.137 PRDM13 Ivone Leong Tag for-review tag was added to gene: PRDM13.
Retinal disorders v2.137 PRDM13 Ivone Leong Mode of pathogenicity for gene: PRDM13 was changed from to Other
Retinal disorders v2.136 PRDM13 Ivone Leong Mode of inheritance for gene: PRDM13 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.82 AGMO Arina Puzriakova Classified gene: AGMO as Amber List (moderate evidence)
Severe microcephaly v2.82 AGMO Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. With addition of the publication identified by Zornitza Stark, there are now 2/3 unrelated cases with microcephaly (PMIDs: 31555905 and 27000257). Rating Amber awaiting further cases prior to inclusion as diagnostic-grade.
Severe microcephaly v2.82 AGMO Arina Puzriakova Gene: agmo has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.81 AGMO Arina Puzriakova Publications for gene: AGMO were set to 27000257
Severe microcephaly v2.80 AGMO Arina Puzriakova commented on gene: AGMO
Retinal disorders v2.135 PRDM13 Ivone Leong Phenotypes for gene: PRDM13 were changed from to North Carolina macular dystrophy, MONDO:0007630
Retinal disorders v2.134 PRDM13 Ivone Leong Publications for gene: PRDM13 were set to
Retinal disorders v2.133 POMGNT1 Ivone Leong commented on gene: POMGNT1: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.133 POMGNT1 Ivone Leong Tag for-review tag was added to gene: POMGNT1.
Retinal disorders v2.133 POMGNT1 Ivone Leong Mode of inheritance for gene: POMGNT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.132 POMGNT1 Ivone Leong Publications for gene: POMGNT1 were set to
Retinal disorders v2.131 POMGNT1 Ivone Leong Phenotypes for gene: POMGNT1 were changed from to Retinitis pigmentosa 76, OMIM:617123, MONDO:0014929
Mitochondrial disorder with complex IV deficiency v1.8 COX4I1 Carl Fratter edited their review of gene: COX4I1: Added comment: GMS to consider whether there is now sufficient evidence for this gene to be green; Changed publications: 28766551, 31290619; Changed phenotypes: OMIM #619060
Possible mitochondrial disorder - nuclear genes v1.31 COX4I1 Carl Fratter edited their review of gene: COX4I1: Added comment: GMS to consider whether there is now sufficient evidence for this gene to be green; Changed publications: 28766551, 31290619; Changed phenotypes: OMIM #619060
Adult solid tumours cancer susceptibility v2.7 RABL3 Israel Gomy Deleted their review
Adult solid tumours cancer susceptibility v2.7 RABL3 Israel Gomy Deleted their comment
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 PJA1 Eleanor Williams commented on gene: PJA1
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 PJA1 Eleanor Williams Phenotypes for gene: PJA1 were changed from Trigonocephaly; Intellectual disability to Trigonocephaly; Intellectual disability; Neurodevelopmental disorders
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 PTCH1 Eleanor Williams commented on gene: PTCH1: This gene should be discussed as to gene rating/phenotypic scope of this panel at the next GMS review.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 SOX6 Eleanor Williams changed review comment from: 3 unrelated cases reported in Tolchin et al, 2020 with a craniosynotosis phenotype but segregation data only for 2 patients. Additional evidence in Tagariello et al 2004 who reports a patient with brachycephaly and a translocation disrupting SOX6. Borderline green/amber.; to: 3 unrelated cases reported in Tolchin et al, 2020 with a craniosynotosis phenotype but segregation data only for 2 patients.. Additional evidence in Tagariello et al 2004 who reports a patient with brachycephaly and a translocation disrupting SOX6. Borderline green/amber but based on review by Expert Reviewer Helen Lord, will keep amber for now.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 SOX6 Eleanor Williams commented on gene: SOX6: 3 unrelated cases reported in Tolchin et al, 2020 with a craniosynotosis phenotype but segregation data only for 2 patients. Additional evidence in Tagariello et al 2004 who reports a patient with brachycephaly and a translocation disrupting SOX6. Borderline green/amber.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 SOX6 Eleanor Williams changed review comment from: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown. 16 other patients from 14 families were also reported with variants in SOX6 but no craniosynostosis phenotype.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.; to: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the third this is unknown. 16 other patients from 14 families were also reported with variants in SOX6 but no craniosynostosis phenotype.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.
Fetal anomalies v1.185 NUAK2 Arina Puzriakova Tag watchlist tag was added to gene: NUAK2.
Fetal anomalies v1.185 NUAK2 Arina Puzriakova Publications for gene: NUAK2 were set to 32845958
Fetal anomalies v1.184 NUAK2 Arina Puzriakova Classified gene: NUAK2 as Amber List (moderate evidence)
Fetal anomalies v1.184 NUAK2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single consanguineous family with three consecutive fetuses with anencephaly. Exome sequencing revealed a recessive 21-bp in-frame deletion in NUAK2 segregating with the disease. Pathogenicity is supported by in vitro and animal model data.

Rating Amber, awaiting further cases/clinical evidence prior to inclusion as diagnostic-grade (added 'watchlist' tag)
Fetal anomalies v1.184 NUAK2 Arina Puzriakova Gene: nuak2 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 TRAF7 Eleanor Williams edited their review of gene: TRAF7: Added comment: Both Andrew Wilkie and Helen Lord cite a publication that lists several patients with craniosynostosis and TRAF7 variants. Therefore this gene has a green rating recommendation for the next review.; Changed rating: GREEN
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 B3GAT3 Eleanor Williams Phenotypes for gene: B3GAT3 were changed from Craniosynostosis and bone fragility to Craniosynostosis and bone fragility; Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects OMIM:245600; Larsen-like syndrome, B3GAT3 type MONDO:0009511
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.21 B3GAT3 Eleanor Williams Publications for gene: B3GAT3 were set to 28771243
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.20 B3GAT3 Eleanor Williams Classified gene: B3GAT3 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.20 B3GAT3 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as amber for now, but with recommendation for green rating following GMS review. 3 independent cases with dolichocephaly/craniosynostosis reported and variants in B3GAT3. Cases from Morocco and India have a c.667G>A (p.Gly223Ser) variant but Ritelli et al 2019 reports an additional case with two different compound het variants.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.20 B3GAT3 Eleanor Williams Gene: b3gat3 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 B3GAT3 Eleanor Williams Tag for-review tag was added to gene: B3GAT3.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 B3GAT3 Eleanor Williams commented on gene: B3GAT3: As reported by 2 expert reviewers, PMID:31438591 (Ritelli et al 2019) report a further case of a patient with compound het missense changes (c.481C>T, p.(Arg161Trp) and c.889C>T (p.(Arg297Trp)) in B3GAT3 and a clinical presentation suggestive of spondylodysplastic Ehlers-Danlos syndrome which includes dolichocephaly. In Table 2 the paper lists the clinical features of all patients with B3GAT3 variants reported to date, however, some of these patients appear to have variants in AEBP1 (ENSG00000106624) rather than B3GAT3 (ENSG00000149541) e.g. PMID: 29606302 (reference 2 in the table).

PMID: 31196143 - Colman et al 2019 - report an Indian boy with complex linkeropathy and phenotypic features that include dolichocephaly. He was found to have a homozygous variant in B3GAT3 (c.667G > A, p.(Gly223Ser)) that was previously reported by Yauy et al. Another patient with a B3GAT3 variant is reported but dolichocephaly is not noted.
Inherited phaeochromocytoma and paraganglioma v1.6 MDH2 Ivone Leong Added comment: Comment on publications: Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. J. Natl. Cancer Inst. J Natl Cancer Inst 2015 May 11;107(5). Epub 2015 Mar 11.
Inherited phaeochromocytoma and paraganglioma v1.6 MDH2 Ivone Leong Publications for gene: MDH2 were set to Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. J. Natl. Cancer Inst. J Natl Cancer Inst 2015 May 11; 107(5). Epub 2015 Mar 11.
Fetal anomalies v1.183 AMBRA1 Arina Puzriakova Classified gene: AMBRA1 as Amber List (moderate evidence)
Fetal anomalies v1.183 AMBRA1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient unrelated cases and supportive functional data. However, only a single publication linking this gene to human disease at present (PMID:32333458). Segregation data was not provided and penetrance remains unclear. AMBRA1 was investigated by targeted sequencing and so there also is a possibility of variants in other genes.

Currently the evidence is insufficient for a Green rating, but this may be revised if further cases/clinical evidence arise (added 'watchlist' tag)
Fetal anomalies v1.183 AMBRA1 Arina Puzriakova Gene: ambra1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.182 AMBRA1 Arina Puzriakova Tag watchlist tag was added to gene: AMBRA1.
Fetal anomalies v1.182 AMBRA1 Arina Puzriakova reviewed gene: AMBRA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32333458, 17589504; Phenotypes: Neural tube defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorder with complex IV deficiency v1.8 SQOR Sarah Leigh Publications for gene: SQOR were set to PMID: 32160317
Mitochondrial disorder with complex IV deficiency v1.7 SQOR Sarah Leigh Tag for-review tag was added to gene: SQOR.
Mitochondrial disorder with complex IV deficiency v1.7 SQOR Sarah Leigh Classified gene: SQOR as Amber List (moderate evidence)
Mitochondrial disorder with complex IV deficiency v1.7 SQOR Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorder with complex IV deficiency v1.7 SQOR Sarah Leigh Gene: sqor has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v1.31 SQOR Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM or in Gen2Phen. At least 2 variants reported in unrelated cases, together with supportive functional studies. The authors of PMID 32160317 hypothesise that in their patients, the low residual SQOR activity was likely sufficient to support H2S clearance during stable episodes but was insufficient during acute illness with catabolism resulting in H2S accumulation and toxicity.; to: Not associated with relevant phenotype in OMIM or in Gen2Phen. At least 2 variants reported in unrelated cases, together with supportive functional studies. The authors of PMID 32160317 hypothesise that in their patients, the low residual SQOR activity was likely sufficient to support H2S clearance during stable episodes but was insufficient during acute illness with catabolism resulting in H2S accumulation and toxicity. They conclude that "SQOR deficiency represents a new, potentially treatable, cause of Leigh disease".
Mitochondrial disorder with complex IV deficiency v1.6 SQOR Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM or in Gen2Phen. At least 2 variants reported in unrelated cases, together with supportive functional studies. The authors of PMID 32160317 hypothesise that in their patients, the low residual SQOR activity was likely sufficient to support H2S clearance during stable episodes but was insufficient during acute illness with catabolism resulting in H2S accumulation and toxicity.; to: Not associated with relevant phenotype in OMIM or in Gen2Phen. At least 2 variants reported in unrelated cases, together with supportive functional studies. The authors of PMID 32160317 hypothesise that in their patients, the low residual SQOR activity was likely sufficient to support H2S clearance during stable episodes but was insufficient during acute illness with catabolism resulting in H2S accumulation and toxicity. They conclude that "SQOR deficiency represents a new, potentially treatable, cause of Leigh disease".
Possible mitochondrial disorder - nuclear genes v1.31 SQOR Sarah Leigh Classified gene: SQOR as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v1.31 SQOR Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v1.31 SQOR Sarah Leigh Gene: sqor has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v1.30 SQOR Sarah Leigh Tag for-review tag was added to gene: SQOR.
Possible mitochondrial disorder - nuclear genes v1.30 SQOR Sarah Leigh reviewed gene: SQOR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorder with complex IV deficiency v1.6 SQOR Sarah Leigh reviewed gene: SQOR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.182 CALCRL Arina Puzriakova Phenotypes for gene: CALCRL were changed from Lymphatic malformation 8 (MIM# 618773); hydrops fetalis to Lymphatic malformation 8, OMIM:618773; Lymphatic malformation 8, MONDO:0032907; Hydrops fetalis
Fetal anomalies v1.181 CALCRL Arina Puzriakova Publications for gene: CALCRL were set to 30115739
Fetal anomalies v1.180 CALCRL Arina Puzriakova Classified gene: CALCRL as Red List (low evidence)
Fetal anomalies v1.180 CALCRL Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single family with recurrent hydrops fetalis (PMID:30115739), supported by in vitro and animal model data. Rating Red as additional cases required to corroborate this gene-disease association.
Fetal anomalies v1.180 CALCRL Arina Puzriakova Gene: calcrl has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v1.30 SQOR Sarah Leigh Publications for gene: SQOR were set to PMID: 32160317
Possible mitochondrial disorder - nuclear genes v1.29 SQOR Sarah Leigh Classified gene: SQOR as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v1.29 SQOR Sarah Leigh Gene: sqor has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex I deficiency v1.7 NDUFC2 Sarah Leigh Publications for gene: NDUFC2 were set to
Mitochondrial disorder with complex I deficiency v1.6 NDUFC2 Sarah Leigh Phenotypes for gene: NDUFC2 were changed from No OMIM phenotype to No OMIM phenotype; early-onset Leigh syndrome and stalled biogenesis of complex I
Mitochondrial disorder with complex I deficiency v1.5 NDUFC2 Sarah Leigh Mode of inheritance for gene: NDUFC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.4 NDUFC2 Sarah Leigh Classified gene: NDUFC2 as Amber List (moderate evidence)
Mitochondrial disorder with complex I deficiency v1.4 NDUFC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorder with complex I deficiency v1.4 NDUFC2 Sarah Leigh Gene: ndufc2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex I deficiency v1.3 NDUFC2 Sarah Leigh Tag for-review tag was added to gene: NDUFC2.
Mitochondrial disorder with complex I deficiency v1.3 NDUFC2 Sarah Leigh reviewed gene: NDUFC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Possible mitochondrial disorder - nuclear genes v1.28 NDUFC2 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM or in Gen2Phen. At least 2 variants have been reported in two unrelated cases (PMID 32969598), these are in addition to the 2 familes with complex I deficiency reported by Carl Fratter (review below 10 May 2019).; to: Not associated with relevant phenotype in OMIM or in Gen2Phen. At least 2 variants have been reported in two unrelated cases, together with supportive functional evidence (PMID 32969598). There are also 2 families with complex I deficiency with reported by Carl Fratter (review below 10 May 2019).
Intellectual disability v3.740 ABCC9 Arina Puzriakova changed review comment from: Comment on list classification: Intellectual impairment as been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. However, this is less prominent than other features of the disease presentation (e.g. cardiac, skeletal defects) and often ID is perhaps too mild.

Therefore, ABCC9 will be flagged for review by the GMS team with regards to phenotypic fit for this panel and determine whether it should be demoted from Green to Amber (added for-review tag).; to: Comment on list classification: Intellectual impairment has been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. ID is typically mild, however it is plausible that patients may still be tested for this panel, particularly if recruited under Coffin-Siris-like coarse facial features which can be associated with this gene. Therefore, maintaining Green gene rating.

Comment on mode of inheritance: Leaving MOI as Monoallelic as only 2 families with the same biallelic variant (possible founder variant) reported to date (PMID:31575858), and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Possible mitochondrial disorder - nuclear genes v1.28 NDUFC2 Sarah Leigh edited their review of gene: NDUFC2: Added comment: Not associated with relevant phenotype in OMIM or in Gen2Phen. At least 2 variants have been reported in two unrelated cases (PMID 32969598), these are in addition to the 2 familes with complex I deficiency reported by Carl Fratter (review below 10 May 2019).; Changed rating: GREEN
Possible mitochondrial disorder - nuclear genes v1.28 NDUFC2 Sarah Leigh Classified gene: NDUFC2 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v1.28 NDUFC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v1.28 NDUFC2 Sarah Leigh Gene: ndufc2 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v1.27 NDUFC2 Sarah Leigh Tag for-review tag was added to gene: NDUFC2.
Possible mitochondrial disorder - nuclear genes v1.27 NDUFC2 Sarah Leigh Phenotypes for gene: NDUFC2 were changed from No OMIM phenotype to No OMIM phenotype; early-onset Leigh syndrome and stalled biogenesis of complex I
Possible mitochondrial disorder - nuclear genes v1.26 NDUFC2 Sarah Leigh Mode of inheritance for gene: NDUFC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.25 NDUFC2 Sarah Leigh Publications for gene: NDUFC2 were set to
Intellectual disability v3.740 ABCC9 Arina Puzriakova Tag for-review was removed from gene: ABCC9.
Mitochondrial disorders v2.14 HPDL Sarah Leigh edited their review of gene: HPDL: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 16 variants reported in 17 cases from 13 unrelated families, supportive functional studies were reported, including localization of HPDL protein to the mitochrondria and muscle fibre abnormalies in some cases tested (PMID 32707086).; Changed rating: GREEN
Possible mitochondrial disorder - nuclear genes v1.24 HPDL Sarah Leigh edited their review of gene: HPDL: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 16 variants reported in 17 cases from 13 unrelated families, supportive functional studies were reported, including localization of HPDL protein to the mitochrondria and muscle fibre abnormalies in some cases tested (PMID 32707086).; Changed rating: GREEN
Adult onset neurodegenerative disorder v2.38 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG: Tagged 'for-review' to highlight the recent review by Helen Brittain (Genomics England Clinical Team) indicating that exclusion of this STR may increase risk of missed diagnoses. HTT_CAG was removed from this panel in October 2020 at request of the GMS Specialist Test Group.
Albinism or congenital nystagmus v1.17 DCT Ivone Leong Classified gene: DCT as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.17 DCT Ivone Leong Added comment: Comment on list classification: New gene added by Simon Ramsden (NHS). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33100333 describes 2 unrelated patients with variants in DCT. Both patients had mild hair and skin hypopigmentation, and classical ocular features. The paper also describes a mouse model and zebrafish model which replicate the human phenotype.

There is enough evidence to support a gene-disease associaton. Therefore, this gene should be promoted to Green status at the next review.
Albinism or congenital nystagmus v1.17 DCT Ivone Leong Gene: dct has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v2.38 HTT_CAG Arina Puzriakova Tag for-review tag was added to STR: HTT_CAG.
Albinism or congenital nystagmus v1.16 DCT Ivone Leong Tag for-review tag was added to gene: DCT.
Albinism or congenital nystagmus v1.16 DCT Ivone Leong Publications for gene: DCT were set to PMID 33100333
Albinism or congenital nystagmus v1.15 BLOC1S3 Ivone Leong reviewed gene: BLOC1S3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Albinism or congenital nystagmus v1.15 BLOC1S3 Ivone Leong Publications for gene: BLOC1S3 were set to
Possible mitochondrial disorder - nuclear genes v1.24 HPDL Sarah Leigh Classified gene: HPDL as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v1.24 HPDL Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v1.24 HPDL Sarah Leigh Gene: hpdl has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.14 HPDL Sarah Leigh Classified gene: HPDL as Amber List (moderate evidence)
Mitochondrial disorders v2.14 HPDL Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v2.14 HPDL Sarah Leigh Gene: hpdl has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.13 HPDL Sarah Leigh Phenotypes for gene: HPDL were changed from Leigh-like phenotype; progressive neurological disease to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities OMIM:619026; Spastic paraplegia 83, autosomal recessive OMIM:619027
Albinism or congenital nystagmus v1.14 BLOC1S3 Ivone Leong Tag for-review tag was added to gene: BLOC1S3.
Possible mitochondrial disorder - nuclear genes v1.23 HPDL Sarah Leigh Phenotypes for gene: HPDL were changed from OMIM #619026; OMIM #619027 to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities OMIM:619026; Spastic paraplegia 83, autosomal recessive OMIM:619027
Possible mitochondrial disorder - nuclear genes v1.22 HPDL Sarah Leigh Publications for gene: HPDL were set to PMID: 32707086
Mitochondrial disorders v2.12 HPDL Sarah Leigh Tag for-review tag was added to gene: HPDL.
Possible mitochondrial disorder - nuclear genes v1.21 HPDL Sarah Leigh Tag for-review tag was added to gene: HPDL.
Albinism or congenital nystagmus v1.14 BLOC1S3 Ivone Leong Phenotypes for gene: BLOC1S3 were changed from Hermansky-Pudlak syndrome 8 614077 AR to Hermansky-Pudlak syndrome 8, OMIM:614077, MONDO:0013560
Albinism or congenital nystagmus v1.13 BLOC1S5 Ivone Leong Classified gene: BLOC1S5 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.13 BLOC1S5 Ivone Leong Added comment: Comment on list classification: New gene added by Simon Ramsden (NHS). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 32565547 describes 2 unrelated cases of patients with homozygous variants in BLOC1S5. Patients had mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules. The paper also includes a mouse model.

Based on the available information there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Albinism or congenital nystagmus v1.13 BLOC1S5 Ivone Leong Gene: bloc1s5 has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v1.12 BLOC1S5 Ivone Leong Tag for-review tag was added to gene: BLOC1S5.
Albinism or congenital nystagmus v1.12 BLOC1S5 Ivone Leong Phenotypes for gene: BLOC1S5 were changed from Hermansky-Pudlak syndrome to Hermansky-Pudlak syndrome, MONDO:0019312
Albinism or congenital nystagmus v1.11 BLOC1S5 Ivone Leong Publications for gene: BLOC1S5 were set to PMID 32565547
Intellectual disability v3.740 UBR7 Arina Puzriakova Tag for-review tag was added to gene: UBR7.
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Classified gene: UBR7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but sufficient number of unrelated cases with relevant phenotype to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Gene: ubr7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.273 UBR7 Arina Puzriakova gene: UBR7 was added
gene: UBR7 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: UBR7.
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Review for gene: UBR7 was set to GREEN
Added comment: - PMID: 33340455 (2021) - At least 6 SNVs and 1 intragenic deletion reported in 7 individuals from 6 families with a comparable neurodevelopmental disorder. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile).
Sources: Literature
Intellectual disability v3.740 UBR7 Arina Puzriakova Classified gene: UBR7 as Amber List (moderate evidence)
Intellectual disability v3.740 UBR7 Arina Puzriakova Added comment: Comment on list classification: In view of recent expert review by Zornitza Stark, upgraded from Red to Amber but with a recommendation of rating Green at the next GMS panel update (added 'for-review' tag)

At least 6 SNVs and 1 intragenic deletion reported in 7 individuals from 6 families with a comparable neurodevelopmental disorder. DD/ID was a feature in all cases (PMID:33340455)
Intellectual disability v3.740 UBR7 Arina Puzriakova Gene: ubr7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.739 UBR7 Arina Puzriakova Publications for gene: UBR7 were set to 21937992
Intellectual disability v3.738 UBR7 Arina Puzriakova Phenotypes for gene: UBR7 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
White matter disorders and cerebral calcification - narrow panel v1.32 RNU7-1 Arina Puzriakova Classified gene: RNU7-1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.32 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag) - extensive intracranial calcification and white matter abnormalities were a commonly reported feature in patients with biallelic variants in this gene (PMID:33230297)
White matter disorders and cerebral calcification - narrow panel v1.32 RNU7-1 Arina Puzriakova Gene: rnu7-1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.31 RNU7-1 Arina Puzriakova gene: RNU7-1 was added
gene: RNU7-1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
for-review tags were added to gene: RNU7-1.
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like; Type I interferonopathy
Review for gene: RNU7-1 was set to GREEN
Added comment: Not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including spasticity, dystonia, epilepsy, peripheral neuropathy, brain calcification, mild skin involvement and delayed psychomotor development. Upregulated interferon signalling was detected in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005, and no biallelic variants were identified in control populations. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.25 RNU7-1 Arina Puzriakova Classified gene: RNU7-1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.25 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag) - spasticity (with or without dystonia) was a feature in all 11 families reported with biallelic variants in this gene (PMID:33230297)
Childhood onset hereditary spastic paraplegia v2.25 RNU7-1 Arina Puzriakova Gene: rnu7-1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.24 RNU7-1 Arina Puzriakova gene: RNU7-1 was added
gene: RNU7-1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
for-review tags were added to gene: RNU7-1.
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Type I interferonopathy; Aicardi-Goutières syndrome
Review for gene: RNU7-1 was set to GREEN
Added comment: Not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including spasticity, dystonia, epilepsy, peripheral neuropathy, brain calcification, mild skin involvement and delayed psychomotor development. Upregulated interferon signalling was detected in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005, and no biallelic variants were identified in control populations. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
Sources: Literature
Early onset or syndromic epilepsy v2.272 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954
Childhood onset dystonia, chorea or related movement disorder v1.74 RNU7-1 Arina Puzriakova Classified gene: RNU7-1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.74 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag) - spastic dystonia was a feature in 9/16 patients (7 families) reported with biallelic variants in this gene (PMID:33230297)
Childhood onset dystonia, chorea or related movement disorder v1.74 RNU7-1 Arina Puzriakova Gene: rnu7-1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.271 PMPCB Sarah Leigh Tag for-review tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.271 FLNA Sarah Leigh Phenotypes for gene: FLNA were changed from Heterotopia, periventricular 300049 to Heterotopia, periventricular OMIM:300049
Early onset or syndromic epilepsy v2.270 ASNS Sarah Leigh Classified gene: ASNS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.270 ASNS Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.270 ASNS Sarah Leigh Gene: asns has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.269 ASNS Sarah Leigh reviewed gene: ASNS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia, chorea or related movement disorder v1.73 RNU7-1 Arina Puzriakova gene: RNU7-1 was added
gene: RNU7-1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
for-review tags were added to gene: RNU7-1.
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like; Type I interferonopathy
Review for gene: RNU7-1 was set to GREEN
Added comment: Not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including spasticity, dystonia, epilepsy, peripheral neuropathy, brain calcification, mild skin involvement and delayed psychomotor development. Upregulated interferon signalling was detected in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005, and no biallelic variants were identified in control populations. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
Sources: Literature
Early onset or syndromic epilepsy v2.269 ASNS Sarah Leigh Publications for gene: ASNS were set to
Intellectual disability v3.737 RNU7-1 Arina Puzriakova Classified gene: RNU7-1 as Amber List (moderate evidence)
Intellectual disability v3.737 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: Various degrees of cognitive impairment reported (PMID:33230297). However, DD is an early feature often preceding other neurological concerns, and there are enough cases with sufficiently severe ID for inclusion on this panel.

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.737 RNU7-1 Arina Puzriakova Gene: rnu7-1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.268 ASNS Sarah Leigh Phenotypes for gene: ASNS were changed from Asparagine synthetase deficiency, MIM# 615574 to Asparagine synthetase deficiency OMIM:615574
Early onset or syndromic epilepsy v2.267 ASNS Sarah Leigh Tag for-review tag was added to gene: ASNS.
Albinism or congenital nystagmus v1.10 BLOC1S5 Simon Ramsden gene: BLOC1S5 was added
gene: BLOC1S5 was added to Albinism or congenital nystagmus. Sources: NHS GMS
Mode of inheritance for gene: BLOC1S5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S5 were set to PMID 32565547
Phenotypes for gene: BLOC1S5 were set to Hermansky-Pudlak syndrome
Penetrance for gene: BLOC1S5 were set to Complete
Review for gene: BLOC1S5 was set to GREEN
Added comment: This is a newly described gen association and should be considered for inclusion in the Albinism panel
Sources: NHS GMS
Albinism or congenital nystagmus v1.10 DCT Simon Ramsden gene: DCT was added
gene: DCT was added to Albinism or congenital nystagmus. Sources: NHS GMS
Mode of inheritance for gene: DCT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCT were set to PMID 33100333
Phenotypes for gene: DCT were set to Ocutaneous albinism
Penetrance for gene: DCT were set to Complete
Review for gene: DCT was set to GREEN
Added comment: This is a newly described gene that should be considered for inclusion in the Albinism panel
Sources: NHS GMS
Adult onset neurodegenerative disorder v2.38 HTT_CAG Helen Brittain reviewed STR: HTT_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Huntington disease # 143100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.736 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi–Goutières syndrome-like to Aicardi–Goutières syndrome-like; Type I interferonopathy
Intellectual disability v3.735 RNU7-1 Arina Puzriakova Tag for-review tag was added to gene: RNU7-1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 RNU7-1 Arina Puzriakova changed review comment from: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including upregulated interferon signalling in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.; to: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including upregulated interferon signalling in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005; no biallelic variants were identified in control populations. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
Intellectual disability v3.735 APC2 Sarah Leigh Phenotypes for gene: APC2 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Cortical dysplasia, complex, with other brain malformations 10 OMIM:618677
Intellectual disability v3.734 RNU7-1 Arina Puzriakova reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33230297; Phenotypes: Aicardi–Goutières syndrome-like, Type I interferonopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.42 APC2 Sarah Leigh Publications for gene: APC2 were set to 31585108
Early onset or syndromic epilepsy v2.267 APC2 Sarah Leigh Phenotypes for gene: APC2 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system to Cortical dysplasia, complex, with other brain malformations 10 OMIM:618677
Malformations of cortical development v2.41 APC2 Sarah Leigh Phenotypes for gene: APC2 were changed from Cortical dysplasia, complex, with other brain malformations 10, MIM#618677 to Cortical dysplasia, complex, with other brain malformations 10 OMIM:618677
Malformations of cortical development v2.40 APC2 Sarah Leigh Classified gene: APC2 as Amber List (moderate evidence)
Malformations of cortical development v2.40 APC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Malformations of cortical development v2.40 APC2 Sarah Leigh Gene: apc2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.39 APC2 Sarah Leigh Tag for-review tag was added to gene: APC2.
Malformations of cortical development v2.39 APC2 Sarah Leigh reviewed gene: APC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh edited their review of gene: APC2: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 9 variants in 8 unrealated cases of Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay (PMID 31585108).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Tag for-review tag was added to gene: APC2.
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Classified gene: APC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Gene: apc2 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.42 RPGR Gabrielle Wheway reviewed gene: RPGR: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 16055928, PMID: 22888088; Phenotypes: primary ciliary dyskinesia, non-CF bronchiectasis; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.15 SMN1 Sarah Leigh reviewed gene: SMN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.15 SMN1 Sarah Leigh Tag for-review tag was added to gene: SMN1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Type I interferonopathy; Aicardi-Goutières syndrome to Aicardi-Goutières syndrome-like; Type 1 interferonopathy
Primary immunodeficiency or monogenic inflammatory bowel disease v2.391 RNU7-1 Arina Puzriakova Tag watchlist was removed from gene: RNU7-1.
Tag for-review tag was added to gene: RNU7-1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.391 RNU7-1 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Boaz Palterer. Currently only one paper (PMID: 33230297) indicating pathogenicity of RNU7-1 variants, which also reports on a healthy individual with biallelic rare variants in this gene. Rating Amber awaiting further publications/clinical evidence to corroborate this gene-disease association (added 'watchlist' tag); to: Comment on list classification: New gene added by Boaz Palterer. Rating Amber with recommendation of review by the GMS team with regards to phenotypic fit for the PID panel - Aicardi-Goutieres syndrome genes are Green on this panel. Sufficient unrelated cases, supported by functional analysis (PMID: 33230297), to promote to Green if appropriate.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.391 RNU7-1 Arina Puzriakova changed review comment from: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome which is relevant to this panel. 4/12 variants were observed in 2 or more families. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
However, RNU7-1 variants have also been reported in control populations. 7 variants are recorded in gnomAD at a frequency of ≤0.005, and screening of 663 controls yielded 1 healthy individual with biallelic rare variants in RNU7-1 (Supplementary Table 4).; to: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including upregulated interferon signalling in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
Hereditary neuropathy v1.383 PNKP Sarah Leigh Phenotypes for gene: PNKP were changed from Ataxia-oculomotor apraxia 4, 616267; Microcephaly, seizures, and developmental delay, 613402; Microcephaly, global developmental delay, progressive cerebellar ataxia and atrophy, sensory-motor axonal neuropathy to ?Charcot-Marie-Tooth disease, type 2B2 605589; Ataxia-oculomotor apraxia 4 OMIM:616267; Microcephaly, seizures, and developmental delay OMIM:613402
Hereditary neuropathy or pain disorder v1.21 PNKP Sarah Leigh Tag for-review tag was added to gene: PNKP.
Hereditary neuropathy or pain disorder v1.21 PNKP Sarah Leigh Classified gene: PNKP as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.21 PNKP Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v1.21 PNKP Sarah Leigh Gene: pnkp has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.20 PNKP Sarah Leigh Publications for gene: PNKP were set to 30039206
Hereditary neuropathy or pain disorder v1.19 PNKP Sarah Leigh reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy v1.382 PNKP Sarah Leigh Classified gene: PNKP as Green List (high evidence)
Hereditary neuropathy v1.382 PNKP Sarah Leigh Gene: pnkp has been classified as Green List (High Evidence).
Hereditary neuropathy v1.381 PNKP Sarah Leigh reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: 27066567; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.734 FGFR1 Arina Puzriakova Phenotypes for gene: FGFR1 were changed from Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600; Encephalocraniocutaneous lipomatosis, somatic mosaic, OMIM:613001
Intellectual disability v3.733 FGFR1 Arina Puzriakova Publications for gene: FGFR1 were set to 28825856
Intellectual disability v3.732 FGFR1 Arina Puzriakova Phenotypes for gene: FGFR1 were changed from Encephalocraniocutaneous lipomatosis, 613001; KALLMANN SYNDROME TYPE 2; Pfeiffer syndrome,101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600
Intellectual disability v3.731 FGFR1 Arina Puzriakova reviewed gene: FGFR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.731 TANC2 Arina Puzriakova Classified gene: TANC2 as Amber List (moderate evidence)
Intellectual disability v3.731 TANC2 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update - multiple unrelated families with a comparable neurodevelopmental disorder (including ID). As highlighted in review by Zornitza Stark, most reported SNVs are de novo putative disruptive variants, or missense variants that are predicted in silico to have a damaging or possibly damaging effect. Gene expression and function are neurodevelopmentally-relevant, and there is some limited functional data.

Gene-disease association is also now listed in both OMIM and Gene2Phenotype.
Intellectual disability v3.731 TANC2 Arina Puzriakova Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.730 TANC2 Arina Puzriakova Publications for gene: TANC2 were set to 26350204; 31616000
Intellectual disability v3.729 TANC2 Arina Puzriakova commented on gene: TANC2: Removed 'watchlist' tag and added 'for-review' tag as there is now sufficient evidence to promote this gene to Green
Intellectual disability v3.729 TANC2 Arina Puzriakova Tag watchlist was removed from gene: TANC2.
Tag for-review tag was added to gene: TANC2.
Intellectual disability v3.729 TANC2 Arina Puzriakova edited their review of gene: TANC2: Changed phenotypes: Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906
Intellectual disability v3.729 TANC2 Arina Puzriakova reviewed gene: TANC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31616000, 33160097, 30021165; Phenotypes: TANC2-related neurodevelopmental and psychiatric disorder, OMIM:618906; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Classified gene: ATP1A3 as Amber List (moderate evidence)
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating on this panel, in line with the previous comments by Louise Daugherty (Genomics England) and internal clinical review.

Heterozygous variants are associated with several phenotypes, not all of which include cognitive impairment. Gain from inclusion on the ID panel is likely smaller than the risk of incidental information for the majority of the ID cohort. Patients are expected to be tested under the paroxysmal central nervous system disorders or dystonia GMS panels.
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Gene: atp1a3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.728 LAMB2 Zornitza Stark edited their review of gene: LAMB2: Changed rating: GREEN
Possible mitochondrial disorder - nuclear genes v1.21 HPDL Carl Fratter gene: HPDL was added
gene: HPDL was added to Possible mitochondrial disorder - nuclear genes. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to PMID: 32707086
Phenotypes for gene: HPDL were set to OMIM #619026; OMIM #619027
Review for gene: HPDL was set to AMBER
Added comment: Requires review by GMS - should this be considered primary mitochondrial disease?
Sources: Literature
Mitochondrial disorder with complex IV deficiency v1.6 SQOR Carl Fratter gene: SQOR was added
gene: SQOR was added to Mitochondrial disorder with complex IV deficiency. Sources: Literature
Mode of inheritance for gene: SQOR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQOR were set to PMID: 32160317
Phenotypes for gene: SQOR were set to Leigh syndrome
Review for gene: SQOR was set to AMBER
Added comment: Requires review for GMS - should this be considered a primary mitochondrial disorder?
Sources: Literature
Possible mitochondrial disorder - nuclear genes v1.21 SQOR Carl Fratter gene: SQOR was added
gene: SQOR was added to Possible mitochondrial disorder - nuclear genes. Sources: Literature
Mode of inheritance for gene: SQOR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQOR were set to PMID: 32160317
Phenotypes for gene: SQOR were set to Leigh syndrome
Review for gene: SQOR was set to AMBER
Added comment: Requires review for GMS - should this be considered a primary mitochondrial disorder?
Sources: Literature
Mitochondrial disorder with complex I deficiency v1.3 NDUFC2 Carl Fratter edited their review of gene: NDUFC2: Added comment: Suggest update to green in view of recent publication; Changed rating: GREEN; Changed publications: PMID: 32969598; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.21 NDUFC2 Carl Fratter edited their review of gene: NDUFC2: Added comment: Suggest update to green in view of recent publication; Changed rating: GREEN; Changed publications: PMID: 32969598; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Classified gene: PPIL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with relevant phenotype, supported by functional data.
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Gene: ppil1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.264 PPIL1 Arina Puzriakova gene: PPIL1 was added
gene: PPIL1 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: PPIL1.
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Review for gene: PPIL1 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on: 10/07/2001) but has a 'probable' gene rating for 'PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

- PMID: 33220177 (2021) - At least 12 variants identified in 17 individuals from 9 unrelated families. All displayed pontocerebellar hypoplasia and progressive congenital microcephaly. Infantile-onset seizures were reported in 7/9 families - medically controlled in only 1 individual.
Further common phenotypes included hypotonia, intellectual disability with delayed language and motor development, and cortical changes on brain MRI, most notably simplified gyri pattern. Pathogenicity is supported by mouse model.
Sources: Literature
Severe microcephaly v2.80 PPIL1 Arina Puzriakova Classified gene: PPIL1 as Amber List (moderate evidence)
Severe microcephaly v2.80 PPIL1 Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with relevant phenotype, supported by functional data.
Severe microcephaly v2.80 PPIL1 Arina Puzriakova Gene: ppil1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.79 PPIL1 Arina Puzriakova gene: PPIL1 was added
gene: PPIL1 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: PPIL1.
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Review for gene: PPIL1 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on: 10/07/2001) but has a 'probable' gene rating for 'PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

- PMID: 33220177 (2021) - At least 12 variants identified in 17 individuals from 9 unrelated families. All displayed pontocerebellar hypoplasia and progressive congenital microcephaly (-4 to -8 SD HC). Further common phenotypes included hypotonia, seizures, intellectual disability with delayed language and motor development, and cortical changes on brain MRI, most notably simplified gyri pattern. Pathogenicity is supported by mouse model.
Sources: Literature
Intellectual disability v3.728 PPIL1 Arina Puzriakova Tag for-review tag was added to gene: PPIL1.
Intellectual disability v3.728 PPIL1 Arina Puzriakova Classified gene: PPIL1 as Amber List (moderate evidence)
Intellectual disability v3.728 PPIL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Currently not associated with any phenotype in OMIM (last edited on: 10/07/2001) but has a 'probable' gene rating for 'PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

At least 12 variants identified in 17 individuals from 9 unrelated families (PMID: 33220177). All displayed pontocerebellar hypoplasia and congenital microcephaly. Severe ID, with or without seizures, was noted in all subjects (14) where information was provided (see table S1). Pathogenicity is supported by animal model.

Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.728 PPIL1 Arina Puzriakova Gene: ppil1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.727 PPIL1 Arina Puzriakova Phenotypes for gene: PPIL1 were changed from Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disbility to PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Classified gene: FGF13 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with relevant phenotype (early-onset epilepsy represents the main feature of the disorder), supported by functional data.
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Gene: fgf13 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.262 FGF13 Arina Puzriakova Mode of pathogenicity for gene: FGF13 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Early onset or syndromic epilepsy v2.261 FGF13 Arina Puzriakova edited their review of gene: FGF13: Changed mode of pathogenicity: Other
Early onset or syndromic epilepsy v2.261 FGF13 Arina Puzriakova gene: FGF13 was added
gene: FGF13 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: FGF13.
Mode of inheritance for gene: FGF13 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: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Developmental and epileptic encephalopathy; Intellectual disability; Infantile-onset seizures
Mode of pathogenicity for gene: FGF13 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: FGF13 was set to GREEN
Added comment: - PMID: 33245860 (2021) - Three variants (c.31C>T, c.41G>C, c.32G>C) identified by WES/WGS in seven individuals from five unrelated families who presented with severe infantile-onset seizures and severe-to-profound ID. Supportive functional data indicating variants impair long-term inactivation of voltage-gated sodium channels while retaining pro-excitatory properties of A isoform - consistent with the epileptic potential of FGF13 variants
Sources: Literature
Intellectual disability v3.726 FGF13 Arina Puzriakova Classified gene: FGF13 as Amber List (moderate evidence)
Intellectual disability v3.726 FGF13 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Three variants (c.31C>T, c.41G>C, c.32G>C) identified by WES/WGS in seven individuals from five unrelated families who presented with severe infantile-onset seizures and severe-to-profound ID. Supportive functional data.

Sufficient number of unrelated cases with relevant phenotype; however, early-onset epilepsy represents the main feature of the disorder and ID appears to be a secondary manifestation (see supplemental note in PMID:33245860 for clinical details). Therefore, rating Amber on this panel but will add the FGF13 gene to 'Genetic epilepsy syndromes'
Intellectual disability v3.726 FGF13 Arina Puzriakova Gene: fgf13 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 B3GAT3 Helen Lord reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31438591; Phenotypes: craniosynostosis MIM245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Helen Lord reviewed gene: TRAF7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32376980, 29961569; Phenotypes: craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.725 FGF13 Arina Puzriakova Phenotypes for gene: FGF13 were changed from Intellectual disability; epilepsy to Developmental and epileptic encephalopathy; Intellectual disability; Infantile-onset seizures
Intellectual disability v3.724 FGF13 Arina Puzriakova Mode of inheritance for gene: FGF13 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.723 FBRSL1 Arina Puzriakova Phenotypes for gene: FBRSL1 were changed from Intellectual disability; congenital anomalies to Intellectual disability; Microcephaly; Heart defect; Cleft palate; Contractures; Hearing impairment; Skin creases
Severe microcephaly v2.78 FBRSL1 Arina Puzriakova Phenotypes for gene: FBRSL1 were changed from to Intellectual disability; Microcephaly; Heart defect; Cleft palate; Contractures; Hearing impairment; Skin creases
Severe microcephaly v2.77 FBRSL1 Arina Puzriakova Publications for gene: FBRSL1 were set to
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova edited their review of gene: FBRSL1: Changed publications: 32424618; Changed phenotypes: Intellectual disability, Microcephaly, Heart defect, Cleft palate, Contractures, Hearing impairment, Skin creases
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova Tag for-review tag was added to gene: FBRSL1.
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova Classified gene: FBRSL1 as Amber List (moderate evidence)
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with distinct variants and relevant phenotype, supported by functional data.
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova Gene: fbrsl1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.75 FBRSL1 Arina Puzriakova gene: FBRSL1 was added
gene: FBRSL1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: FBRSL1 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 32424618 (2020): Three different de novo truncating variants identified by WES in three unrelated individuals with a congenital malformation syndrome. Clinical characteristics include respiratory insufficiency, postnatal growth restriction, microcephaly, ID/GDD and other malformations. 2/3 had heart defects, cleft palate and hearing impairment.

Knockdown of Fbrsl1 in Xenopus laevis embryos resulted in disturbance in the outgrowth of cranial nerves and motor neurons, and craniofacial abnormalities which were rescued with the short N-terminal isoform but not with the isoform bearing one of the human variants.
Sources: Literature
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Classified gene: FBRSL1 as Amber List (moderate evidence)
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with distinct variants and relevant phenotype, supported by functional data.

Currently not associated with any phenotype in OMIM or Gene2Phenotype.
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Gene: fbrsl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.721 FBRSL1 Arina Puzriakova Tag for-review tag was added to gene: FBRSL1.
Intellectual disability v3.721 FBRSL1 Arina Puzriakova reviewed gene: FBRSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32424618; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.130 ROM1 Ivone Leong Classified gene: ROM1 as Amber List (moderate evidence)
Retinal disorders v2.130 ROM1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is sufficient evidence to support a gene-disease association and it is recommended that this gene should be given Green status.
Retinal disorders v2.130 ROM1 Ivone Leong Gene: rom1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.129 ROM1 Ivone Leong Tag for-review tag was added to gene: ROM1.
Retinal disorders v2.129 ROM1 Ivone Leong Mode of inheritance for gene: ROM1 was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 SOX6 Helen Lord reviewed gene: SOX6: Rating: AMBER; Mode of pathogenicity: None; Publications: 32442410; Phenotypes: Developmental delay, intellectual disability, craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.128 PEX6 Ivone Leong Classified gene: PEX6 as Amber List (moderate evidence)
Retinal disorders v2.128 PEX6 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Retinal disorders v2.128 PEX6 Ivone Leong Gene: pex6 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.127 PEX6 Ivone Leong Tag for-review tag was added to gene: PEX6.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PTCH1 Helen Lord reviewed gene: PTCH1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: metopic synostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.127 PAX2 Ivone Leong commented on gene: PAX2: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.127 PAX2 Ivone Leong Tag for-review tag was added to gene: PAX2.
Retinal disorders v2.127 PAX2 Ivone Leong Publications for gene: PAX2 were set to
Retinal disorders v2.126 PAX2 Ivone Leong Mode of inheritance for gene: PAX2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.125 PAX2 Ivone Leong Phenotypes for gene: PAX2 were changed from to Papillorenal syndrome, OMIM:120330; renal coloboma syndrome, MONDO:0007352
Retinal disorders v2.124 NEUROD1 Ivone Leong commented on gene: NEUROD1: This gene is not associated with an eye phenotype in OMIM and with no phenotype in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.124 NEUROD1 Ivone Leong Tag for-review tag was added to gene: NEUROD1.
Intellectual disability v3.721 DPH2 Arina Puzriakova Classified gene: DPH2 as Amber List (moderate evidence)
Intellectual disability v3.721 DPH2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Currently not associated with any phenotype in OMIM or Gene2Phenotype.

At least 2 unrelated families with biallelic variants in this gene. Phenotypes included DD with expressive language delays in the 19-month-old male in PMID: 32576952 (2020); and intellectual disability in both sibs in PMID: 27421267 (2016), albeit within the mild range (Stanford-Binet scale IQ = 58 and 68, respectively). However in the latter case, KALRN was proposed as the causative gene at the time of publication, as scarce data was known for the DPH2 gene.

Additional cases would help corroborate this gene-disease association and so rating Amber, awaiting further cases/clinical evidence.
Intellectual disability v3.721 DPH2 Arina Puzriakova Gene: dph2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.124 GDF6 Ivone Leong Classified gene: GDF6 as Amber List (moderate evidence)
Retinal disorders v2.124 GDF6 Ivone Leong Added comment: Comment on list classification: This gene has been promoted from Red to Amber. As there is not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Retinal disorders v2.124 GDF6 Ivone Leong Gene: gdf6 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.123 GDF6 Ivone Leong Mode of inheritance for gene: GDF6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.122 GDF6 Ivone Leong commented on gene: GDF6
Intellectual disability v3.720 CDC40 Arina Puzriakova Tag watchlist tag was added to gene: CDC40.
Intellectual disability v3.720 CDC40 Arina Puzriakova Classified gene: CDC40 as Red List (low evidence)
Intellectual disability v3.720 CDC40 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. CDC40 currently not associated with any phenotype in OMIM (last edited: 23/08/19) but has a 'possible' disease confidence for 'CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

Rating Red as currently only a single individual reported in PMID: 33220177 (2021). There is some functional and animal model data to support pathogenicity, so have added 'watchlist' tag. If additional cases arise, CDC40 may also be considered for other panels (e.g. Malformations of cortical development, Genetic epilepsy syndromes, Cytopenia - NOT Fanconi anaemia, etc)
Intellectual disability v3.720 CDC40 Arina Puzriakova Gene: cdc40 has been classified as Red List (Low Evidence).
Intellectual disability v3.719 CDC40 Arina Puzriakova Phenotypes for gene: CDC40 were changed from Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disability to CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Retinal disorders v2.122 GDF6 Ivone Leong Tag watchlist tag was added to gene: GDF6.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord reviewed gene: PJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32530565; Phenotypes: Neurodevelopmental disorders, trigonocephaly; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord Deleted their review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord commented on gene: PJA1
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord Deleted their review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord reviewed gene: PJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32530565; Phenotypes: Neurodevelopmental disorders, trigonocephaly; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.718 ABCC9 Arina Puzriakova Classified gene: ABCC9 as Green List (high evidence)
Intellectual disability v3.718 ABCC9 Arina Puzriakova Added comment: Comment on list classification: Intellectual impairment as been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. However, this is less prominent than other features of the disease presentation (e.g. cardiac, skeletal defects) and often ID is perhaps too mild.

Therefore, ABCC9 will be flagged for review by the GMS team with regards to phenotypic fit for this panel and determine whether it should be demoted from Green to Amber (added for-review tag).
Intellectual disability v3.718 ABCC9 Arina Puzriakova Gene: abcc9 has been classified as Green List (High Evidence).
Intellectual disability v3.717 ABCC9 Arina Puzriakova Tag for-review tag was added to gene: ABCC9.
DDG2P v2.18 ABCC9 Arina Puzriakova commented on gene: ABCC9
Intellectual disability v3.717 ABCC9 Arina Puzriakova reviewed gene: ABCC9: Rating: ; Mode of pathogenicity: None; Publications: 31575858; Phenotypes: mild ID, similar facies, myopathy, cerebral white matter hyperintensities, cardiac systolic dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.122 GDF6 Ivone Leong Phenotypes for gene: GDF6 were changed from Klippel-Feil syndrome 1, autosomal dominant, 118100; Leber congenital amaurosis 17; Microphthalmia with coloboma 6, digenic; Microphthalmia, isolated 4 to Klippel-Feil syndrome 1, autosomal dominant, 118100; Leber congenital amaurosis 17, 615360; Microphthalmia with coloboma 6, digenic, 613703; Microphthalmia, isolated 4, 613094
Retinal disorders v2.121 GDF6 Ivone Leong Publications for gene: GDF6 were set to PMID: 23307924
Iron metabolism disorders - NOT common HFE mutations v1.4 HEPH Zornitza Stark reviewed gene: HEPH: Rating: RED; Mode of pathogenicity: None; Publications: 30182051, 30060949; Phenotypes: Iron metabolism defect; Mode of inheritance: None
Iron metabolism disorders - NOT common HFE mutations v1.4 FTH1 Zornitza Stark reviewed gene: FTH1: Rating: RED; Mode of pathogenicity: None; Publications: 11389486; Phenotypes: Hemochromatosis, type 5, MIM# 615517; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Iron metabolism disorders - NOT common HFE mutations v1.4 CYBRD1 Zornitza Stark reviewed gene: CYBRD1: Rating: RED; Mode of pathogenicity: None; Publications: 15338274; Phenotypes: Iron overload; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v2.32 TRAF7 Eleanor Williams Classified gene: TRAF7 as Amber List (moderate evidence)
Limb disorders v2.32 TRAF7 Eleanor Williams Added comment: Comment on list classification: Leaving the rating at amber for now, but with recommendation for green rating following GMS review as there are now several more cases with hand anomalies relevant to this panel reported in the publication from Castilla-Vallmanya et al 2020
Limb disorders v2.32 TRAF7 Eleanor Williams Gene: traf7 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.31 TRAF7 Eleanor Williams Tag for-review tag was added to gene: TRAF7.
Limb disorders v2.31 TRAF7 Eleanor Williams edited their review of gene: TRAF7: Added comment: PMID: 32376980 - Castilla-Vallmanya et al 2020 - report on a set of 45 patients with a developmental delay-malformation syndrome in which heterozygous missense variants in TRAF7 were identified. Variable anomalies of the hands were reported including brachydactyly (n = 6), and syndactyly (n = 5).; Changed publications: 32376980; Changed phenotypes: developmental delay-malformation syndrome, brachydactyly, syndactyly
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Eleanor Williams Tag for-review tag was added to gene: TRAF7.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Eleanor Williams Classified gene: TRAF7 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with recommendation for green rating following GMS review. Expert reviewer highlights more than 3 cases in which patients with variants in TRAF7 have a craniosynostosis phenotype.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Eleanor Williams Gene: traf7 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Tag for-review tag was added to gene: PTCH1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Classified gene: PTCH1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for green review following evidence provided by expert reviewer.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Gene: ptch1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.17 SIX1 Eleanor Williams Classified gene: SIX1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.17 SIX1 Eleanor Williams Added comment: Comment on list classification: Leaving the rating at amber for now, but with recommendation for green rating following the next GMS review. More than 3 cases with a craniosynostosis phenotype and variants in this gene now published.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.17 SIX1 Eleanor Williams Gene: six1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 SIX1 Eleanor Williams Tag for-review tag was added to gene: SIX1.
Skeletal dysplasia v2.76 TBXAS1 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as BOTH for now, but with recommendation to change to just BIALLELIC following expert review that monallelic inheritance is not seen in the skeletal phenotype.
Skeletal dysplasia v2.76 TBXAS1 Eleanor Williams Mode of inheritance for gene: TBXAS1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.75 NPR3 Eleanor Williams Classified gene: NPR3 as Amber List (moderate evidence)
Skeletal dysplasia v2.75 NPR3 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation for green rating following GMS review. 3 unrelated cases with a similar phenotype and supporting functional data and mouse model.
Skeletal dysplasia v2.75 NPR3 Eleanor Williams Gene: npr3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.74 NPR3 Eleanor Williams Publications for gene: NPR3 were set to PMID: 30032985; 10468599
Skeletal dysplasia v2.73 NPR3 Eleanor Williams Tag for-review tag was added to gene: NPR3.
Skeletal dysplasia v2.73 NPR3 Eleanor Williams reviewed gene: NPR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30032985, 10468599; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.179 SHROOM4 Arina Puzriakova Classified gene: SHROOM4 as Red List (low evidence)
Fetal anomalies v1.179 SHROOM4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Suzanne Drury. Rating Red as currently only a single case with a fetally-relevant phenotype (PMID: 32565546). Additional unrelated cases required to support this gene-disease association.
Fetal anomalies v1.179 SHROOM4 Arina Puzriakova Gene: shroom4 has been classified as Red List (Low Evidence).
Cystic kidney disease v2.23 COL4A5 Eleanor Williams commented on gene: COL4A5: Removed 'for-review' tag as only 1 case, so red rating.
Cystic kidney disease v2.23 COL4A5 Eleanor Williams Tag for-review was removed from gene: COL4A5.
Cystic kidney disease v2.23 COL4A4 Eleanor Williams edited their review of gene: COL4A4: Changed rating: GREEN
Fetal anomalies v1.178 SHROOM4 Arina Puzriakova Phenotypes for gene: SHROOM4 were changed from HP:0001274 to Stocco dos Santos X-linked mental retardation syndrome, 300434
Fetal anomalies v1.177 TMEM260 Arina Puzriakova Publications for gene: TMEM260 were set to
Fetal anomalies v1.176 TMEM260 Arina Puzriakova Phenotypes for gene: TMEM260 were changed from Neurodevelopmental, Cardiac, and Renal Syndrome to Structural heart defects and renal anomalies syndrome, OMIM:617478; Structural heart defects and renal anomalies syndrome, MONDO:0044321
Intellectual disability v3.717 TMEM260 Arina Puzriakova Mode of inheritance for gene: TMEM260 was changed from to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.73 PFN1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber. There are 3 familial cases reported but they all come from the same region of Italy and have the same variant, so possible founder effect. There is some functional data and some CNV data in addition.; to: Comment on list classification: Promoting from grey to amber. There are 3 familial cases reported but they all come from the same region of Italy and have the same variant, so possible founder effect. There is some functional data and some CNV data in addition. Wait for confirmation of this gene's involvement in Paget disease of bone in probands with different variants or that are confirmed as unrelated to the cases already described.
Skeletal dysplasia v2.73 PFN1 Eleanor Williams Phenotypes for gene: PFN1 were changed from Paget’s disease of bone to Paget’s disease of bone; bone Paget disease MONDO:0005382
Skeletal dysplasia v2.72 PFN1 Eleanor Williams Classified gene: PFN1 as Amber List (moderate evidence)
Skeletal dysplasia v2.72 PFN1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. There are 3 familial cases reported but they all come from the same region of Italy and have the same variant, so possible founder effect. There is some functional data and some CNV data in addition.
Skeletal dysplasia v2.72 PFN1 Eleanor Williams Gene: pfn1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.71 PFN1 Eleanor Williams edited their review of gene: PFN1: Changed rating: AMBER; Changed phenotypes: bone Paget disease MONDO:0005382; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.71 PFN1 Eleanor Williams commented on gene: PFN1
Fetal anomalies v1.175 GREB1L Arina Puzriakova Publications for gene: GREB1L were set to 29261186; 29100091
Arthrogryposis v3.52 AGRN Arina Puzriakova Phenotypes for gene: AGRN were changed from Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects, OMIM:615120 to Fetal akinesia deformation sequence (FADS)
Arthrogryposis v3.51 AGRN Arina Puzriakova reviewed gene: AGRN: Rating: ; Mode of pathogenicity: None; Publications: 31730230; Phenotypes: Fetal akinesia deformation sequence; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.174 AGRN Arina Puzriakova Classified gene: AGRN as Red List (low evidence)
Fetal anomalies v1.174 AGRN Arina Puzriakova Added comment: Comment on list classification: Maintaining Red rating and currently only a single case (PMID: 31730230) has been reported with a relevant phenotype to this panel.
Fetal anomalies v1.174 AGRN Arina Puzriakova Gene: agrn has been classified as Red List (Low Evidence).
Fetal anomalies v1.173 AGRN Arina Puzriakova Phenotypes for gene: AGRN were changed from Myasthenia, limb-girdle, familial 615120 to Fetal akinesia deformation sequence (FADS)
Fetal anomalies v1.172 AGRN Arina Puzriakova Publications for gene: AGRN were set to
Arthrogryposis v3.51 AGRN Arina Puzriakova Publications for gene: AGRN were set to
Arthrogryposis v3.50 AGRN Arina Puzriakova Phenotypes for gene: AGRN were changed from Myasthenia, limb-girdle, familial, 254300 to Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects, OMIM:615120
Arthrogryposis v3.49 AGRN Arina Puzriakova Mode of inheritance for gene: AGRN was changed from to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.171 NONO Arina Puzriakova Phenotypes for gene: NONO were changed from SYNDROMIC INTELLECTUAL DISABILITY to Left ventricular non-compaction cardiomyopathy (LVNC); Ventricular septal defect (VSD); Pulmonary stenosis; Atresia; Ebstein’s anomaly
Fetal anomalies v1.170 NONO Arina Puzriakova Classified gene: NONO as Amber List (moderate evidence)
Fetal anomalies v1.170 NONO Arina Puzriakova Added comment: Comment on list classification: Currently there is not enough evidence to promote this gene to Green. Additional cases with a fetally-relevant phenotype are required prior to inclusion at diagnostic-grade. Maintaining Amber rating on this panel.
Fetal anomalies v1.170 NONO Arina Puzriakova Gene: nono has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.169 NONO Arina Puzriakova reviewed gene: NONO: Rating: AMBER; Mode of pathogenicity: None; Publications: 32397791; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.169 NONO Arina Puzriakova Publications for gene: NONO were set to
Malformations of cortical development v2.39 SNAP29 Arina Puzriakova Phenotypes for gene: SNAP29 were changed from Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (MIM#609528) to Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome, OMIM:609528; CEDNIK syndrome, MONDO:0012290
Malformations of cortical development v2.38 SNAP29 Arina Puzriakova Publications for gene: SNAP29 were set to 29051910; 21073448; 30793783
Malformations of cortical development v2.37 SNAP29 Arina Puzriakova Tag for-review tag was added to gene: SNAP29.
Malformations of cortical development v2.37 SNAP29 Arina Puzriakova Classified gene: SNAP29 as Amber List (moderate evidence)
Malformations of cortical development v2.37 SNAP29 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Cerebral dysgenesis is a universal feature among patients with CEDNIK syndrome caused by biallelic variants in the SNAP29 gene. Reported cerebral abnormalities of various degrees include absence of corpus callosum, cortical dysplasia, pachygyria and polymicrogyria.

There is sufficient evidence to promote SNAP29 to Green at the next GMS panel update (added 'for-review' tag)
Malformations of cortical development v2.37 SNAP29 Arina Puzriakova Gene: snap29 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.71 NPR2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the MOI as both, because there are both AD and AR inheritances associated with different types of skeletal dysplasia in OMIM.
Skeletal dysplasia v2.71 NPR2 Eleanor Williams Mode of inheritance for gene: NPR2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.168 SNAP29 Arina Puzriakova Classified gene: SNAP29 as Amber List (moderate evidence)
Fetal anomalies v1.168 SNAP29 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as currently there is not enough evidence to promote to Green. Phenotypes do not appear to be fetally-relevant and gestation is typically uneventful. However, symptoms do arise during the first year of life.
Fetal anomalies v1.168 SNAP29 Arina Puzriakova Gene: snap29 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.167 SNAP29 Arina Puzriakova Phenotypes for gene: SNAP29 were changed from CEDNIK SYNDROME to Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome, OMIM:609528; CEDNIK syndrome, MONDO:0012290
Arthrogryposis v3.48 FLNC Ivone Leong Tag for-review tag was added to gene: FLNC.
Fetal anomalies v1.166 SNAP29 Arina Puzriakova Publications for gene: SNAP29 were set to
Bilateral congenital or childhood onset cataracts v2.58 SLC16A12 Ivone Leong Tag for-review tag was added to gene: SLC16A12.
Congenital myopathy v2.20 GFER Ivone Leong Tag for-review tag was added to gene: GFER.
Skeletal dysplasia v2.70 NPR2 Eleanor Williams commented on gene: NPR2: PMID: 33288834 - Simsek-Kiper et al 2020 - they investigated 26 AMDM patients from 22 unrelated families. Sanger sequencing of NPR2 was performed in 23 patients and exome sequencing was performed in 5 patients They found
NPR2 variants in 23 patients (19 were homozygotes, 4 were compound heterozygotes). 22 distinct NPR2 (NM_003995) variants (14 missense, 5 nonsense, 2 intronic, and 1 single-amino acid deletion) were detected. In 14 families, segregation analysis was performed and showed the heterozygous NPR2 carrier status of the parents. Detailed radiographic evaluations were done, showing osteopenia, shortness in long tubular bones, radial bowing and radial head dislocation in the majority of cases. Other phenotypic features included motor developmental delay (11/23), global developmental delay/intellectual disability (GDD/ID) (5/23), spinal canal stenosis (2/23), and atlantoaxial dislocation (1/23), renal abnormalities and oligodontia. However, the authors note that the high level of parental consanguinity (18 patients) might have contributed to these phenotypes, from other gene variants.
The height of carrier parents was also assessed and found to be significantly lower than controls.
Arthrogryposis v3.48 NUP88 Arina Puzriakova Phenotypes for gene: NUP88 were changed from Fetal akinesia deformation sequence 4, MIM# 618393 to Fetal akinesia deformation sequence 4, OMIM:618393; Fetal akinesia deformation sequence 4, MONDO:0100104
Arthrogryposis v3.47 NUP88 Arina Puzriakova Classified gene: NUP88 as Amber List (moderate evidence)
Arthrogryposis v3.47 NUP88 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Two unrelated families with lethal FADS and different biallelic variants in the NUP88 gene (PMID: 30543681). Zebrafish model recapitulated some human phenotypes such as locomotor and neuromuscular junction defects.

NUP88 is associated with a relevant phenotype in OMIM but is not currently in Gene2Phenotype. Rating Amber awaiting additional cases prior to inclusion as diagnostic-grade.
Arthrogryposis v3.47 NUP88 Arina Puzriakova Gene: nup88 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.165 NUP88 Arina Puzriakova Tag watchlist tag was added to gene: NUP88.
Fetal anomalies v1.165 NUP88 Arina Puzriakova Classified gene: NUP88 as Amber List (moderate evidence)
Fetal anomalies v1.165 NUP88 Arina Puzriakova Added comment: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). Two unrelated families with lethal FADS and different biallelic variants in the NUP88 gene (PMID: 30543681). Zebrafish model recapitulated some human phenotypes such as locomotor and neuromuscular junction defects.

NUP88 is associated with a relevant phenotype in OMIM but is not currently in Gene2Phenotype. Fetally-relevant phenotype but additional cases required prior to inclusion as diagnostic-grade. Added 'watchlist' tag.
Fetal anomalies v1.165 NUP88 Arina Puzriakova Gene: nup88 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.72 KIF1A Zornitza Stark gene: KIF1A was added
gene: KIF1A was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: KIF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF1A were set to 32096284; 32935419
Phenotypes for gene: KIF1A were set to Dystonia; spastic paraplegia; intellectual disability
Review for gene: KIF1A was set to GREEN
gene: KIF1A was marked as current diagnostic
Added comment: Dystonia was a feature of the phenotype in 4/10 cases with de novo or parental germline mosaic variants.
Sources: Literature
Neurological ciliopathies v1.14 CBY1 Zornitza Stark gene: CBY1 was added
gene: CBY1 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: CBY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBY1 were set to 33131181; 25103236; 25220153
Phenotypes for gene: CBY1 were set to intellectual disability; cerebellar ataxia; molar tooth sign; polydactyly; Joubert syndrome
Review for gene: CBY1 was set to GREEN
gene: CBY1 was marked as current diagnostic
Added comment: Three cases in two unrelated consanguineous families with homozygous loss of function variants, with ID as a feature of the phenotype. Multiple null model organisms recapitulate the human phenotype: Null mouse model had cystic kidneys, a phenotype common to ciliopathies. Reducing Cby levels in Xenopus laevis model reduced the density of multiciliated cells, the number of basal bodies per multiciliated cell, and the numbers of neural tube primary cilia; it also led to abnormal development of the neural crest, central nervous system, and pronephros. Depletion of cby1 in zebrafish results in ciliopathy‐related phenotypes.
Sources: Literature
Skeletal dysplasia v2.70 TMEM251 Zornitza Stark gene: TMEM251 was added
gene: TMEM251 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM251 were set to 33252156
Phenotypes for gene: TMEM251 were set to Dysostosis multiplex‐like skeletal dysplasia; severe short stature
Review for gene: TMEM251 was set to AMBER
Added comment: Two unrelated consanguineous families with homozygous variants (c.133C>T; p.Arg45Trp and c.215dupA; p.Tyr72Ter), with co-segregation data in one family. Preliminary in vitro functional assays conducted - Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes.
Sources: Literature
Fetal anomalies v1.164 NUP88 Arina Puzriakova Publications for gene: NUP88 were set to PMID: 30543681
Fetal anomalies v1.163 NUP88 Arina Puzriakova Phenotypes for gene: NUP88 were changed from fetal akinesia to Fetal akinesia deformation sequence 4, OMIM:618393; Fetal akinesia deformation sequence 4, MONDO:0100104
Skeletal dysplasia v2.70 GZF1 Eleanor Williams Phenotypes for gene: GZF1 were changed from Larsen syndrome to Larsen syndrome; joint laxity, short stature, and myopia OMIM:617662; joint laxity, short stature, and myopia MONDO:0060556
Skeletal dysplasia v2.69 GZF1 Eleanor Williams Publications for gene: GZF1 were set to 28475863
Skeletal dysplasia v2.68 GZF1 Eleanor Williams Classified gene: GZF1 as Amber List (moderate evidence)
Skeletal dysplasia v2.68 GZF1 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as amber for now, but with a recommendation of green following GMS review.
Skeletal dysplasia v2.68 GZF1 Eleanor Williams Gene: gzf1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.67 GZF1 Eleanor Williams edited their review of gene: GZF1: Added comment: Associated with Joint laxity, short stature, and myopia #617662 (AR) in OMIM.

As reported by Zornitza Stark, PMID: 33009817 (Zeng et al 2020) reported two Chinese sisters who presented with severe myopia, scoliosis and hearing loss. Using WES they identified two compound heterozygous variants in GZF1 (c.397400del, p. Leu133fs; c.1474del, p. Met492fs). The parents were heterozygous carriers of the variants. Functional data showed decreased levels of HA‐tagged M492fs‐GZF1 protein and no HA-tagged L133fs‐GZF1 protein or the control vector. HA‐tagged M492fs‐GZF1 protein was also localized to the cytoplasm rather than the nuclei in which wild type protein was found.

This now brings the case number to 3.; Changed rating: GREEN; Changed publications: 33009817; Changed phenotypes: joint laxity, short stature, and myopia OMIM:617662, joint laxity, short stature, and myopia MONDO:0060556; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.67 MBTPS1 Eleanor Williams Tag for-review tag was added to gene: MBTPS1.
Skeletal dysplasia v2.67 MBTPS1 Eleanor Williams Phenotypes for gene: MBTPS1 were changed from Skeletal dysplasia to Skeletal dysplasia; ?Spondyloepiphyseal dysplasia, Kondo-Fu type OMIM:618392; spondyloepiphyseal dysplasia, kondo-fu type MONDO:0032721
Skeletal dysplasia v2.66 MBTPS1 Eleanor Williams Publications for gene: MBTPS1 were set to 32857899; 32420688; 30046013
Skeletal dysplasia v2.65 MBTPS1 Eleanor Williams Classified gene: MBTPS1 as Amber List (moderate evidence)
Skeletal dysplasia v2.65 MBTPS1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with recommendation of green rating following GMS review. 3 independent cases reported with biallelic variants in this gene and a skeletal phenotype.
Skeletal dysplasia v2.65 MBTPS1 Eleanor Williams Gene: mbtps1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.64 MBTPS1 Eleanor Williams reviewed gene: MBTPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32857899, 32420688, 30046013, 31070020; Phenotypes: ?Spondyloepiphyseal dysplasia, Kondo-Fu type OMIM:618392, spondyloepiphyseal dysplasia, kondo-fu type MONDO:0032721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.64 PLCB3 Eleanor Williams Phenotypes for gene: PLCB3 were changed from Spondylometaphyseal dysplasia with corneal dystrophy, MIM# 618961 to Spondylometaphyseal dysplasia with corneal dystrophy OMIM:618961; spondylometaphyseal dysplasia with corneal dystrophy MONDO:0030074
Skeletal dysplasia v2.63 PLCB3 Eleanor Williams Classified gene: PLCB3 as Red List (low evidence)
Skeletal dysplasia v2.63 PLCB3 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red. 1 case reported and some functional data showing the effect on protein levels of the variant found.
Skeletal dysplasia v2.63 PLCB3 Eleanor Williams Gene: plcb3 has been classified as Red List (Low Evidence).
Skeletal dysplasia v2.62 PLCB3 Eleanor Williams reviewed gene: PLCB3: Rating: RED; Mode of pathogenicity: None; Publications: 29122926; Phenotypes: Spondylometaphyseal dysplasia with corneal dystrophy OMIM:618961, spondylometaphyseal dysplasia with corneal dystrophy MONDO:0030074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.62 ANO5 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance at BIALLELIC just now, but it should be changed to MONOALLELIC at the next GMS review.
Skeletal dysplasia v2.62 ANO5 Eleanor Williams Mode of inheritance for gene: ANO5 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.61 ANO5 Eleanor Williams Phenotypes for gene: ANO5 were changed from Gnatodiaphyseal dysplasia; Osteogenesis Imperfecta and Decreased Bone Density; skeletal dysplasias; skeletal dysplasias; Disproportionate Short Stature to Gnathodiaphyseal dysplasia OMIM:166260; gnathodiaphyseal dysplasia MONDO:0008151; Osteogenesis Imperfecta and Decreased Bone Density; skeletal dysplasias; skeletal dysplasias; Disproportionate Short Stature
Skeletal dysplasia v2.60 ANO5 Eleanor Williams Publications for gene: ANO5 were set to
Skeletal dysplasia v2.59 ANO5 Eleanor Williams Added comment: Comment on mode of pathogenicity: The missense variants seen in patients with Gnathodiaphyseal dysplasia are thought to act by gain-of-function
Skeletal dysplasia v2.59 ANO5 Eleanor Williams Mode of pathogenicity for gene: ANO5 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
Skeletal dysplasia v2.58 ANO5 Eleanor Williams edited their review of gene: ANO5: Added comment: Associated with Gnathodiaphyseal dysplasia #166260 in OMIM with an autosomal dominant mode of inheritance. Two types of muscular dystrophy are listed with a autosomal recessive mode of inheritance.

ANO5 is also known as GDD1 and TMEM16E.

PMID: 15124103 - Tsutsumi et al 2004 - identified two heterozygous missense mutations (C356R and C356G) in ANO5/GDD1 in probands from a Japanese and an African American family with gnathodiaphyseal dysplasia.

PMID: 23047743 - Marconi et al 2013 - sequenced the ANO5 gene in a large Italian family with gnathodiaphyseal dysplasia. They identified a novel heterozygous missense mutation c.1538C-T, T513I. The mutation segregates with the disease in the family.

PMID: 32112655 - Di Zanni et al 2020 - used HEK293‐based functional assays to investigate the effects of a series of amino acid exchanges, related either to MD or GDD, at the level of the TMEM16E protein. They find a loss of TMEM16E activity for those associated with MD, and a gain‐of‐function phenotype for seven GDD‐causing mutations.; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 15124103, 23047743, 32112655; Changed phenotypes: Gnathodiaphyseal dysplasia OMIM:166260, gnathodiaphyseal dysplasia MONDO:0008151; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.31 UBA2 Eleanor Williams Classified gene: UBA2 as Amber List (moderate evidence)
Limb disorders v2.31 UBA2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber as there are 2 cases with variants in this gene and ectrodactyly reported. Also currently on the Skeletal dysplasia panel as amber.
Limb disorders v2.31 UBA2 Eleanor Williams Gene: uba2 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.30 UBA2 Eleanor Williams gene: UBA2 was added
gene: UBA2 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: UBA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBA2 were set to 31332306; 24243649; 29988626; 31587267
Phenotypes for gene: UBA2 were set to split hand-foot malformation MONDO:0016576; aplasia cutis congenita (disease) MONDO:0007145; ectrodactyly
Review for gene: UBA2 was set to AMBER
Added comment: Two reports of SNV in UBA2 in patients with split-hand/foot malformation. There are also reports of microdeletions including the UBA2 gene in 2 patients with split-hand/foot malformation/ectrodactyly

PMID: 31332306 - Yamoto et al 2019 - report one Japanese patient (38-II-1) with split-hand/foot malformation and a de novo c.1324dupT p.(Tyr442Leufs17) variant in UBA2 was found by exome sequencing. Not found in gnomAD. The UBA2 gene was considered a candidate gene because deletion of the region containing this gene (19q13.11) was found in a SHFM patient in this study using aCGH (patient 26-II-3) and in two other studies where microdeletions encompassing the UBA2 gene (among many other genes) were found in singular patients with ectrodactyly; PMID: 24243649 Chowdhury et al 2013 and PMID: 29988626 Abe et al 2019.

PMID: 31587267 - mother and son with aplasia cutis congenita. The son also has bilateral ectrodactyly, a horseshoe kidney, low‐lying conus medullaris and tracheo‐oesophageal fistula. WES identified a heterozygous deletion at c.327delT of UBA2, which leads to a frameshift and early top codon, in both the son and his mother.
Sources: Literature
Skeletal dysplasia v2.58 UBA2 Eleanor Williams edited their review of gene: UBA2: Changed phenotypes: split hand-foot malformation MONDO:0016576, aplasia cutis congenita (disease) MONDO:0007145, ectrodactyly
Intellectual disability v3.716 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Developmental delay to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Intellectual disability v3.715 TRAPPC12 Arina Puzriakova Publications for gene: TRAPPC12 were set to 28777934
Intellectual disability v3.714 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669, Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.260 TRAPPC12 Arina Puzriakova Publications for gene: TRAPPC12 were set to 28777934
Skeletal dysplasia v2.58 UBA2 Eleanor Williams Phenotypes for gene: UBA2 were changed from Split-Hand/Foot Malformation; Aplasia Cutis Congenita; Ectrodactyly to split hand-foot malformation MONDO:0016576; aplasia cutis congenita (disease) MONDO:0007145; Ectrodactyly
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Classified gene: TRAPPC12 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Added comment: Comment on list classification: With addition of the recently reported case, there are now at least 3 unrelated patients with epilepsy and biallelic variants in this gene (PMIDs: 28777934 and 32369837).

This now reaches threshold for inclusion as diagnostic-grade, and therefore TRAPPC12 can be promoted to Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.57 UBA2 Eleanor Williams Publications for gene: UBA2 were set to 31332306; 31587267
Skeletal dysplasia v2.56 UBA2 Eleanor Williams Classified gene: UBA2 as Amber List (moderate evidence)
Skeletal dysplasia v2.56 UBA2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber as there are two cases with SNVs reported.
Skeletal dysplasia v2.56 UBA2 Eleanor Williams Gene: uba2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.55 UBA2 Eleanor Williams edited their review of gene: UBA2: Changed rating: AMBER; Changed publications: 31332306, 24243649, 29988626, 31587267; Changed phenotypes: split hand-foot malformation MONDO:0016576, aplasia cutis congenita (disease) MONDO:0007145; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC12.
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.55 UBA2 Eleanor Williams commented on gene: UBA2
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Severe microcephaly v2.74 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Severe microcephaly v2.73 TRAPPC12 Arina Puzriakova Classified gene: TRAPPC12 as Amber List (moderate evidence)
Severe microcephaly v2.73 TRAPPC12 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) - sufficient unrelated published cases, plus an internally diagnosed individual; where measurements were indicated (3/5 cases), microcephaly was of relevant severity to this panel (<−3 SD)
Severe microcephaly v2.73 TRAPPC12 Arina Puzriakova Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.72 TRAPPC12 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC12.
Severe microcephaly v2.72 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777934, 32369837; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669, Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696; Mode of inheritance: None
COVID-19 research v1.73 IFNG Eleanor Williams Mode of inheritance for gene: IFNG was changed from to Unknown
Adult onset neurodegenerative disorder v2.38 ATN1_CAG Arina Puzriakova Tag for-review was removed from STR: ATN1_CAG.
Adult onset neurodegenerative disorder v2.38 ATN1_CAG Arina Puzriakova Tag for-review tag was added to STR: ATN1_CAG.
Clefting v2.20 HYAL2 Ivone Leong Tag for-review tag was added to gene: HYAL2.
Monogenic hearing loss v2.146 COL9A3 Eleanor Williams commented on gene: COL9A3: Removed the for-review tag as this gene is not a candidate for promoting to green as there are only two cases. However, once a decision is made about including Stickler syndrome green genes (e.g. COL9A1) or not on this panel, this gene may need further revision as regards to rating.
Cystic kidney disease v2.23 COL4A4 Ivone Leong Tag for-review tag was added to gene: COL4A4.
Intellectual disability v3.714 SMG8 Ivone Leong Tag for-review tag was added to gene: SMG8.
Intellectual disability v3.714 NUP214 Arina Puzriakova Tag for-review was removed from gene: NUP214.
Intellectual disability v3.714 NARS Ivone Leong Tag for-review tag was added to gene: NARS.
Clefting v2.20 POLR1B Eleanor Williams changed review comment from: Comment on list classification: Promoting from red to amber but with green recommendation. 3 cases reported in which cleft palate was a feature.; to: Comment on list classification: Promoting from red to amber but with green recommendation following phenotype review by the GMS. 3 cases reported in which cleft palate was a feature.
Clefting v2.20 POLR1B Eleanor Williams Classified gene: POLR1B as Amber List (moderate evidence)
Clefting v2.20 POLR1B Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with green recommendation. 3 cases reported in which cleft palate was a feature.
Clefting v2.20 POLR1B Eleanor Williams Gene: polr1b has been classified as Amber List (Moderate Evidence).
Clefting v2.19 POLR1B Eleanor Williams Tag for-review tag was added to gene: POLR1B.
Clefting v2.19 POLR1B Eleanor Williams changed review comment from: Associated with Treacher-Collins syndrome 4 #618939 (AD) in OMIM

PMID: 31649276 - Sanchez et al 2020 - using exome sequencing they identified 6 patients (5 unrelated families) with heterozygous missense variants in POLR1B. In 3 cases the variants were de novo. One was inherited from the mother, and one from the father who was mosaic for the variant. 3 different variants are reported. The clinical phenotype was variable but all patients were reported with downward slanting palpebral fissures, Malar hypoplasia, and Conductive deafness, and 3 individuals from 3 different families had dleft palate. Morphilino knockdown of polr1b showed abnormal craniofacial development of zebrafish embryos
Sources: Literature; to: Associated with Treacher-Collins syndrome 4 #618939 (AD) in OMIM

PMID: 31649276 - Sanchez et al 2020 - using exome sequencing they identified 6 patients (5 unrelated families) with heterozygous missense variants in POLR1B. In 3 cases the variants were de novo. One was inherited from the mother, and one from the father who was mosaic for the variant. 3 different variants are reported. The clinical phenotype was variable but all patients were reported with downward slanting palpebral fissures, Malar hypoplasia, and Conductive deafness, and 3 individuals from 3 different families had cleft palate. Morphilino knockdown of polr1b showed abnormal craniofacial development of zebrafish embryos
Sources: Literature
Clefting v2.19 POLR1B Eleanor Williams gene: POLR1B was added
gene: POLR1B was added to Clefting. Sources: Literature
Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR1B were set to 31649276
Phenotypes for gene: POLR1B were set to Treacher-Collins syndrome 4 OMIM:618939; treacher collins syndrome 4 MONDO:0030067
Review for gene: POLR1B was set to GREEN
Added comment: Associated with Treacher-Collins syndrome 4 #618939 (AD) in OMIM

PMID: 31649276 - Sanchez et al 2020 - using exome sequencing they identified 6 patients (5 unrelated families) with heterozygous missense variants in POLR1B. In 3 cases the variants were de novo. One was inherited from the mother, and one from the father who was mosaic for the variant. 3 different variants are reported. The clinical phenotype was variable but all patients were reported with downward slanting palpebral fissures, Malar hypoplasia, and Conductive deafness, and 3 individuals from 3 different families had dleft palate. Morphilino knockdown of polr1b showed abnormal craniofacial development of zebrafish embryos
Sources: Literature
Skeletal dysplasia v2.55 POLR1B Eleanor Williams Tag for-review tag was added to gene: POLR1B.
Skeletal dysplasia v2.55 POLR1B Eleanor Williams Phenotypes for gene: POLR1B were changed from Treacher-Collins syndrome type 4 to Treacher-Collins syndrome 4 OMIM:618939; treacher collins syndrome 4 MONDO:0030067
Skeletal dysplasia v2.54 POLR1B Eleanor Williams Classified gene: POLR1B as Amber List (moderate evidence)
Skeletal dysplasia v2.54 POLR1B Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, with a recommendation for a green rating following GMS review. 5 families reported plus supportive zebrafish model.
Skeletal dysplasia v2.54 POLR1B Eleanor Williams Gene: polr1b has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.53 POLR1B Eleanor Williams edited their review of gene: POLR1B: Changed rating: GREEN; Changed publications: 31649276; Changed phenotypes: Treacher-Collins syndrome 4 OMIM:618939, treacher collins syndrome 4 MONDO:0030067; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.53 POLR1B Eleanor Williams commented on gene: POLR1B
DDG2P v2.18 TRAPPC12 Arina Puzriakova Mode of inheritance for gene: TRAPPC12 was changed from to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.162 TRAPPC12 Arina Puzriakova Classified gene: TRAPPC12 as Amber List (moderate evidence)
Fetal anomalies v1.162 TRAPPC12 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as currently there are not enough unrelated cases with a fetally-relevant phenotype to promote to Green. Added 'watchlist' tag.
Fetal anomalies v1.162 TRAPPC12 Arina Puzriakova Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.161 TRAPPC12 Arina Puzriakova Publications for gene: TRAPPC12 were set to
Fetal anomalies v1.160 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Progressive Childhood Encephalopathy and Golgi Dysfunction to Hydrocephaly; Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Fetal anomalies v1.159 TRAPPC12 Arina Puzriakova Mode of inheritance for gene: TRAPPC12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.158 TRAPPC12 Arina Puzriakova commented on gene: TRAPPC12: Removed 'polygenic' tag as published cases revealed no evidence to indicate polygenic inheritance
Skeletal dysplasia v2.53 PKDCC Eleanor Williams Classified gene: PKDCC as Amber List (moderate evidence)
Skeletal dysplasia v2.53 PKDCC Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. 2 cases plus mouse knockout, with a similar but not exactly the same phenotype to the cases reported.
Skeletal dysplasia v2.53 PKDCC Eleanor Williams Gene: pkdcc has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.158 TRAPPC12 Arina Puzriakova Tag polygenic was removed from gene: TRAPPC12.
Tag watchlist tag was added to gene: TRAPPC12.
Skeletal dysplasia v2.52 PKDCC Eleanor Williams reviewed gene: PKDCC: Rating: AMBER; Mode of pathogenicity: None; Publications: 30478137, 19097194; Phenotypes: Rhizomelic limb shortening with dysmorphic features OMIM:618821, rhizomelic limb shortening with dysmorphic features MONDO:0032935; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.158 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: AMBER; Mode of pathogenicity: None; Publications: 32347653, 28777934; Phenotypes: Hydrocephaly, Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669, Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.52 MIA3 Eleanor Williams Classified gene: MIA3 as Red List (low evidence)
Skeletal dysplasia v2.52 MIA3 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red based on 1 family reported so far.
Skeletal dysplasia v2.52 MIA3 Eleanor Williams Gene: mia3 has been classified as Red List (Low Evidence).
Skeletal dysplasia v2.51 MIA3 Eleanor Williams Phenotypes for gene: MIA3 were changed from short stature; skeletal dysplasia; amelogenesis to short stature; skeletal dysplasia; amelogenesis; dentinogenesis imperfecta; short stature; brachydactyly; Platyspondyly; insulin-dependent diabetes mellitus; sensorineural hearing loss; mild intellectual disability
Skeletal dysplasia v2.50 MIA3 Eleanor Williams reviewed gene: MIA3: Rating: RED; Mode of pathogenicity: None; Publications: 32101163; Phenotypes: dentinogenesis imperfecta, short stature, brachydactyly, Platyspondyly, insulin-dependent diabetes mellitus, sensorineural hearing loss, mild intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.50 RINT1 Eleanor Williams Phenotypes for gene: RINT1 were changed from liver failure; short stature; skeletal abnormalities to liver failure; short stature; skeletal abnormalities; Infantile liver failure syndrome 3 OMIM:618641; infantile liver failure syndrome 3 MONDO:0032844
Skeletal dysplasia v2.49 RINT1 Eleanor Williams Publications for gene: RINT1 were set to PMID: 31204009
Skeletal dysplasia v2.48 RINT1 Eleanor Williams Classified gene: RINT1 as Amber List (moderate evidence)
Skeletal dysplasia v2.48 RINT1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for a green rating following GMS review. 3 cases with compound het variants in this gene.
Skeletal dysplasia v2.48 RINT1 Eleanor Williams Gene: rint1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.47 RINT1 Eleanor Williams Tag for-review tag was added to gene: RINT1.
Skeletal dysplasia v2.47 RINT1 Eleanor Williams edited their review of gene: RINT1: Changed rating: GREEN; Changed publications: 31204009; Changed phenotypes: Infantile liver failure syndrome 3 OMIM:618641, infantile liver failure syndrome 3 MONDO:0032844; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.47 RINT1 Eleanor Williams commented on gene: RINT1
Structural eye disease v1.42 DYRK1A Ivone Leong Classified gene: DYRK1A as Amber List (moderate evidence)
Structural eye disease v1.42 DYRK1A Ivone Leong Added comment: Comment on list classification: New gene added by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust). There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at the next review.
Structural eye disease v1.42 DYRK1A Ivone Leong Gene: dyrk1a has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.41 DYRK1A Ivone Leong Tag for-review tag was added to gene: DYRK1A.
Structural eye disease v1.41 CDK5RAP2 Ivone Leong Classified gene: CDK5RAP2 as Amber List (moderate evidence)
Structural eye disease v1.41 CDK5RAP2 Ivone Leong Added comment: Comment on list classification: New gene added by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust). There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Structural eye disease v1.41 CDK5RAP2 Ivone Leong Gene: cdk5rap2 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.40 CDK5RAP2 Ivone Leong Tag watchlist tag was added to gene: CDK5RAP2.
Structural eye disease v1.40 WDR37 Ivone Leong Classified gene: WDR37 as Amber List (moderate evidence)
Structural eye disease v1.40 WDR37 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Structural eye disease v1.40 WDR37 Ivone Leong Gene: wdr37 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.39 WDR37 Ivone Leong Tag for-review tag was added to gene: WDR37.
Structural eye disease v1.39 WDR37 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BIALLELIC, autosomal or pseudoautosomal" to "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown".
Structural eye disease v1.39 WDR37 Ivone Leong Mode of inheritance for gene: WDR37 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v1.38 WDR37 Ivone Leong Phenotypes for gene: WDR37 were changed from corneal opacity; Peters anomaly; coloboma; microcornea to corneal opacity; Peters anomaly; coloboma; microcornea; Neurooculocardiogenitourinary syndrome, OMIM:61865, MONDO:0032850
Structural eye disease v1.37 TOGARAM1 Ivone Leong Classified gene: TOGARAM1 as Amber List (moderate evidence)
Structural eye disease v1.37 TOGARAM1 Ivone Leong Added comment: Comment on list classification: New gene added by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust). Based on the available evidence this gene has been given an Amber rating.
Structural eye disease v1.37 TOGARAM1 Ivone Leong Gene: togaram1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.36 TOGARAM1 Ivone Leong Tag watchlist tag was added to gene: TOGARAM1.
Structural eye disease v1.36 CDON Ivone Leong Classified gene: CDON as Amber List (moderate evidence)
Structural eye disease v1.36 CDON Ivone Leong Added comment: Comment on list classification: New gene added by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust). This gene should be promoted from Amber to Green at the next review.
Structural eye disease v1.36 CDON Ivone Leong Gene: cdon has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.35 CDON Ivone Leong Tag for-review tag was added to gene: CDON.
Structural eye disease v1.35 FZD5 Ivone Leong commented on gene: FZD5: This gene should be promoted from Amber to Green at the next review.
Structural eye disease v1.35 FZD5 Ivone Leong Publications for gene: FZD5 were set to 26908622
Structural eye disease v1.34 FZD5 Ivone Leong Tag for-review tag was added to gene: FZD5.
Structural eye disease v1.34 RHOA Ivone Leong Classified gene: RHOA as Amber List (moderate evidence)
Structural eye disease v1.34 RHOA Ivone Leong Added comment: Comment on list classification: New gene added by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust). Based on the available evidence this gene has been given an Amber rating.
Structural eye disease v1.34 RHOA Ivone Leong Gene: rhoa has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.33 RHOA Ivone Leong Tag watchlist tag was added to gene: RHOA.
Structural eye disease v1.33 CENPF Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber. This gene should be promoted to Green status when the panel is reviewed.; to: Comment on list classification: New gene added by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust). This gene should be promoted to Green status when the panel is reviewed.
Structural eye disease v1.33 NUP188 Ivone Leong Tag watchlist tag was added to gene: NUP188.
Structural eye disease v1.33 NUP188 Ivone Leong Classified gene: NUP188 as Amber List (moderate evidence)
Structural eye disease v1.33 NUP188 Ivone Leong Added comment: Comment on list classification: New gene added by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust). This gene has been promoted from Red to Amber based on available evidence.
Structural eye disease v1.33 NUP188 Ivone Leong Gene: nup188 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.73 TSPYL1 Eleanor Williams Classified gene: TSPYL1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.73 TSPYL1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, but with a green recommendation for GMS review. 3 cases reported.
Paediatric disorders - additional genes v1.73 TSPYL1 Eleanor Williams Gene: tspyl1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.72 TSPYL1 Eleanor Williams Tag for-review tag was added to gene: TSPYL1.
Structural eye disease v1.32 SEMA3E Ivone Leong Publications for gene: SEMA3E were set to
Paediatric disorders - additional genes v1.72 TSPYL1 Eleanor Williams changed review comment from: Associated with Sudden infant death with dysgenesis of the testes syndrome #608800 (AR) in OMIM.

3 independent cases with biallelic variants in TSPYL1 in patients with Sudden Infant Death with Dysgenesis of the Testes syndrome reported.

PMID: 32885560 - Slater et al 2020 - report a Hispanic, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Mild T-cell lymphopenia, absent uterus and adnexal structures, with no gonads visible and intractable epilepsy are also reported. The patient died of respiratory failure at 8 months of age. Exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52). The variant has a frequency of 0.002% in gnomAD but has not been reported in the homozygous state.

PMID: 33075815 - Buyse et al 2020 - report 3 affected siblings from a consanguineous Turkish family. The phenotype was characterized by visceroautonomic dysfunction, severe postnatal progressive neurological abnormalities, visual impairment, testicular dysgenesis in males and sudden death at infant age. WES analysis found a homozygous frameshift variant p.Val242GlufsTer52 in TSPYL1 in the affected siblings. The variant is found in gnomAD at a MAF of 0.0021%, but no homozygous individuals are reported. The parents and one unaffected sibling were heterozygous for the variant. The truncated protein was retained in the Golgi in patient fibroblasts whereas in control fibroblasts the full length protein was found in the nucleus. Patient cells also showed prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depleted zebrafish showed a similar phenotype with early lethality, defects in neurogenesis and cardiac dilation.

PMID: 15273283 - Puffenberger et al 2004 - report 21 individuals from a large Old Order Amish kinship with a phenotype of sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males. A homozygous frameshift mutation c.457dupG (p.Glu153Glyfs*17) was detected after autozygosity scanning and sequencing of the the TSPYL (now known as TSPYL1) gene. All parents were heterozygous for the mutation. Functional experiments showed that there was a loss of nuclear localization of truncated TSPYL

Two reports where SIDS cases were screened for TSPYL1 variants but only heterozygous variants were found:

PMID: 25449952 - Schubert et al 2015 - screened TSPYL1 in 165 SIDS cases with mostly Swiss ethnic origin, and 163 German control adults. 8 known polymorphisms were detected, 3 affected individuals were found to have rare heterozygous missense variants (1 x c.106C>G (p.Leu36Val), 2 x c.1098C>A, p.Phe366Leu). The p.Phe366Leu variants was also found in a control individual. 2 silent rare variants were also found (1 case, 1 control).

PMID: 16418600 - Hering et al 2006 - screen TSPYL1 in 126 SIDS cases and 261 controls. Found one female one female patient with a heterozygous p.F366L amino acid polymorphism which was not found in the controls. Concluded that the genetic analysis of TSPYL1 was of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.

Reports where male infertility cases were screened for TSPYL1 variants:

PMID: 19463995 - Vinci et al 2009 - screened 100 individuals with anomalies of testicular development or function for mutations in the TSPYL1 gene. 2 heterozygous variants reported. One in a 46,XY female with complete gonadal dysgenesis (p.K320R in the conserved NAP domain) and a 46,XY male with idiopathic azoospermia (p.R89H).

PMID: 22137496 - Javaher et al 2012 - screen 104 infertile men for variants in TSPYL1. 2 potentially pathogenic heterozygous variants identified. 1 with azoospermia had a c.419C>G (p.Ser140Cys) variant and 1 with OAT syndrome had the rare c.1098C>A (p.Phe366Leu). However, 1 fertile man was also found to be heterozygous for the rare variant c.487G>A (p.Val163Ile). The authors concluded that TSPYL1 variants did not play a major role in idiopathic male infertility and would not recommend inclusion in diagnostic screening.
Sources: Literature; to: Associated with Sudden infant death with dysgenesis of the testes syndrome #608800 (AR) in OMIM.

3 independent cases with biallelic variants in TSPYL1 in patients with Sudden Infant Death with Dysgenesis of the Testes syndrome reported.

PMID: 32885560 - Slater et al 2020 - report a Hispanic, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Mild T-cell lymphopenia, absent uterus and adnexal structures, with no gonads visible and intractable epilepsy are also reported. The patient died of respiratory failure at 8 months of age. Exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52). The variant has a frequency of 0.002% in gnomAD but has not been reported in the homozygous state.

PMID: 33075815 - Buyse et al 2020 - report 3 affected siblings from a consanguineous Turkish family. The phenotype was characterized by visceroautonomic dysfunction, severe postnatal progressive neurological abnormalities, visual impairment, testicular dysgenesis in males and sudden death at infant age. WES analysis found a homozygous frameshift variant p.Val242GlufsTer52 in TSPYL1 in the affected siblings. The variant is found in gnomAD at a MAF of 0.0021%, but no homozygous individuals are reported. The parents and one unaffected sibling were heterozygous for the variant. The truncated protein was retained in the Golgi in patient fibroblasts whereas in control fibroblasts the full length protein was found in the nucleus. Patient cells also showed prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depleted zebrafish showed a similar phenotype with early lethality, defects in neurogenesis and cardiac dilation.

PMID: 15273283 - Puffenberger et al 2004 - report 21 individuals from a large Old Order Amish kinship with a phenotype of sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males. A homozygous frameshift mutation c.457dupG (p.Glu153Glyfs*17) was detected after autozygosity scanning and sequencing of the the TSPYL (now known as TSPYL1) gene. All parents were heterozygous for the mutation. Functional experiments showed that there was a loss of nuclear localization of truncated TSPYL

Two reports where SIDS cases were screened for TSPYL1 variants but only heterozygous variants were found:

PMID: 25449952 - Schubert et al 2015 - screened TSPYL1 in 165 SIDS cases with mostly Swiss ethnic origin, and 163 German control adults. 8 known polymorphisms were detected, 3 affected individuals were found to have rare heterozygous missense variants (1 x c.106C>G (p.Leu36Val), 2 x c.1098C>A, p.Phe366Leu). The p.Phe366Leu variants was also found in a control individual. 2 silent rare variants were also found (1 case, 1 control).

PMID: 16418600 - Hering et al 2006 - screen TSPYL1 in 126 SIDS cases and 261 controls. Found one female one female patient with a heterozygous p.F366L amino acid polymorphism which was not found in the controls. Concluded that the genetic analysis of TSPYL1 was of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.
Structural eye disease v1.31 CENPF Ivone Leong Classified gene: CENPF as Amber List (moderate evidence)
Structural eye disease v1.31 CENPF Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene should be promoted to Green status when the panel is reviewed.
Structural eye disease v1.31 CENPF Ivone Leong Gene: cenpf has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.72 TSPYL1 Eleanor Williams gene: TSPYL1 was added
gene: TSPYL1 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: TSPYL1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TSPYL1 were set to Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Review for gene: TSPYL1 was set to GREEN
Added comment: Associated with Sudden infant death with dysgenesis of the testes syndrome #608800 (AR) in OMIM.

3 independent cases with biallelic variants in TSPYL1 in patients with Sudden Infant Death with Dysgenesis of the Testes syndrome reported.

PMID: 32885560 - Slater et al 2020 - report a Hispanic, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Mild T-cell lymphopenia, absent uterus and adnexal structures, with no gonads visible and intractable epilepsy are also reported. The patient died of respiratory failure at 8 months of age. Exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52). The variant has a frequency of 0.002% in gnomAD but has not been reported in the homozygous state.

PMID: 33075815 - Buyse et al 2020 - report 3 affected siblings from a consanguineous Turkish family. The phenotype was characterized by visceroautonomic dysfunction, severe postnatal progressive neurological abnormalities, visual impairment, testicular dysgenesis in males and sudden death at infant age. WES analysis found a homozygous frameshift variant p.Val242GlufsTer52 in TSPYL1 in the affected siblings. The variant is found in gnomAD at a MAF of 0.0021%, but no homozygous individuals are reported. The parents and one unaffected sibling were heterozygous for the variant. The truncated protein was retained in the Golgi in patient fibroblasts whereas in control fibroblasts the full length protein was found in the nucleus. Patient cells also showed prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depleted zebrafish showed a similar phenotype with early lethality, defects in neurogenesis and cardiac dilation.

PMID: 15273283 - Puffenberger et al 2004 - report 21 individuals from a large Old Order Amish kinship with a phenotype of sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males. A homozygous frameshift mutation c.457dupG (p.Glu153Glyfs*17) was detected after autozygosity scanning and sequencing of the the TSPYL (now known as TSPYL1) gene. All parents were heterozygous for the mutation. Functional experiments showed that there was a loss of nuclear localization of truncated TSPYL

Two reports where SIDS cases were screened for TSPYL1 variants but only heterozygous variants were found:

PMID: 25449952 - Schubert et al 2015 - screened TSPYL1 in 165 SIDS cases with mostly Swiss ethnic origin, and 163 German control adults. 8 known polymorphisms were detected, 3 affected individuals were found to have rare heterozygous missense variants (1 x c.106C>G (p.Leu36Val), 2 x c.1098C>A, p.Phe366Leu). The p.Phe366Leu variants was also found in a control individual. 2 silent rare variants were also found (1 case, 1 control).

PMID: 16418600 - Hering et al 2006 - screen TSPYL1 in 126 SIDS cases and 261 controls. Found one female one female patient with a heterozygous p.F366L amino acid polymorphism which was not found in the controls. Concluded that the genetic analysis of TSPYL1 was of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.

Reports where male infertility cases were screened for TSPYL1 variants:

PMID: 19463995 - Vinci et al 2009 - screened 100 individuals with anomalies of testicular development or function for mutations in the TSPYL1 gene. 2 heterozygous variants reported. One in a 46,XY female with complete gonadal dysgenesis (p.K320R in the conserved NAP domain) and a 46,XY male with idiopathic azoospermia (p.R89H).

PMID: 22137496 - Javaher et al 2012 - screen 104 infertile men for variants in TSPYL1. 2 potentially pathogenic heterozygous variants identified. 1 with azoospermia had a c.419C>G (p.Ser140Cys) variant and 1 with OAT syndrome had the rare c.1098C>A (p.Phe366Leu). However, 1 fertile man was also found to be heterozygous for the rare variant c.487G>A (p.Val163Ile). The authors concluded that TSPYL1 variants did not play a major role in idiopathic male infertility and would not recommend inclusion in diagnostic screening.
Sources: Literature
Structural eye disease v1.30 CENPF Ivone Leong Tag for-review tag was added to gene: CENPF.
Structural eye disease v1.30 CRYBB1 Ivone Leong commented on gene: CRYBB1: This gene has been tagged "for-review" at the next GMS panel review and should be promoted to Green based on evidence provided by Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust).
Structural eye disease v1.30 CRYBB1 Ivone Leong Tag for-review tag was added to gene: CRYBB1.
Structural eye disease v1.30 CRYBB1 Ivone Leong Publications for gene: CRYBB1 were set to 29386872
Bilateral congenital or childhood onset cataracts v2.58 NUP188 Nicola Ragge reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: ; Publications: 32021605, 32275884; Phenotypes: Sandestig-Stefanove Syndrome, AR, MIM:618804; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.29 KIF26B Nicola Ragge reviewed gene: KIF26B: Rating: RED; Mode of pathogenicity: ; Publications: 26571382, 32799327; Phenotypes: ; Mode of inheritance:
Structural eye disease v1.29 DYRK1A Nicola Ragge reviewed gene: DYRK1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 28135719, 19081073; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v1.29 CDK5RAP2 Nicola Ragge reviewed gene: CDK5RAP2: Rating: AMBER; Mode of pathogenicity: ; Publications: 32015000, 31355417; Phenotypes: Microcephaly 3, primary, autosomal recessive, MIM:604804; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.29 WDR37 Nicola Ragge reviewed gene: WDR37: Rating: GREEN; Mode of pathogenicity: ; Publications: 31327510, 32530092; Phenotypes: Neurooculocardiogenitourinary syndrome, MIM:618652; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v1.29 TOGARAM1 Nicola Ragge reviewed gene: TOGARAM1: Rating: AMBER; Mode of pathogenicity: ; Publications: 32453716, 32747439; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.29 CDON Nicola Ragge reviewed gene: CDON: Rating: GREEN; Mode of pathogenicity: ; Publications: 32729136, 31502381, 31502381, 19754878; Phenotypes: Holoprosencephaly 11, MIM:614226; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.29 FZD5 Nicola Ragge edited their review of gene: FZD5: Added comment: Liu et al identified a rare heterozygous mutation cosegregating with coloboma. Zebrafish model showing role of gene in the phenotype. Aubert-Mucca et al. 2020: novel variants in three independent families.; Changed rating: GREEN; Changed publications: 26908622, 32737437; Set current diagnostic: yes
Structural eye disease v1.29 CAPN15 Nicola Ragge reviewed gene: CAPN15: Rating: GREEN; Mode of pathogenicity: ; Publications: 32885237; Phenotypes: ; Mode of inheritance:
Structural eye disease v1.29 RHOA Nicola Ragge reviewed gene: RHOA: Rating: AMBER; Mode of pathogenicity: ; Publications: 31821646, 31570889; Phenotypes: Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic, MIM:618727; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v1.29 NUP188 Nicola Ragge reviewed gene: NUP188: Rating: AMBER; Mode of pathogenicity: ; Publications: 32021605, 32275884; Phenotypes: Sandestig-Stefanove Syndrome, AR, MIM:618804; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.29 SEMA3E Nicola Ragge edited their review of gene: SEMA3E: Added comment: Lalani et al. published case with CHARGE syndrome including iris coloboma with a de novo missense mutation in SEMA3E as well as balanced translocation - not convincing. Liu et al. published a zebrafish knockout with small eyes. ; Changed publications: 15235037, 31464029
Structural eye disease v1.29 CENPF Nicola Ragge reviewed gene: CENPF: Rating: GREEN; Mode of pathogenicity: ; Publications: 8261651, 26820108, 28407396, 31953238; Phenotypes: Stromme syndrome, MIM:600236; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.29 RARA Nicola Ragge reviewed gene: RARA: Rating: RED; Mode of pathogenicity: ; Publications: 31343737; Phenotypes: ; Mode of inheritance:
Structural eye disease v1.29 CRYBB1 Nicola Ragge edited their review of gene: CRYBB1: Added comment: Sun: simplex case with cataract coloboma with a rare missense variant. ; Jin et al. 2019 have published large dominant pedigree with cataract and microphthalmia with novel missense variant segregating. Willougby reported a novel stoploss variant segregating in a family with cataract and microcornea.; Changed rating: GREEN; Changed publications: 31566446, 16110300; Set current diagnostic: yes
Structural eye disease v1.28 KIF26B Ivone Leong gene: KIF26B was added
gene: KIF26B was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: KIF26B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF26B were set to 26571382; 32799327
Structural eye disease v1.28 DYRK1A Ivone Leong gene: DYRK1A was added
gene: DYRK1A was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: DYRK1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DYRK1A were set to 19081073; 28135719
Phenotypes for gene: DYRK1A were set to Mental retardation, autosomal dominant 7, OMIM:614104
Structural eye disease v1.28 CDK5RAP2 Ivone Leong gene: CDK5RAP2 was added
gene: CDK5RAP2 was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: CDK5RAP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK5RAP2 were set to 31355417; 32015000
Phenotypes for gene: CDK5RAP2 were set to Microcephaly 3, primary, autosomal recessive, OMIM:604804, MONDO:0011488
Structural eye disease v1.28 TOGARAM1 Ivone Leong gene: TOGARAM1 was added
gene: TOGARAM1 was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: TOGARAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM1 were set to 32747439; 32453716
Phenotypes for gene: TOGARAM1 were set to TOGARAM1-related ciliopathy
Structural eye disease v1.28 CDON Ivone Leong gene: CDON was added
gene: CDON was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: CDON was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDON were set to 31502381; 19754878; 32729136
Phenotypes for gene: CDON were set to Holoprosencephaly 11, OMIM:614226, MONDO:0013642
Structural eye disease v1.28 RHOA Ivone Leong gene: RHOA was added
gene: RHOA was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: RHOA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RHOA were set to 31821646; 31570889
Phenotypes for gene: RHOA were set to ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, MONDO:0032884; Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic, OMIM:618727
Structural eye disease v1.28 NUP188 Ivone Leong gene: NUP188 was added
gene: NUP188 was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to 32021605; 32275884
Phenotypes for gene: NUP188 were set to Sandestig-Stefanova syndrome, OMIM:618804, MONDO:0032926
Structural eye disease v1.28 CENPF Ivone Leong gene: CENPF was added
gene: CENPF was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: CENPF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CENPF were set to 28407396; 8261651; 31953238; 26820108
Phenotypes for gene: CENPF were set to Stromme syndrome, OMIM:243605, MONDO:0009477
Clefting v2.18 AMOTL1 Eleanor Williams Classified gene: AMOTL1 as Red List (low evidence)
Clefting v2.18 AMOTL1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red. 2 cases but mouse model does not recapitulate the phenotype.
Clefting v2.18 AMOTL1 Eleanor Williams Gene: amotl1 has been classified as Red List (Low Evidence).
Clefting v2.17 AMOTL1 Eleanor Williams Phenotypes for gene: AMOTL1 were changed from Cleft lip and palate; imperforate anus; dysmorphism to cleft lip/palate MONDO:0016044; imperforate anus; dysmorphism
Clefting v2.16 AMOTL1 Eleanor Williams Publications for gene: AMOTL1 were set to 33026150
Clefting v2.15 AMOTL1 Eleanor Williams edited their review of gene: AMOTL1: Changed rating: RED
Clefting v2.15 AMOTL1 Eleanor Williams reviewed gene: AMOTL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33026150, 30375152; Phenotypes: cleft lip/palate MONDO:0016044; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Clefting v2.15 HYAL2 Eleanor Williams Phenotypes for gene: HYAL2 were changed from Cleft lip and palate, cor triatriatum to cleft lip/palate MONDO:0016044; triatrial heart MONDO:0015450
Clefting v2.14 HYAL2 Eleanor Williams Classified gene: HYAL2 as Amber List (moderate evidence)
Clefting v2.14 HYAL2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with recommendation for green rating following GMS review. This is based on 2 reported unrelated cases with different proposed causative variants in HYAL2, plus a mouse knockout model which replicates the human phenotype and some functional data reporting the effect of patient variants on protein levels.
Clefting v2.14 HYAL2 Eleanor Williams Gene: hyal2 has been classified as Amber List (Moderate Evidence).
Clefting v2.13 HYAL2 Eleanor Williams edited their review of gene: HYAL2: Changed rating: GREEN
Clefting v2.13 HYAL2 Eleanor Williams reviewed gene: HYAL2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28081210; Phenotypes: cleft lip/palate MONDO:0016044; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.72 SMO Eleanor Williams Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis to Microcephaly HP:0000252; postaxial polydactyly MONDO:0020927; congenital heart disease MONDO:0005453; Hirschsprung disease MONDO:0018309
Severe microcephaly v2.71 SMO Eleanor Williams Classified gene: SMO as Red List (low evidence)
Severe microcephaly v2.71 SMO Eleanor Williams Added comment: Comment on list classification: Comment on list classification: Promoting from grey to red. Although the expert reviewer recommends green, there is only one case in PMID: 32413283 where the patient is reported as having microcephaly.
Severe microcephaly v2.71 SMO Eleanor Williams Gene: smo has been classified as Red List (Low Evidence).
Familial Hirschsprung Disease v1.9 SMO Eleanor Williams changed review comment from: As reported by expert reviewer, PMID: 32413283 - Le et al 2020 , report biallelic variants in 7 individuals from 5 families that present with a wide spectrum of phenotypes in a condition that is distinct from Curry-Jones syndrome. However, the phenotype of only 1 proband included Hirschsprung disease.; to: As reported by expert reviewer, PMID: 32413283 - Le et al 2020 , report biallelic variants in 7 individuals from 5 families that present with a wide spectrum of phenotypes in a condition that is distinct from Curry-Jones syndrome. However, only 1 proband was reported as having Hirschsprung disease.
Severe microcephaly v2.70 SMO Eleanor Williams commented on gene: SMO
Familial Hirschsprung Disease v1.9 SMO Eleanor Williams Classified gene: SMO as Red List (low evidence)
Familial Hirschsprung Disease v1.9 SMO Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red. Although the expert reviewer recommends green, there is only one case in PMID: 32413283 where the patient is reported as having Hirschsprung disease.
Familial Hirschsprung Disease v1.9 SMO Eleanor Williams Gene: smo has been classified as Red List (Low Evidence).
Familial Hirschsprung Disease v1.8 SMO Eleanor Williams Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis; Hirschsprung disease MONDO:0018309 to postaxial polydactyly MONDO:0020927; Microcephaly HP:0000252; congenital heart disease MONDO:0005453; Hirschsprung disease MONDO:0018309
Familial Hirschsprung Disease v1.7 SMO Eleanor Williams Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis to Microcephaly, congenital heart disease, polydactyly, aganglionosis; Hirschsprung disease MONDO:0018309
Familial Hirschsprung Disease v1.6 SMO Eleanor Williams reviewed gene: SMO: Rating: RED; Mode of pathogenicity: None; Publications: 32413283; Phenotypes: Hirschsprung disease MONDO:0018309; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.20 UNC45B Sarah Leigh edited their review of gene: UNC45B: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Congenital myopathy v2.20 UNC45B Sarah Leigh changed review comment from: Comment on list classification: Not associated with relevant phenotype in OMIM (OMIM have beeb notified about PMID 33217308) and as probable Gen2Phen gene for UNC45B-associated Progressive Myopathy with Eccentric Cores. At least 5 variants reported in at least 6 apparently unrelated cases, together with supportive functional studies.; to: Comment on list classification: Not associated with relevant phenotype in OMIM (OMIM have been notified about PMID 33217308) and as probable Gen2Phen gene for UNC45B-associated Progressive Myopathy with Eccentric Cores. At least 5 variants reported in at least 6 apparently unrelated cases, together with supportive functional studies.
Congenital myopathy v2.20 UNC45B Sarah Leigh Added comment: Comment on phenotypes: UNC45B-associated Progressive Myopathy with Eccentric Cores (Gen2Phen)(https://www.ebi.ac.uk/gene2phenotype/gfd?search_type=gfd&dbID=4636). OMIM, MONDO and Orphanet have yet to list this phenotype (20210119)
Congenital myopathy v2.20 UNC45B Sarah Leigh Phenotypes for gene: UNC45B were changed from Progressive Myopathy with Eccentric Cores to Progressive Myopathy with Eccentric Cores
Congenital myopathy v2.19 UNC45B Sarah Leigh Classified gene: UNC45B as Amber List (moderate evidence)
Congenital myopathy v2.19 UNC45B Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM (OMIM have beeb notified about PMID 33217308) and as probable Gen2Phen gene for UNC45B-associated Progressive Myopathy with Eccentric Cores. At least 5 variants reported in at least 6 apparently unrelated cases, together with supportive functional studies.
Congenital myopathy v2.19 UNC45B Sarah Leigh Gene: unc45b has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.18 UNC45B Sarah Leigh Tag for-review tag was added to gene: UNC45B.
Malformations of cortical development v2.36 VLDLR Sarah Leigh edited their review of gene: VLDLR: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Malformations of cortical development v2.36 VLDLR Sarah Leigh Classified gene: VLDLR as Amber List (moderate evidence)
Malformations of cortical development v2.36 VLDLR Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least sic variants reported six unrelated cases, in which cerebellar hypoplasia was evident in five cases and two of these had cerebral gyral simplification.
Malformations of cortical development v2.36 VLDLR Sarah Leigh Gene: vldlr has been classified as Amber List (Moderate Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.16 DGKE Eleanor Williams Added comment: Comment on mode of inheritance: Reverting the mode of inheritance to BOTH monalllelic and biallelic to reflect the signed off version in March 2020. However, the recommendation is to change this to just BIALLELIC, following GMS review.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.16 DGKE Eleanor Williams Mode of inheritance for gene: DGKE was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.15 DGKE Eleanor Williams Tag for-review tag was added to gene: DGKE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.15 CFH Eleanor Williams Tag for-review tag was added to gene: CFH.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.15 CFH Eleanor Williams Added comment: Comment on mode of inheritance: Reverting the mode of inheritance to BOTH monalllelic and biallelic to reflect the signed off version in March 2020. However, the recommendation is to change this to just BIALLELIC, following GMS review.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.15 CFH Eleanor Williams Mode of inheritance for gene: CFH was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Malformations of cortical development v2.35 VLDLR Sarah Leigh Tag for-review tag was added to gene: VLDLR.
Malformations of cortical development v2.35 VLDLR Sarah Leigh Phenotypes for gene: VLDLR were changed from Cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1 (MIM#224050) to Cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1 OMIM:224050
Renal tubulopathies v2.25 SLC5A2 Eleanor Williams Tag for-review was removed from gene: SLC5A2.
Renal tubulopathies v2.25 SLC5A2 Eleanor Williams Classified gene: SLC5A2 as Green List (high evidence)
Renal tubulopathies v2.25 SLC5A2 Eleanor Williams Added comment: Comment on list classification: Reverting this gene to green. It was green at the initial sign off (v2.3 in Feb 2020) and was reverted to amber in error in October 2020 before re-sign off.
Renal tubulopathies v2.25 SLC5A2 Eleanor Williams Gene: slc5a2 has been classified as Green List (High Evidence).
Malformations of cortical development v2.34 LAMA2 Sarah Leigh edited their review of gene: LAMA2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Malformations of cortical development v2.34 LAMA2 Sarah Leigh Tag for-review tag was added to gene: LAMA2.
Malformations of cortical development v2.34 LAMA2 Sarah Leigh Classified gene: LAMA2 as Amber List (moderate evidence)
Malformations of cortical development v2.34 LAMA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. Numerous variants reported as biallelic in Muscular dystrophy, congenital, merosin deficient or partially deficient OMIM:607855, with over three cases exhibiting occipital agyria / polymicrogyria.
Malformations of cortical development v2.34 LAMA2 Sarah Leigh Gene: lama2 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v1.39 ARMC9 Eleanor Williams Classified gene: ARMC9 as Green List (high evidence)
Renal ciliopathies v1.39 ARMC9 Eleanor Williams Added comment: Comment on list classification: Reverting this gene to green so that it is the same rating as the signed off version of this panel (v1.2). It should be reviewed at the next GMS update.
Renal ciliopathies v1.39 ARMC9 Eleanor Williams Gene: armc9 has been classified as Green List (High Evidence).
Renal ciliopathies v1.38 ARMC9 Eleanor Williams commented on gene: ARMC9
Malformations of cortical development v2.33 LAMA2 Sarah Leigh Publications for gene: LAMA2 were set to 20207543; 18406646
Malformations of cortical development v2.32 LAMA2 Sarah Leigh Phenotypes for gene: LAMA2 were changed from Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855 to Muscular dystrophy, congenital, merosin deficient or partially deficient OMIM:607855
Intellectual disability v3.714 FGF13 Helen Lord Deleted their review
Intellectual disability v3.714 FGF13 Helen Lord commented on gene: FGF13
Cholestasis v1.76 CC2D2A Ivone Leong Tag for-review was removed from gene: CC2D2A.
Cholestasis v1.76 RPGRIP1L Ivone Leong Tag for-review was removed from gene: RPGRIP1L.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 TRAF7 Andrew Wilkie gene: TRAF7 was added
gene: TRAF7 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: TRAF7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRAF7 were set to 32376980
Phenotypes for gene: TRAF7 were set to craniosynostosis
Penetrance for gene: TRAF7 were set to Incomplete
Review for gene: TRAF7 was set to GREEN
Added comment: Castilla-Vallmanya et al (2020) reported the phenotypes associated with 45 heterozygous variants in TRAF7, missense mutations of which cause a recently recognised neurodevelopmental disorder. 3 of these individuals were reported to have craniosynostosis.
The submitter is aware of two additional unpublished cases with TRAF7 missense variants and craniosynostosis; one of these was missed in 100kGP by the GEL/GMC pipeline because TRAF7 was not included in PanelApp, the other is an unpublished case from Rotterdam.
In summary there appears to be sufficient evidence that craniosynostosis is a significant albeit low-frequency complication of pathogenic TRAF7 variants, which cause a complex neurodevelopmental disorder.
Sources: Expert Review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 PTCH1 Andrew Wilkie gene: PTCH1 was added
gene: PTCH1 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTCH1 were set to 31578813
Phenotypes for gene: PTCH1 were set to metopic craniosynostosis
Penetrance for gene: PTCH1 were set to Incomplete
Review for gene: PTCH1 was set to GREEN
Added comment: Several lines of evidence support that heterozygous loss-of-function mutations in PTCH1, which cause the classical genetic disorder Gorlin (basal cell naevus) syndrome, rarely also cause metopic synostosis. It is especially important to recognise this association, given the implications for patient management from a diagnosis of Gorlin syndrome.
(1) Beltrami et al (see PMID 31578813) described a frameshift variant in PTCH1 in a child with metopic synostosis.
(2) At the ESHG conference 2020, Di Giovanni et al reported 2 cases of apparently isolated trigonocephaly found to have nonsense or frameshift varaints in PTCH1. The abstract is available on weblink: https://www.abstractsonline.com/pp8/#!/9102/presentation/1801.
(3) Deletions of 9q22.3 including PTCH1 are well recognised to be associated with metopic synostosis (reviewed Yamada PMID:32028043), although genes additional to PTCH1 are included in the deleted region.
(4) In the 100kGP, the submitter is aware of a case that was missed by GEL/GMC pipeline (found by research lab) because PTCH1 was not included in the Panel for craniosynostosis.
(5) The consequence of PTCH1 loss-of-function mutations is to increase hedgehog (Hh) signalling through de-repression of Smoothened. Mutations in other genes associated with Hh overactivity, in the genes SMO, RAB23 and MEGF8, are all associated with craniosynostosis and are green panel app genes. A mice mutated in the Ptch1 orthologue, dogface-like, has lambdoid craniosynostosis (PMID:23897749). Hence, a clear biological mechanism exists accounting for craniosynostosis.
Sources: Expert Review
Ataxia and cerebellar anomalies - narrow panel v2.39 GLS Arina Puzriakova Classified gene: GLS as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.39 GLS Arina Puzriakova Added comment: Comment on list classification: Progressive ataxia is the main feature of the disease presentation (childhood-onset), and there are sufficient unrelated cases for inclusion as diagnostic-grade.

However, detection of the 5' UTR triplet expansion must first be validated within the Genomics England pipeline. In the meantime, rating Amber but will raise the STR for validation with the Rare Disease team.
Ataxia and cerebellar anomalies - narrow panel v2.39 GLS Arina Puzriakova Gene: gls has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.38 GLS Arina Puzriakova gene: GLS was added
gene: GLS was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
STR, for-review tags were added to gene: GLS.
Mode of inheritance for gene: GLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLS were set to 30970188
Phenotypes for gene: GLS were set to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Review for gene: GLS was set to GREEN
Added comment: GLS is associated with relevant phenotype in OMIM, but currently is not in Gene2Phenoype.
----------

- PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine (MIM# 618412). One patient also showed cerebellar atrophy.

All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency.
Sources: Literature
Limb disorders v2.29 SMO Eleanor Williams Tag for-review tag was added to gene: SMO.
Limb disorders v2.29 SMO Eleanor Williams Added comment: Comment on mode of inheritance: Leaving MOI has monoallelic just now, but with recommendation for updating to BOTH monoallelic and biallelic at the next review, due to additional biallelic cases now reported.
Limb disorders v2.29 SMO Eleanor Williams Mode of inheritance for gene: SMO was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.28 SMO Eleanor Williams Phenotypes for gene: SMO were changed from Polydactyly; Curry-Jones syndrome, somatic mosaic, MIM:601500; Cutaneous syndactyly; Preaxial polydactyly to Curry-Jones syndrome, somatic mosaic, OMIM:601500; postaxial polydactyly MONDO:0020927; Microcephaly HP:0000252; congenital heart disease MONDO:0005453; Hirschsprung disease MONDO:0018309
Limb disorders v2.27 SMO Eleanor Williams Publications for gene: SMO were set to 27236920
Limb disorders v2.26 SMO Eleanor Williams reviewed gene: SMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 32413283; Phenotypes: postaxial polydactyly MONDO:0020927, Microcephaly HP:0000252, congenital heart disease MONDO:0005453, Hirschsprung disease MONDO:0018309; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.57 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, 618339 to ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Likely inborn error of metabolism v2.50 GLS_GCA Arina Puzriakova Classified STR: GLS_GCA as Red List (low evidence)
Likely inborn error of metabolism v2.50 GLS_GCA Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases and supportive functional data for inclusion as diagnostic-grade.

However, detection of this 5' UTR triplet expansion must first be validated within the Genomics England pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Likely inborn error of metabolism v2.50 GLS_GCA Arina Puzriakova Str: gls_gca has been classified as Red List (Low Evidence).
Likely inborn error of metabolism v2.49 GLS_GCA Arina Puzriakova STR: GLS_GCA was added
STR: GLS_GCA was added to Inborn errors of metabolism. Sources: Literature
STR, NGS Not Validated, for-review tags were added to STR: GLS_GCA.
Mode of inheritance for STR: GLS_GCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: GLS_GCA were set to 30970188
Phenotypes for STR: GLS_GCA were set to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Review for STR: GLS_GCA was set to GREEN
Added comment: GLS is associated with relevant phenotypes in OMIM, but currently is not in Gene2Phenoype.
----------

- PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine (MIM# 618412). One patient also showed cerebellar atrophy.

All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v2.37 GLS_GCA Arina Puzriakova Classified STR: GLS_GCA as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v2.37 GLS_GCA Arina Puzriakova Added comment: Comment on list classification: Progressive ataxia is the main feature of the disease presentation (childhood-onset), and there are sufficient unrelated cases for inclusion as diagnostic-grade.

However, detection of this 5' UTR triplet expansion must first be validated within the Genomics England pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Ataxia and cerebellar anomalies - narrow panel v2.37 GLS_GCA Arina Puzriakova Str: gls_gca has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.36 GLS_GCA Arina Puzriakova STR: GLS_GCA was added
STR: GLS_GCA was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
STR, NGS Not Validated, for-review tags were added to STR: GLS_GCA.
Mode of inheritance for STR: GLS_GCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: GLS_GCA were set to 30970188
Phenotypes for STR: GLS_GCA were set to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Review for STR: GLS_GCA was set to GREEN
Added comment: GLS is associated with relevant phenotypes in OMIM, but currently is not in Gene2Phenoype.
----------

- PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine (MIM# 618412). One patient also showed cerebellar atrophy.

All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency.
Sources: Literature
Malformations of cortical development v2.31 CASK Sarah Leigh Tag for-review tag was added to gene: CASK.
Malformations of cortical development v2.31 CASK Sarah Leigh edited their review of gene: CASK: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Malformations of cortical development v2.31 CASK Sarah Leigh Classified gene: CASK as Amber List (moderate evidence)
Malformations of cortical development v2.31 CASK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. Numerous variants and cases reported.
Malformations of cortical development v2.31 CASK Sarah Leigh Gene: cask has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.30 CASK Sarah Leigh Publications for gene: CASK were set to 21954287; 20595373
Malformations of cortical development v2.29 CASK Sarah Leigh Phenotypes for gene: CASK were changed from Gyral simplification to Mental retardation and microcephaly with pontine and cerebellar hypoplasia OMIM:300749
Likely inborn error of metabolism v2.48 GLS Arina Puzriakova Classified gene: GLS as Green List (high evidence)
Likely inborn error of metabolism v2.48 GLS Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases, supported by functional data, to rate this gene Green - however, detection of the 5' UTR triplet expansion (PMID:30970188) has not yet been validated within the Genomics England pipeline.

When excluding cases with the STR, the remaining evidence is not sufficient for inclusion as diagnostic-grade and therefore this gene is tagged 'for-review' to assess whether it should be downgraded to Amber until the STR is validated or additional cases arise.
Likely inborn error of metabolism v2.48 GLS Arina Puzriakova Gene: gls has been classified as Green List (High Evidence).
Likely inborn error of metabolism v2.47 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Glucosidase 1 deficiency (Disorders of protein N-glycosylation); Epileptic encephalopathy, early infantile, 71 618328; Global developmental delay, progressive ataxia, and elevated glutamine 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Likely inborn error of metabolism v2.46 GLS Arina Puzriakova Publications for gene: GLS were set to 27604308; 30575854; 29468182
Likely inborn error of metabolism v2.45 GLS Arina Puzriakova Added comment: Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Likely inborn error of metabolism v2.45 GLS Arina Puzriakova Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.44 GLS Arina Puzriakova Tag STR tag was added to gene: GLS.
Tag for-review tag was added to gene: GLS.
Likely inborn error of metabolism v2.44 GLS Arina Puzriakova reviewed gene: GLS: Rating: ; Mode of pathogenicity: None; Publications: 30970188, 30575854, 30239721; Phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412, Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733, Developmental and epileptic encephalopathy 71, OMIM:618328, Developmental and epileptic encephalopathy, 71, MONDO:0032678, ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339, Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.440 GLS Arina Puzriakova Classified gene: GLS as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.440 GLS Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. There are sufficient cases, supported by functional data, to rate this gene Green - however, detection of the 5' UTR triplet expansion (PMID:30970188) must first be validated within the Genomics England pipeline.

When excluding cases with the STR, the remaining evidence is not sufficient for inclusion as diagnostic-grade and therefore keeping Amber until the STR is validated or additional cases arise.
Undiagnosed metabolic disorders v1.440 GLS Arina Puzriakova Gene: gls has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 SIX1 Andrew Wilkie edited their review of gene: SIX1: Added comment: Calpena et al (2021) identified 7 families in which the proband had craniosynostosis (affecting at least the sagittal suture in all cases) and a heterozygous SIX1 variant (4 nonsense + 3 missense in highly conserved residues of SIX domain or homeodomain). SIX1 mutations (mostly missense) were previously described in branchio-otic syndrome (BOS). Patients and carriers in the extended family variably had features of BOS (including branchial cysts, ear tags or pits, and hearing loss), but there were also several non-penetrant heterozygous individuals, indicating substantial variation in expressivity.
The absolute proportion of all craniosynostosis cases found to have SIX1 variants was low (7/1629, 0.4%), but much higher [4/23 (17%)] in those with the rare "Mercedez-Benz" pattern (sagittal + bilambdoid synostosis).
SIX1 analysis is therefore particularly indicated in individuals with either (1) additional BOS features or (2) sagittal+bilambdoid synostosis.; Changed rating: GREEN; Changed publications: 33436522
Undiagnosed metabolic disorders v1.439 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Glucosidase 1 deficiency (Disorders of protein N-glycosylation) to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Undiagnosed metabolic disorders v1.438 GLS Arina Puzriakova Publications for gene: GLS were set to 27604308
Undiagnosed metabolic disorders v1.437 GLS Arina Puzriakova Added comment: Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Undiagnosed metabolic disorders v1.437 GLS Arina Puzriakova Mode of inheritance for gene: GLS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.436 GLS Arina Puzriakova Tag STR tag was added to gene: GLS.
Tag for-review tag was added to gene: GLS.
Undiagnosed metabolic disorders v1.436 GLS Arina Puzriakova reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30970188, 30575854, 30239721; Phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412, Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733, Developmental and epileptic encephalopathy 71, OMIM:618328, Developmental and epileptic encephalopathy, 71, MONDO:0032678, ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339, Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Tag NGS Not Validated tag was added to STR: GLS_GCA.
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Classified gene: GLS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Biallelic variants identified in two families with three individuals affected by neonatal lethal epileptic encephalopathy and respiratory insufficiency (PMID: 30575854). The variants were predicted to result in loss of function, supported by elevated glutamine in all cases.

Rating Amber, awaiting further cases/clinical evidence prior to inclusion as diagnostic-grade.
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Gene: gls has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.256 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328 to Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678
Intellectual disability v3.714 GLS_GCA Arina Puzriakova changed review comment from: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.; to: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be validated within the Genomics England pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Malformations of cortical development v2.28 CASK Sarah Leigh Publications for gene: CASK were set to PMID: 21954287, 20595373
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Classified STR: GLS_GCA as Red List (low evidence)
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Added comment: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of this 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Str: gls_gca has been classified as Red List (Low Evidence).
Intellectual disability v3.713 GLS_GCA Arina Puzriakova Tag STR tag was added to STR: GLS_GCA.
Tag for-review tag was added to STR: GLS_GCA.
Intellectual disability v3.713 GLS Arina Puzriakova Deleted their comment
Intellectual disability v3.713 GLS Arina Puzriakova Tag STR tag was added to gene: GLS.
Tag for-review tag was added to gene: GLS.
Intellectual disability v3.713 GLS Arina Puzriakova Classified gene: GLS as Amber List (moderate evidence)
Intellectual disability v3.713 GLS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of the 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Amber but will raise the STR for validation with the Rare Disease team.
Intellectual disability v3.713 GLS Arina Puzriakova Gene: gls has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v1.6 ST14 Sarah Leigh Publications for gene: ST14 were set to
Palmoplantar keratodermas v1.5 ST14 Sarah Leigh Classified gene: ST14 as Green List (high evidence)
Palmoplantar keratodermas v1.5 ST14 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN on this panel, so it should be changed to RED at the next major review.
Palmoplantar keratodermas v1.5 ST14 Sarah Leigh Gene: st14 has been classified as Green List (High Evidence).
Palmoplantar keratodermas v1.4 ST14 Sarah Leigh Tag for-review tag was added to gene: ST14.
Palmoplantar keratodermas v1.4 ST14 Sarah Leigh reviewed gene: ST14: Rating: RED; Mode of pathogenicity: None; Publications: 17273967, 18445049, 18843291, 29611532; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.712 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Intellectual disability v3.712 GLS Arina Puzriakova Added comment: Comment on phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Intellectual disability v3.712 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412
Intellectual disability v3.711 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Intellectual disability v3.710 GLS Arina Puzriakova Added comment: Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Intellectual disability v3.710 GLS Arina Puzriakova Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.709 GLS Arina Puzriakova edited their review of gene: GLS: Added comment: One case reported with a de novo (i.e. monoallelic) gain-of-function variant, associated with profound developmental delay, infantile cataract, skin abnormalities, and glutamate excess. Functional analysis showed the variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS (PMID: 30239721).; Changed publications: 30970188, 30239721; Changed phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412, Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Ectodermal dysplasia v1.19 ST14 Sarah Leigh Phenotypes for gene: ST14 were changed from Ichthyosis, congenital, autosomal recessive 11, 602400; Some affected persons exhibit scarring alopecia to Ichthyosis, congenital, autosomal recessive 11 OMIM:602400; Some affected persons exhibit scarring alopecia
Ectodermal dysplasia v1.18 ST14 Sarah Leigh edited their review of gene: ST14: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in unrelated cases. There is considerable phenotypic overlap with ectodermal dysplasia according to Rachel Jones (see review).; Changed rating: GREEN
Ectodermal dysplasia v1.18 ST14 Sarah Leigh Tag for-review tag was added to gene: ST14.
Ectodermal dysplasia v1.18 ST14 Sarah Leigh Classified gene: ST14 as Amber List (moderate evidence)
Ectodermal dysplasia v1.18 ST14 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ectodermal dysplasia v1.18 ST14 Sarah Leigh Gene: st14 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.17 ST14 Sarah Leigh Publications for gene: ST14 were set to 18843291; 29611532
Ectodermal dysplasia v1.16 ST14 Sarah Leigh Publications for gene: ST14 were set to
Structural eye disease v1.27 NF2 Eleanor Williams Tag for review was removed from gene: NF2.
Tag for-review tag was added to gene: NF2.
Renal ciliopathies v1.38 DLG5 Eleanor Williams Tag for review was removed from gene: DLG5.
Tag for-review tag was added to gene: DLG5.
Proteinuric renal disease v2.44 GON7 Eleanor Williams Tag for-reivew was removed from gene: GON7.
Tag for-review tag was added to gene: GON7.
Limb disorders v2.26 KIAA0825 Eleanor Williams Classified gene: KIAA0825 as Amber List (moderate evidence)
Limb disorders v2.26 KIAA0825 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with recommendation for green rating following GMS review. 3 cases reported.
Limb disorders v2.26 KIAA0825 Eleanor Williams Gene: kiaa0825 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.25 KIAA0825 Eleanor Williams Tag for-review tag was added to gene: KIAA0825.
Limb disorders v2.25 KIAA0825 Eleanor Williams Phenotypes for gene: KIAA0825 were changed from Polydactyly, postaxial, type A10, MIM# 618498 to Polydactyly, postaxial, type A10 OMIM:618498; polydactyly, postaxial, type a10 MONDO:0032785
Limb disorders v2.24 KIAA0825 Eleanor Williams edited their review of gene: KIAA0825: Changed rating: GREEN; Changed publications: 32147526, 30982135; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v2.24 KIAA0825 Eleanor Williams reviewed gene: KIAA0825: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Polydactyly, postaxial, type A10 OMIM:618498, polydactyly, postaxial, type a10 MONDO:0032785; Mode of inheritance: None
Skeletal ciliopathies v1.7 IQCE Eleanor Williams Tag for-review tag was added to gene: IQCE.
Skeletal ciliopathies v1.7 IQCE Eleanor Williams Classified gene: IQCE as Amber List (moderate evidence)
Skeletal ciliopathies v1.7 IQCE Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, but with recommendation of promoting to green following GMS review. 4 cases now reported.
Skeletal ciliopathies v1.7 IQCE Eleanor Williams Gene: iqce has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v1.6 IQCE Eleanor Williams gene: IQCE was added
gene: IQCE was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: IQCE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IQCE were set to 28488682; 31549751
Phenotypes for gene: IQCE were set to Polydactyly, postaxial, type A7 OMIM:617642; polydactyly, postaxial, type a7 MONDO:0060550
Review for gene: IQCE was set to GREEN
Added comment: Green Expert Review of this gene on the Limb disorders panel.
PMID: 28488682 Umair et al 2017 report a large consanguineous family of Pakistani origin segregating post-axial polydactyly type A in the feet. A homozygous splice acceptor site variant (c.395-1G>A) was identified by WES in the IQCE gene, which completely co-segregated with the phenotype in the family. They report that the Iqce knockout mouse (MGI:1921489) shows various types of skeletal deformities including pre-axial polydactyly, digit abnormalities, and short and long tibia.

PMID: 31549751 - Estrada-Cuzcano et al 2019 - report 3 families with biallelic pathogenic variations in IQCE identified by WES. The same variant c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. In one family this variant as compound heterozygous with another IQCE variant p.Glu451Argfs*15. These families with post-axial polydactyly were initially recruited as syndromic ciliopathies and two have additional pathogenic variations in other genes (TULP1 and ATP6V1B1) explaining their apparent syndromic phenotype. Functional studies based on the patient's cells or zebrafish (Danio rerio) assays confirm the ciliary role of IQCE.
Sources: Literature
Limb disorders v2.24 IQCE Eleanor Williams Tag for-review tag was added to gene: IQCE.
Limb disorders v2.24 IQCE Eleanor Williams Phenotypes for gene: IQCE were changed from Polydactyly, postaxial, type A7 617642 to Polydactyly, postaxial, type A7 OMIM:617642; polydactyly, postaxial, type a7 MONDO:0060550
Limb disorders v2.23 IQCE Eleanor Williams edited their review of gene: IQCE: Changed phenotypes: Polydactyly, postaxial, type A7 OMIM:617642, polydactyly, postaxial, type a7 MONDO:0060550
Limb disorders v2.23 IQCE Eleanor Williams edited their review of gene: IQCE: Changed phenotypes: Polydactyly, postaxial, type A7 OMIM:617642
Limb disorders v2.23 IQCE Eleanor Williams Publications for gene: IQCE were set to 28488682
Limb disorders v2.22 IQCE Eleanor Williams Classified gene: IQCE as Amber List (moderate evidence)
Limb disorders v2.22 IQCE Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, but with recommendation of promoting to green following GMS review. 4 cases now reported.
Limb disorders v2.22 IQCE Eleanor Williams Gene: iqce has been classified as Amber List (Moderate Evidence).
Limb disorders v2.21 IQCE Eleanor Williams edited their review of gene: IQCE: Added comment: PMID: 28488682 Umair et al 2017 report a large consanguineous family of Pakistani origin segregating post-axial polydactyly type A in the feet. A homozygous splice acceptor site variant (c.395-1G>A) was identified by WES in the IQCE gene, which completely co-segregated with the phenotype in the family. They report that the Iqce knockout mouse (MGI:1921489) shows various types of skeletal deformities including pre-axial polydactyly, digit abnormalities, and short and long tibia.

PMID: 31549751 - Estrada-Cuzcano et al 2019 - report 3 families with biallelic pathogenic variations in IQCE identified by WES. The same variant c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. In one family this variant as compound heterozygous with another IQCE variant p.Glu451Argfs*15. These families with post-axial polydactyly were initially recruited as syndromic ciliopathies and two have additional pathogenic variations in other genes (TULP1 and ATP6V1B1) explaining their apparent syndromic phenotype. Functional studies based on the patient's cells or zebrafish (Danio rerio) assays confirm the ciliary role of IQCE.; Changed rating: GREEN; Changed publications: 28488682, 31549751; Changed phenotypes: postaxial polydactyly MONDO:0020927; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.709 GLS_GCA Arina Puzriakova STR: GLS_GCA was added
STR: GLS_GCA was added to Intellectual disability. Sources: Literature
Mode of inheritance for STR: GLS_GCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: GLS_GCA were set to 30970188
Phenotypes for STR: GLS_GCA were set to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
Review for STR: GLS_GCA was set to GREEN
Added comment: - PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine. One patient also showed cerebellar atrophy.

All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency.
Sources: Literature
Intellectual disability v3.708 GLS Arina Puzriakova reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30970188; Phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM: 618412; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.46 NEK9 Arina Puzriakova commented on gene: NEK9: NEK9 is associated with relevant phenotypes in OMIM (MIM# 614262 and 617022) but currently is not in Gene2Phenotype.
Adult onset neurodegenerative disorder v2.38 APP Sarah Leigh Phenotypes for gene: APP were changed from Clinical syndrome Alzheimer disease; Dementia to Alzheimer disease 1, familial OMIM:104300; Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants OMIM:605714
Arthrogryposis v3.46 NEK9 Arina Puzriakova Publications for gene: NEK9 were set to 26633546; 21271645; 26908619
Arthrogryposis v3.45 NEK9 Arina Puzriakova Classified gene: NEK9 as Amber List (moderate evidence)
Arthrogryposis v3.45 NEK9 Arina Puzriakova Added comment: Comment on list classification: With addition of the recent report, there are now at least 3 unrelated families presenting arthrogryposis and different biallelic variants in this gene. This now reaches threshold for inclusion, and therefore NEK9 should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Arthrogryposis v3.45 NEK9 Arina Puzriakova Gene: nek9 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.44 NEK9 Arina Puzriakova Tag for-review tag was added to gene: NEK9.
Arthrogryposis v3.44 NEK9 Arina Puzriakova edited their review of gene: NEK9: Added comment: Deden et al. 2020 (PMID: 32333414) report a further family with two consecutive prenatal presentations with compound heterozygous NEK9 variants. Both fetuses had arthrogryposis.

Both variants were reported as VUS when detected in the first fetus, which initially presented with 'short long bones, bowed femur, micrognathia, talipes and deviated hand' but re-evaluated after the phenotype progressed to arthrogryposis and then the next pregnancy showed the same ultrasound abnormalities and the same compound het variants. At this point the authors felt this represented a conclusive diagnosis.; Changed rating: GREEN; Changed publications: 26908619, 21271645, 26633546, 32333414; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.158 NEK9 Arina Puzriakova Classified gene: NEK9 as Amber List (moderate evidence)
Fetal anomalies v1.158 NEK9 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 (added 'for-review' tag). At least 3 unrelated families presenting a similar fetally-relevant phenotype in association with different biallelic variants in this gene.

NEK9 is associated with relevant phenotypes in OMIM (MIM# 614262 and 617022) but currently is not in Gene2Phenotype.
Fetal anomalies v1.158 NEK9 Arina Puzriakova Gene: nek9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.157 NEK9 Arina Puzriakova Publications for gene: NEK9 were set to 26908619
Fetal anomalies v1.156 NEK9 Arina Puzriakova Tag for-review tag was added to gene: NEK9.
Fetal anomalies v1.156 NEK9 Arina Puzriakova Phenotypes for gene: NEK9 were changed from Lethal congenital contracture syndrome 10 617022 to ?Arthrogryposis, Perthes disease, and upward gaze palsy, OMIM:614262; Arthrogryposis, Perthes disease, and upward gaze palsy, MONDO:0013660; Lethal congenital contracture syndrome 10, OMIM:617022; NEK9-related lethal skeletal dysplasia, MONDO:0014870
Congenital disorders of glycosylation v2.26 SRD5A3 Sarah Leigh Phenotypes for gene: SRD5A3 were changed from Congenital disorder of glycosylation, type Iq 612379; SRD5A3-CDG (Disorders of protein N-glycosylation) to Congenital Disorder of Glycosylation, Type Iq OMIM:612379; Kahrizi Syndrome OMIM:612713
Congenital disorders of glycosylation v2.25 SRD5A3 Sarah Leigh Publications for gene: SRD5A3 were set to 27480077
Fetal anomalies v1.155 MN1 Arina Puzriakova Tag for-review tag was added to gene: MN1.
Fetal anomalies v1.155 MN1 Arina Puzriakova Classified gene: MN1 as Amber List (moderate evidence)
Fetal anomalies v1.155 MN1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Multiple unrelated individuals (>20) described with a complex developmental disorder and de novo truncating MN1 variants. This gene will be flagged for review to determine whether the phenotype is fetally-relevant and there is enough evidence to include as Green.

Plausible that some features of the disorder, such as craniofacial abnormalities and structural brain anomalies may be detected prenatally. However based on published clinical descriptions, antenatal history was uneventful in most cases - but reports did include fetal brain anomalies (1), NICU admission (1) and IUGR (2). Similarly, neonatal problems were only reported in a few patients but included respiratory issues (3), abnormal ABR (1), congenital diaphragmatic hernia (1), perinatal hypoxia (1), congenital hypothyroidism (1), hearing impairment (1) and SCBU admission (1) (see Supplementary material in PMID: 31834374)
Fetal anomalies v1.155 MN1 Arina Puzriakova Gene: mn1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.154 MN1 Arina Puzriakova Phenotypes for gene: MN1 were changed from CEBALID syndrome, 618774 to CEBALID syndrome, OMIM:618774; CEBALID syndrome, MONDO:0032908
Monogenic hearing loss v2.146 MN1 Arina Puzriakova Phenotypes for gene: MN1 were changed from CEBALID syndrome, 618774 to CEBALID syndrome, OMIM:618774; CEBALID syndrome, MONDO:0032908
Intellectual disability v3.708 MN1 Arina Puzriakova Phenotypes for gene: MN1 were changed from Central hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Hearing impairment; Abnormality of facial skeleton; Craniosynostosis; Abnormality of the face; Abnormality of the cerebellum; Abnormality of the corpus callosum; Polymicrogyria to CEBALID syndrome, OMIM:618774; CEBALID syndrome, MONDO:0032908
Malformations of cortical development v2.27 MN1 Arina Puzriakova Phenotypes for gene: MN1 were changed from CEBALID syndrome, 618774 to CEBALID syndrome, OMIM:618774; CEBALID syndrome, MONDO:0032908
Severe microcephaly v2.70 ATP1A2 Arina Puzriakova Classified gene: ATP1A2 as Amber List (moderate evidence)
Severe microcephaly v2.70 ATP1A2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. At least 4 unrelated families with multiple congenital abnormalities and different homozygous truncating variants in the ATP1A2 gene. All were affected by microcephaly, and where measurements were specified, the severity was within the scope of this panel.

Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.70 ATP1A2 Arina Puzriakova Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.69 ATP1A2 Arina Puzriakova Tag for-review tag was added to gene: ATP1A2.
Malformations of cortical development v2.26 ATP1A2 Arina Puzriakova Publications for gene: ATP1A2 were set to 31608932
Malformations of cortical development v2.25 ATP1A2 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. At least 4 unrelated families with multiple congenital abnormalities and different homozygous truncating variants in the ATP1A2 gene. All affected fetuses display a common cerebral phenotype with multiple cortical malformations and polymicrogyria (PMIDs: 30690204 and 316089320)

Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag); to: Comment on list classification: New gene added by Zornitza Stark. At least 4 unrelated families with multiple congenital abnormalities and different homozygous truncating variants in the ATP1A2 gene. All affected fetuses display a common cerebral phenotype with multiple cortical malformations and polymicrogyria (PMIDs: 30690204 and 31608932)

Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.153 ATP1A2 Arina Puzriakova changed review comment from: Comment on list classification: There are now at least 4 unrelated families reported with a fetally-relevant phenotype and different homozygous truncating variants in the ATP1A2 gene (PMIDs: 30690204 and 316089320). Therefore this gene can now be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag); to: Comment on list classification: There are now at least 4 unrelated families reported with a fetally-relevant phenotype and different homozygous truncating variants in the ATP1A2 gene (PMIDs: 30690204 and 31608932). Therefore this gene can now be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag)
Malformations of cortical development v2.25 ATP1A2 Arina Puzriakova Classified gene: ATP1A2 as Amber List (moderate evidence)
Malformations of cortical development v2.25 ATP1A2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. At least 4 unrelated families with multiple congenital abnormalities and different homozygous truncating variants in the ATP1A2 gene. All affected fetuses display a common cerebral phenotype with multiple cortical malformations and polymicrogyria (PMIDs: 30690204 and 316089320)

Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Malformations of cortical development v2.25 ATP1A2 Arina Puzriakova Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.24 ATP1A2 Arina Puzriakova Tag for-review tag was added to gene: ATP1A2.
Arthrogryposis v3.44 ATP1A2 Arina Puzriakova Classified gene: ATP1A2 as Amber List (moderate evidence)
Arthrogryposis v3.44 ATP1A2 Arina Puzriakova Added comment: Comment on list classification: Two additional unrelated families reported by Chatron et al PMID: 31608932 with affected fetuses described as having polymicrogyria, microcephaly, polyhydramnios and FADS. Two individuals from one family also presented hand contractures and rocker-bottom feet, bringing the total to 3 unrelated families with relevant phenotype.

As number of cases now reaches threshold for inclusion as diagnostic-grade, ATP1A2 should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Arthrogryposis v3.44 ATP1A2 Arina Puzriakova Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.43 ATP1A2 Arina Puzriakova Publications for gene: ATP1A2 were set to 30690204
Arthrogryposis v3.42 ATP1A2 Arina Puzriakova Tag for-review tag was added to gene: ATP1A2.
Fetal anomalies v1.153 ATP1A2 Arina Puzriakova Classified gene: ATP1A2 as Amber List (moderate evidence)
Fetal anomalies v1.153 ATP1A2 Arina Puzriakova Added comment: Comment on list classification: There are now at least 4 unrelated families reported with a fetally-relevant phenotype and different homozygous truncating variants in the ATP1A2 gene (PMIDs: 30690204 and 316089320). Therefore this gene can now be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.153 ATP1A2 Arina Puzriakova Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.152 ATP1A2 Arina Puzriakova Publications for gene: ATP1A2 were set to 30690204
Fetal anomalies v1.151 ATP1A2 Arina Puzriakova Tag for-review tag was added to gene: ATP1A2.
Renal ciliopathies v1.38 DLG5 Eleanor Williams Classified gene: DLG5 as Amber List (moderate evidence)
Renal ciliopathies v1.38 DLG5 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but it could be promoted to green following GMS review. 4 cases, 2 biallelic and 2 monoallelic so mode of inheritance should also be considered. Supportive mouse knockout model.
Renal ciliopathies v1.38 DLG5 Eleanor Williams Gene: dlg5 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v1.37 DLG5 Eleanor Williams Added comment: Comment on mode of inheritance: Note, 2 reported cases with biallelic variants, 2 with monoallelic. Mouse model was biallelic knockout
Renal ciliopathies v1.37 DLG5 Eleanor Williams Mode of inheritance for gene: DLG5 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v1.36 DLG5 Eleanor Williams Publications for gene: DLG5 were set to 32631816
Renal ciliopathies v1.35 DLG5 Eleanor Williams Tag for review tag was added to gene: DLG5.
Renal ciliopathies v1.35 DLG5 Eleanor Williams reviewed gene: DLG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32631816, 17765678; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v2.44 YRDC Eleanor Williams Classified gene: YRDC as Amber List (moderate evidence)
Proteinuric renal disease v2.44 YRDC Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, based on 2 cases plus some functional data. At the next GMS review it could be considered for green rating based on the external expert review.
Proteinuric renal disease v2.44 YRDC Eleanor Williams Gene: yrdc has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.43 YRDC Eleanor Williams Tag for-review tag was added to gene: YRDC.
Proteinuric renal disease v2.43 GON7 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber, based on 4 related cases (founder effect) plus one other case plus some functional data. At the next GMS review it should be considered for green rating based on the external expert review.; to: Comment on list classification: Promoting from grey to amber, based on 4 related cases (founder effect) plus one other case plus some functional data. At the next GMS review it could be considered for green rating based on the external expert review.
Proteinuric renal disease v2.43 YRDC Eleanor Williams reviewed gene: YRDC: Rating: AMBER; Mode of pathogenicity: None; Publications: 31481669; Phenotypes: Galloway-Mowat syndrome MONDO:0009627; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v2.43 GON7 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber, based on 2 cases plus some functional data. At the next GMS review it should be considered for green rating based on the external expert review.; to: Comment on list classification: Promoting from grey to amber, based on 4 related cases (founder effect) plus one other case plus some functional data. At the next GMS review it should be considered for green rating based on the external expert review.
Proteinuric renal disease v2.43 GON7 Eleanor Williams Classified gene: GON7 as Amber List (moderate evidence)
Proteinuric renal disease v2.43 GON7 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, based on 2 cases plus some functional data. At the next GMS review it should be considered for green rating based on the external expert review.
Proteinuric renal disease v2.43 GON7 Eleanor Williams Gene: gon7 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.42 GON7 Eleanor Williams Phenotypes for gene: GON7 were changed from Galloway-Mowat syndrome to Galloway-Mowat syndrome MONDO:0009627
Proteinuric renal disease v2.41 GON7 Eleanor Williams Tag founder-effect tag was added to gene: GON7.
Tag for-reivew tag was added to gene: GON7.
Proteinuric renal disease v2.41 GON7 Eleanor Williams reviewed gene: GON7: Rating: AMBER; Mode of pathogenicity: None; Publications: 31481669; Phenotypes: Galloway-Mowat syndrome MONDO:0009627; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v1.16 PPP2R5D Zornitza Stark gene: PPP2R5D was added
gene: PPP2R5D was added to Adult onset movement disorder. Sources: Literature
Mode of inheritance for gene: PPP2R5D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP2R5D were set to 33338668; 32743835
Phenotypes for gene: PPP2R5D were set to Early onset Parkinsonism; Mental retardation, autosomal dominant 35, MIM# 616355
Review for gene: PPP2R5D was set to GREEN
Added comment: 5 individuals reported with de novo missense variants in this gene, a neurodevelopmental disorder, and onset of parkinsonism between the ages of 20-40 years. Four had the same p.(Glu200Lys) variant, and the fifth had p.(Glu198Lys)
Sources: Literature
Early onset or syndromic epilepsy v2.255 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Changed mode of pathogenicity: Other
Early onset or syndromic epilepsy v2.255 SCAMP5 Zornitza Stark reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31439720, 33390987; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thoracic aortic aneurysm or dissection (GMS) v1.3 THSD4 Zornitza Stark gene: THSD4 was added
gene: THSD4 was added to Thoracic aortic aneurysm and dissection. Sources: Literature
Mode of inheritance for gene: THSD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THSD4 were set to 32855533
Phenotypes for gene: THSD4 were set to Thoracic aortic aneurysm and dissection (TAAD)
Review for gene: THSD4 was set to GREEN
Added comment: 5 heterozygous variants in THSD4 (two lead to a premature termination codon) found in 5 families with TAAD. Variants segregated with disease in other family members. THSD4 encodes ADAMTSL6, a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.
Sources: Literature
Fetal anomalies v1.151 TMEM216 Arina Puzriakova changed review comment from: Comment on list classification: At least 3 variants reported in 6 families with Meckel syndrome, a fetally-relevant phenotype. Therefore, there is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

TMEM216 is associated with Meckel and Joubert syndrome in OMIM and Gene2Phenotype.; to: Comment on list classification: At least 3 reported variants in 6 families with Meckel syndrome, a fetally-relevant phenotype. Therefore, there is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

TMEM216 is associated with Meckel and Joubert syndrome in OMIM and Gene2Phenotype.
Fetal anomalies v1.151 TMEM216 Arina Puzriakova Publications for gene: TMEM216 were set to
Fetal anomalies v1.150 TMEM216 Arina Puzriakova Phenotypes for gene: TMEM216 were changed from JOUBERT SYNDROME 2 to Meckel syndrome 2, OMIM:603194; Meckel syndrome, type 2, MONDO:0011296
Fetal anomalies v1.149 TMEM216 Arina Puzriakova Classified gene: TMEM216 as Amber List (moderate evidence)
Fetal anomalies v1.149 TMEM216 Arina Puzriakova Added comment: Comment on list classification: At least 3 variants reported in 6 families with Meckel syndrome, a fetally-relevant phenotype. Therefore, there is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag).

TMEM216 is associated with Meckel and Joubert syndrome in OMIM and Gene2Phenotype.
Fetal anomalies v1.149 TMEM216 Arina Puzriakova Gene: tmem216 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.24 CASK Ian Berry gene: CASK was added
gene: CASK was added to Malformations of cortical development. Sources: NHS GMS
Mode of inheritance for gene: CASK 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: CASK were set to PMID: 21954287, 20595373
Phenotypes for gene: CASK were set to Gyral simplification
Review for gene: CASK was set to GREEN
gene: CASK was marked as current diagnostic
Added comment: Multiple publications reporting a subset of patients with simplified gyral pattern, in addition to the more recognisable features of cerebellar hypoplasia and microcephaly.
Sources: NHS GMS
Malformations of cortical development v2.24 LAMA2 Ian Berry reviewed gene: LAMA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.148 TMEM216 Arina Puzriakova Tag for-review tag was added to gene: TMEM216.
Malformations of cortical development v2.24 VLDLR Ian Berry reviewed gene: VLDLR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16174313, 6080122; Phenotypes: Gyral simplification; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.148 TMEM107 Arina Puzriakova Publications for gene: TMEM107 were set to 26123494; 26518474; 26595381
Fetal anomalies v1.147 TMEM107 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Associated with relevant phenotype in OMIM, but not in Gen2Phen at present. Biallelic variants identified in at least 5 unrelated families with a range of ciliopathic defects including oral-facial-digital syndrome (PMID: 26518474), Meckel-Gruber syndrome (PMID: 26123494), and Joubert syndrome (PMID: 26595381).

Phenotype is fetally-relevant in the two apparently unrelated MKS-13 infants, although it should be noted that they were found to share a single haplotype (founder effect). However, it is unclear whether this panel is relevant to OFD case, which would be necessary to reach the threshold for inclusion of TMEM107 as Green.

Therefore, rating Amber but will be flagged at the next GMS panel review to assess the phenotypic relevance in context of the panel scope (added 'for-review' tag); to: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Associated with relevant phenotype in OMIM, but not in Gen2Phen at present. Biallelic variants identified in at least 5 unrelated families with a range of ciliopathic defects including oral-facial-digital syndrome (PMID: 26518474 and 26595381), Meckel-Gruber syndrome (PMID: 26123494), and Joubert syndrome (PMID: 26595381).

Phenotype is fetally-relevant in the two unrelated MKS-13 infants, although it should be noted that they were found to share a single haplotype (founder effect), as well as the OFD syndrome cases.

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.147 TMEM107 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Associated with relevant phenotype in OMIM, but not in Gen2Phen at present. Biallelic variants identified in at least 5 unrelated families with a range of ciliopathic defects including oral-facial-digital syndrome (PMID: 26518474), Meckel-Gruber syndrome (PMID: 26123494), and Joubert syndrome (PMID: 26595381).

Phenotype is fetally-relevant in the two apparently unrelated MKS-13 infants, although it should be noted that they were found to share a single haplotype (founder effect). However, it is unclear whether this panel would be applicable in OFD case which would be necessary to reach the threshold for inclusion of TMEM107 as Green.

Therefore, rating Amber but will be flagged at the next GMS panel review to assess the phenotypic relevance in context of the panel scope (added 'for-review' tag); to: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Associated with relevant phenotype in OMIM, but not in Gen2Phen at present. Biallelic variants identified in at least 5 unrelated families with a range of ciliopathic defects including oral-facial-digital syndrome (PMID: 26518474), Meckel-Gruber syndrome (PMID: 26123494), and Joubert syndrome (PMID: 26595381).

Phenotype is fetally-relevant in the two apparently unrelated MKS-13 infants, although it should be noted that they were found to share a single haplotype (founder effect). However, it is unclear whether this panel is relevant to OFD case, which would be necessary to reach the threshold for inclusion of TMEM107 as Green.

Therefore, rating Amber but will be flagged at the next GMS panel review to assess the phenotypic relevance in context of the panel scope (added 'for-review' tag)
Fetal anomalies v1.147 TMEM107 Arina Puzriakova Tag for-review tag was added to gene: TMEM107.
Fetal anomalies v1.147 TMEM107 Arina Puzriakova Classified gene: TMEM107 as Amber List (moderate evidence)
Fetal anomalies v1.147 TMEM107 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Associated with relevant phenotype in OMIM, but not in Gen2Phen at present. Biallelic variants identified in at least 5 unrelated families with a range of ciliopathic defects including oral-facial-digital syndrome (PMID: 26518474), Meckel-Gruber syndrome (PMID: 26123494), and Joubert syndrome (PMID: 26595381).

Phenotype is fetally-relevant in the two apparently unrelated MKS-13 infants, although it should be noted that they were found to share a single haplotype (founder effect). However, it is unclear whether this panel would be applicable in OFD case which would be necessary to reach the threshold for inclusion of TMEM107 as Green.

Therefore, rating Amber but will be flagged at the next GMS panel review to assess the phenotypic relevance in context of the panel scope (added 'for-review' tag)
Fetal anomalies v1.147 TMEM107 Arina Puzriakova Gene: tmem107 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.146 TMEM107 Arina Puzriakova Publications for gene: TMEM107 were set to PMID: 26123494; 26518474; 26595381
Fetal anomalies v1.145 TMEM107 Arina Puzriakova Phenotypes for gene: TMEM107 were changed from ?Joubert syndrome 29; Meckel syndrome 13; Orofaciodigital syndrome XVI to Joubert syndrome 29, OMIM:617562; Meckel syndrome 13, OMIM:617562; Meckel syndrome 13, MONDO:0033044; Orofaciodigital syndrome XVI, OMIM:617563; Orofaciodigital syndrome 16, MONDO:0033045
Severe microcephaly v2.69 KIF14 Arina Puzriakova Tag for-review tag was added to gene: KIF14.
Severe microcephaly v2.69 KIF14 Arina Puzriakova Classified gene: KIF14 as Amber List (moderate evidence)
Severe microcephaly v2.69 KIF14 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM and Gene2Phenotype. At least 8 unrelated families reported (PMIDs: 28892560 and 29343805) with severe primary microcephaly due to different biallelic variants in the KIF14 gene. Kif14 knockout mice also exhibit primary microcephaly.

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.69 KIF14 Arina Puzriakova Gene: kif14 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.144 KIF14 Arina Puzriakova Publications for gene: KIF14 were set to PMID: 24128419; 30388224; 28892560; 29343805
Fetal anomalies v1.143 KIF14 Arina Puzriakova Classified gene: KIF14 as Amber List (moderate evidence)
Fetal anomalies v1.143 KIF14 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Associated with relevant phenotype in OMIM and Gene2Phenotype. At least 13 unrelated families reported with most cases being of fetal relevance. Phenotypes within the spectrum of fetal forms of ciliopathies (MKS) as well as severe primary microcephaly. Also supportive zebrafish model.

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.143 KIF14 Arina Puzriakova Gene: kif14 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.142 KIF14 Arina Puzriakova Tag for-review tag was added to gene: KIF14.
Intellectual disability v3.707 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from Microcephaly 20, primary, autosomal recessive, 617914 to Microcephaly 20, primary, autosomal recessive, OMIM:617914; Microcephaly 20, primary, autosomal recessive, MONDO:0054761
Severe microcephaly v2.68 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from Microcephaly 20, primary, autosomal recessive, MIM# 617914 to Microcephaly 20, primary, autosomal recessive, OMIM:617914; Microcephaly 20, primary, autosomal recessive, MONDO:0054761
Fetal anomalies v1.142 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from ?Meckel syndrome 12; Microcephaly 20, primary to Microcephaly 20, primary, autosomal recessive, OMIM:617914; Microcephaly 20, primary, autosomal recessive, MONDO:0054761; Meckel syndrome 12, OMIM:616258; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, MONDO:0014552
Renal ciliopathies v1.35 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from ?Meckel syndrome 12, 616258; complex brain malformation; ?Meckel syndrome 12; intrauterine growth restriction (IUGR); microcephaly; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome; genitourinary malformation; renal cystic dysplasia/agenesis to Meckel syndrome 12, OMIM:616258; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, MONDO:0014552
Neurological ciliopathies v1.14 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from ?Meckel syndrome 12, 616258; complex brain malformation; ?Meckel syndrome 12; intrauterine growth restriction (IUGR); microcephaly; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome; genitourinary malformation; renal cystic dysplasia/agenesis to Meckel syndrome 12, OMIM:616258; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, MONDO:0014552
Rare multisystem ciliopathy disorders v1.136 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from intrauterine growth restriction (IUGR); microcephaly; renal cystic dysplasia/agenesis; complex brain malformation; genitourinary malformation; ?Meckel syndrome 12, 616258; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome; ?Meckel syndrome 12 to Meckel syndrome 12, OMIM:616258; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, MONDO:0014552
DDG2P v2.17 KIF14 Arina Puzriakova Mode of inheritance for gene: KIF14 was changed from to BIALLELIC, autosomal or pseudoautosomal
Ductal plate malformation v1.14 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from ?Meckel syndrome 12 (616258) to Meckel syndrome 12, OMIM:616258; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, MONDO:0014552
Familial Neural Tube Defects v1.10 KIF14 Arina Puzriakova Mode of inheritance for gene: KIF14 was changed from to BIALLELIC, autosomal or pseudoautosomal
Familial Neural Tube Defects v1.9 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from Meckel Syndrome to Meckel syndrome 12, OMIM:616258; Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, MONDO:0014552
Primary immunodeficiency or monogenic inflammatory bowel disease v2.391 TLR8 Arina Puzriakova Mode of inheritance for gene: TLR8 was changed from Other to Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Tag mosaicism tag was added to gene: TLR8.
Tag somatic tag was added to gene: TLR8.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Classified gene: TLR8 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Added comment: Comment on list classification: 6 unrelated individuals with relevant phenotype, associated with variants in this gene (https://doi.org/10.1182/blood.2020009620). However, 5 cases had somatic mosaicism and this panel is not appropriate for somatic variant detection due to coverage. Therefore, rating Red but this may be reviewed if additional cases with germline variants emerge.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Gene: tlr8 has been classified as Red List (Low Evidence).
Skeletal ciliopathies v1.5 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9, 614209; ciliopathies; Meckel syndrome; Joubert syndrome 27 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Renal ciliopathies v1.34 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9, 614209; ciliopathies; Meckel syndrome; Joubert syndrome 27 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Neurological ciliopathies v1.13 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9, 614209; ciliopathies; Meckel syndrome; Joubert syndrome 27 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Ophthalmological ciliopathies v1.17 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9, 614209; ciliopathies; Meckel syndrome; Joubert syndrome 27 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Intellectual disability v3.706 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9 614209; Joubert syndrome 27 617120 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Rare multisystem ciliopathy disorders v1.135 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9, 614209; ciliopathies; Meckel syndrome; Joubert syndrome 27 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Skeletal dysplasia v2.47 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from Meckel syndrome 9 614209 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Primary ciliary disorders v1.29 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ciliopathies to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Polycystic liver disease v1.7 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9 (614209); Joubert syndrome 27 (617120) to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Ductal plate malformation v1.13 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9 (614209); Joubert syndrome 27 (617120) to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Limb disorders v2.21 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from Polydactyly; ?Meckel syndrome 9 614209; Joubert syndrome 27 617120 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Thoracic dystrophies v1.9 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Familial Neural Tube Defects v1.8 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from Meckel Syndrome to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Fetal anomalies v1.141 B9D1 Arina Puzriakova Publications for gene: B9D1 were set to
Fetal anomalies v1.140 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from MECKEL SYNDROME 9 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Fetal anomalies v1.139 B9D1 Arina Puzriakova commented on gene: B9D1
Renal ciliopathies v1.33 B9D2 Arina Puzriakova commented on gene: B9D2
Neurological ciliopathies v1.12 B9D2 Arina Puzriakova commented on gene: B9D2
Renal ciliopathies v1.33 B9D2 Arina Puzriakova Publications for gene: B9D2 were set to 21763481 - two affected fetuses form the same family displayed overlapping phenotypes including cystic kidneys, ductal plate malformation, polydactyly, and occipital encephalocele. Homozygous variant identified in this gene, which was not present in the unaffected son. Homozygous variants were not identified in other known Meckel syndrome genes; 26092869 - two further cases with Joubert syndrome reported from two different families
Childhood onset dystonia, chorea or related movement disorder v1.72 B9D2 Arina Puzriakova Publications for gene: B9D2 were set to 26092869 - two further cases with Joubert syndrome reported from two different families; 21763481 - two affected fetuses form the same family displayed overlapping phenotypes including cystic kidneys, ductal plate malformation, polydactyly, and occipital encephalocele. Homozygous variant identified in this gene, which was not present in the unaffected son. Homozygous variants were not identified in other known Meckel syndrome genes
Renal ciliopathies v1.32 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Joubert syndrome; Meckel syndrome 10, 614175; ciliopathies; Meckel syndrome to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Childhood onset dystonia, chorea or related movement disorder v1.71 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Meckel syndrome; Joubert syndrome; Meckel syndrome 10, 614175; ciliopathies to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Neurological ciliopathies v1.12 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Joubert syndrome; Meckel syndrome 10, 614175; ciliopathies; Meckel syndrome to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Ophthalmological ciliopathies v1.16 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Joubert syndrome; Meckel syndrome 10, 614175; ciliopathies; Meckel syndrome to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Rare multisystem ciliopathy disorders v1.134 B9D2 Arina Puzriakova Publications for gene: B9D2 were set to 21763481 - two affected fetuses form the same family displayed overlapping phenotypes including cystic kidneys, ductal plate malformation, polydactyly, and occipital encephalocele. Homozygous variant identified in this gene, which was not present in the unaffected son. Homozygous variants were not identified in other known Meckel syndrome genes; 26092869 - two further cases with Joubert syndrome reported from two different families
Rare multisystem ciliopathy disorders v1.133 B9D2 Arina Puzriakova commented on gene: B9D2
Rare multisystem ciliopathy disorders v1.133 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Meckel syndrome 10, 614175; ciliopathies; Meckel syndrome; Joubert syndrome to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Unexplained young onset end-stage renal disease v1.12 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Meckel syndrome; Joubert syndrome; Meckel syndrome 10, 614175; ciliopathies to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Skeletal dysplasia v2.46 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Meckel syndrome 10 614175 to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Primary ciliary disorders v1.28 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from ciliopathies to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Thoracic dystrophies v1.8 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Familial Neural Tube Defects v1.7 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Meckel Syndrome to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Ductal plate malformation v1.12 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Joubert syndrome 34 (614175); ?Meckel syndrome 10 (614175) to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Limb disorders v2.20 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Polydactyly; ?Meckel syndrome 10 614175; Joubert syndrome 34 614175 to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Intellectual disability v3.705 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Joubert syndrome 34 614175; Meckel syndrome 10 614175 to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Fetal anomalies v1.139 B9D2 Arina Puzriakova Tag for-review tag was added to gene: B9D2.
Fetal anomalies v1.139 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Joubert syndrome; Meckel syndrome to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Fetal anomalies v1.138 B9D2 Arina Puzriakova Publications for gene: B9D2 were set to PMID: 21763481; 26092869
Fetal anomalies v1.137 B9D2 Arina Puzriakova Classified gene: B9D2 as Amber List (moderate evidence)
Fetal anomalies v1.137 B9D2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Associated with relevant phenotype in OMIM, but not in Gen2Phen at present. Biallelic variants reported in at least four unrelated cases (2 with Joubert syndrome, PMID: 26092869; and 2 with MKS, PMIDs: 21763481 and 31411728)

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag) as sufficient number of unrelated cases with fetally-relevant phenotype due to variants in the B9D2 gene.
Fetal anomalies v1.137 B9D2 Arina Puzriakova Gene: b9d2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.704 EEF1A2 Eleanor Williams Tag for-review was removed from gene: EEF1A2.
Intellectual disability v3.704 SCN8A Ivone Leong Added comment: Comment on mode of inheritance: MOI was changed back from "Both monoallelic and biallelic" to "Monoallelic", which reflects the original MOI of the signed off panel (version 3.2). The MOI will be changed back to "Both monoallelic and biallelic" after the panel has been reviewed.
Intellectual disability v3.704 SCN8A Ivone Leong Mode of inheritance for gene: SCN8A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.389 TLR8 Arina Puzriakova Publications for gene: TLR8 were set to 10.1182/blood.2020009620
Cytopenia - NOT Fanconi anaemia v1.35 RPL31 Arina Puzriakova Classified gene: RPL31 as Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v1.35 RPL31 Arina Puzriakova Added comment: Comment on list classification: Current Green gene rating based on GMS specialist test group consensus. However, note the recent review by Zornitza Stark (Australian Genomics) highlighting limited published evidence to support this gene-disease association, which is only sufficient for an Amber rating at present. Will be flagged for review at the next GMS panel update (added 'for-review' tag).
Cytopenia - NOT Fanconi anaemia v1.35 RPL31 Arina Puzriakova Gene: rpl31 has been classified as Green List (High Evidence).
Cytopenia - NOT Fanconi anaemia v1.34 RPL31 Arina Puzriakova Tag for-review tag was added to gene: RPL31.
Bleeding and platelet disorders v1.19 FLNA Arina Puzriakova Publications for gene: FLNA were set to 29449050; 21960593
Bleeding and platelet disorders v1.18 FLNA Arina Puzriakova Tag for-review tag was added to gene: FLNA.
Bleeding and platelet disorders v1.18 FLNA Arina Puzriakova Classified gene: FLNA as Amber List (moderate evidence)
Bleeding and platelet disorders v1.18 FLNA Arina Puzriakova Added comment: Comment on list classification: Gene associated with multiple phenotypes which do not include haematological abnormalities. However, thrombocytopenia with or without platelet dysfunction has been reported in at least 11 individuals from 10 pedigrees with a total of 10 different FLNA variants. As this reaches threshold for inclusion as diagnostic-grade, this gene will be flagged for review at the next GMS panel update (added for-review tag)
Bleeding and platelet disorders v1.18 FLNA Arina Puzriakova Gene: flna has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v1.17 NBEA Arina Puzriakova Classified gene: NBEA as Green List (high evidence)
Bleeding and platelet disorders v1.17 NBEA Arina Puzriakova Added comment: Comment on list classification: Current Green gene rating based on GMS specialist test group consensus; however, note the recent review by Zornitza Stark (Australian Genomics) highlighting limited published evidence to support this gene-disease association and recurrence of heterozygous variants in control populations. Will be flagged for review at the next GMS panel update (added 'for-review' tag).
Bleeding and platelet disorders v1.17 NBEA Arina Puzriakova Gene: nbea has been classified as Green List (High Evidence).
Bleeding and platelet disorders v1.16 NBEA Arina Puzriakova Tag for-review tag was added to gene: NBEA.
Congenital disorders of glycosylation v2.24 GMPPA Sarah Leigh edited their review of gene: GMPPA: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in unrelated cases.; Changed rating: GREEN; Changed phenotypes: Alacrima, achalasia, and mental retardation syndrome OMIM:615510
Congenital disorders of glycosylation v2.24 GMPPA Sarah Leigh Tag for-review tag was added to gene: GMPPA.
Congenital disorders of glycosylation v2.24 GMPPA Sarah Leigh Classified gene: GMPPA as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.24 GMPPA Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital disorders of glycosylation v2.24 GMPPA Sarah Leigh Gene: gmppa has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v1.16 PRKACG Arina Puzriakova Phenotypes for gene: PRKACG were changed from 616176BLEEDING DISORDER, PLATELET-TYPE, 19; 616176 BLEEDING DISORDER, PLATELET-TYPE, 19; BDPLT19 to ?Bleeding disorder, platelet-type, 19, OMIM:616176; Platelet-type bleeding disorder 19, MONDO:0014518
Bleeding and platelet disorders v1.15 PRKACG Arina Puzriakova Publications for gene: PRKACG were set to 25061177
Bleeding and platelet disorders v1.14 PRKACG Arina Puzriakova Classified gene: PRKACG as Green List (high evidence)
Bleeding and platelet disorders v1.14 PRKACG Arina Puzriakova Added comment: Comment on list classification: Current Green gene rating based on GMS specialist test group consensus; however, note the recent review by Zornitza Stark (Australian Genomics) highlighting limited published evidence to support this gene-disease association. Based on literature, only sufficient for an Amber/Red rating. Will be flagged for review at the next GMS panel update (added 'for-review' tag).
Bleeding and platelet disorders v1.14 PRKACG Arina Puzriakova Gene: prkacg has been classified as Green List (High Evidence).
Bleeding and platelet disorders v1.13 PRKACG Arina Puzriakova Tag for-review tag was added to gene: PRKACG.
Intellectual disability v3.703 ALKBH8 Ivone Leong Classified gene: ALKBH8 as Green List (high evidence)
Intellectual disability v3.703 ALKBH8 Ivone Leong Added comment: Comment on list classification: This gene has been promoted back to Green status to reflect the rating that was on the signed off version of this panel (version 3.2). This gene should be demoted to Amber at the next review.
Intellectual disability v3.703 ALKBH8 Ivone Leong Gene: alkbh8 has been classified as Green List (High Evidence).
Intellectual disability v3.702 ALKBH8 Ivone Leong Tag for-review tag was added to gene: ALKBH8.
Bleeding and platelet disorders v1.13 HOXA11 Arina Puzriakova Tag for-review tag was added to gene: HOXA11.
Bleeding and platelet disorders v1.13 HOXA11 Arina Puzriakova Classified gene: HOXA11 as Green List (high evidence)
Bleeding and platelet disorders v1.13 HOXA11 Arina Puzriakova Added comment: Comment on list classification: Current Green gene rating based on GMS specialist test group consensus; however, note the recent review by Zornitza Stark (Australian Genomics) highlighting limited published evidence to support this gene-disease association. Will be flagged for review at the next GMS panel update (added 'for-review' tag)
Bleeding and platelet disorders v1.13 HOXA11 Arina Puzriakova Gene: hoxa11 has been classified as Green List (High Evidence).
Proteinuric renal disease v2.41 KIRREL1 Eleanor Williams Classified gene: KIRREL1 as Amber List (moderate evidence)
Proteinuric renal disease v2.41 KIRREL1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. 2 cases plus some limited functional data.
Proteinuric renal disease v2.41 KIRREL1 Eleanor Williams Gene: kirrel1 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.40 KIRREL1 Eleanor Williams Phenotypes for gene: KIRREL1 were changed from Steroid-resistant nephrotic syndrome to steroid-resistant nephrotic syndrome MONDO:0044765
Proteinuric renal disease v2.39 KIRREL1 Eleanor Williams reviewed gene: KIRREL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31472902; Phenotypes: steroid-resistant nephrotic syndrome MONDO:0044765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v2.39 DAAM2 Eleanor Williams Classified gene: DAAM2 as Amber List (moderate evidence)
Proteinuric renal disease v2.39 DAAM2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, with the recommendation of a green rating following GMS review. 4 unrelated cases, with different variants in DAAM2 in patients with steroid-resistant nephrotic syndrome.
Proteinuric renal disease v2.39 DAAM2 Eleanor Williams Gene: daam2 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.38 DAAM2 Eleanor Williams Deleted their comment
Proteinuric renal disease v2.38 DAAM2 Eleanor Williams Tag for-review tag was added to gene: DAAM2.
Proteinuric renal disease v2.38 DAAM2 Eleanor Williams Classified gene: DAAM2 as Amber List (moderate evidence)
Proteinuric renal disease v2.38 DAAM2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, with the recommendation of a green rating following GMS review. 4 unrelated cases, with different variants in DAAM2 in patients with steroid-resistant nephrotic syndrome.
Proteinuric renal disease v2.38 DAAM2 Eleanor Williams Gene: daam2 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.37 DAAM2 Eleanor Williams Phenotypes for gene: DAAM2 were changed from Steroid-resistant nephrotic syndrome (SRNS) to steroid-resistant nephrotic syndrome MONDO:0044765
Proteinuric renal disease v2.36 IL1RAP Eleanor Williams Classified gene: IL1RAP as Red List (low evidence)
Proteinuric renal disease v2.36 IL1RAP Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red based on expert review reporting one case.
Proteinuric renal disease v2.36 IL1RAP Eleanor Williams Gene: il1rap has been classified as Red List (Low Evidence).
Proteinuric renal disease v2.35 NOP10 Eleanor Williams Classified gene: NOP10 as Red List (low evidence)
Proteinuric renal disease v2.35 NOP10 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red as there is one reported family with a missense variant in this gene and a phenotype that includes nephrotic syndrome.
Proteinuric renal disease v2.35 NOP10 Eleanor Williams Gene: nop10 has been classified as Red List (Low Evidence).
Proteinuric renal disease v2.34 NOP10 Eleanor Williams reviewed gene: NOP10: Rating: RED; Mode of pathogenicity: None; Publications: 32554502; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v2.34 DKC1 Eleanor Williams changed review comment from: Variants in this gene have previously been associated with dyskeratosis congenita (bone marrow failure) characterized by telomere attrition. https://omim.org/entry/300126

As reported by expert reviewer PMID: 32554502 - Balogh et al 2020 - reports a large pedigree in which 6 affected males presented with an infantile-onset disorder characterized by steroid-resistant nephrotic syndrome, cataracts (prior to steroid treatment), sensorineural deafness, and enterocolitis and died in early childhood. Using linkage analysis they identified a point mutation in DKC1 (c.616 G>A, p.Glu206Lys) that segregated with the disease in generation II. The variant is absent from gnomAD.; to: Variants in this gene have previously been associated with dyskeratosis congenita (bone marrow failure) characterized by telomere attrition. https://omim.org/entry/300126

As reported by expert reviewer PMID: 32554502 - Balogh et al 2020 - reports a large pedigree in which 6 affected males presented with an infantile-onset disorder characterized by steroid-resistant nephrotic syndrome, cataracts (prior to steroid treatment), sensorineural deafness, and enterocolitis and died in early childhood. Using linkage analysis they identified a point mutation in DKC1 (c.616 G>A, p.Glu206Lys) that segregated with the disease in generation II. The variant is absent from gnomAD. An affected female was found to have skewed x-inactivation.
Proteinuric renal disease v2.34 DKC1 Eleanor Williams Classified gene: DKC1 as Red List (low evidence)
Proteinuric renal disease v2.34 DKC1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red as there is one reported family with a missense variant in this gene and a phenotype that includes nephrotic syndrome.
Proteinuric renal disease v2.34 DKC1 Eleanor Williams Gene: dkc1 has been classified as Red List (Low Evidence).
Proteinuric renal disease v2.33 DKC1 Eleanor Williams reviewed gene: DKC1: Rating: RED; Mode of pathogenicity: None; Publications: 32554502; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cystic kidney disease v2.23 COL4A5 Eleanor Williams Tag for-review tag was added to gene: COL4A5.
Cystic kidney disease v2.23 COL4A5 Eleanor Williams Phenotypes for gene: COL4A5 were changed from cystic kidney disease to cystic kidney disease MONDO:0002473
Cystic kidney disease v2.22 COL4A5 Eleanor Williams Classified gene: COL4A5 as Red List (low evidence)
Cystic kidney disease v2.22 COL4A5 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red, as there is one reported case. But noting the green review from expert reviewer John Sayer, marking this gene as 'for-review' by the GMS.
Cystic kidney disease v2.22 COL4A5 Eleanor Williams Gene: col4a5 has been classified as Red List (Low Evidence).
Cystic kidney disease v2.21 COL4A5 Eleanor Williams changed review comment from: PMID: 31922066 - Gulati et al 2019 - through WES they identified 1 female patient with Thin glomerular basement membrane (TBM) disease and bilateral kidney cysts was heterozygous for a COL4A5 likely pathogenic missense variant (c.C899T: p. P300L); to: PMID: 31922066 - Gulati et al 2019 - through WES they identified 1 female patient with Thin glomerular basement membrane (TBM) disease and bilateral kidney cysts that was heterozygous for a COL4A5 likely pathogenic missense variant (c.C899T: p. P300L)
Cystic kidney disease v2.21 COL4A5 Eleanor Williams reviewed gene: COL4A5: Rating: ; Mode of pathogenicity: None; Publications: 31922066; Phenotypes: cystic kidney disease MONDO:0002473; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Cystic kidney disease v2.21 COL4A4 Eleanor Williams Classified gene: COL4A4 as Amber List (moderate evidence)
Cystic kidney disease v2.21 COL4A4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but there are 3 cases so could be promoted to green following GMS review.
Cystic kidney disease v2.21 COL4A4 Eleanor Williams Gene: col4a4 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.20 COL4A4 Eleanor Williams Phenotypes for gene: COL4A4 were changed from cystic kidney disease to cystic kidney disease MONDO:0002473
Cystic kidney disease v2.19 COL4A4 Eleanor Williams reviewed gene: COL4A4: Rating: AMBER; Mode of pathogenicity: None; Publications: 31922066; Phenotypes: cystic kidney disease MONDO:0002473; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.45 CSGALNACT1 Eleanor Williams Tag for-review tag was added to gene: CSGALNACT1.
Congenital disorders of glycosylation v2.23 CSGALNACT1 Eleanor Williams Tag for-review tag was added to gene: CSGALNACT1.
Congenital disorders of glycosylation v2.23 CSGALNACT1 Eleanor Williams Classified gene: CSGALNACT1 as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.23 CSGALNACT1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with recommendation for green rating following GMS review as there are now 4 cases reported of biallelic variants in this gene in patients with mild skeletal dysplasia thought to result from disturbance of glycosaminoglycan synthesis.
Congenital disorders of glycosylation v2.23 CSGALNACT1 Eleanor Williams Gene: csgalnact1 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v2.22 CSGALNACT1 Eleanor Williams Phenotypes for gene: CSGALNACT1 were changed from Congenital disorder of glycosylation; skeletal dysplasia to Congenital disorder of glycosylation; Skeletal dysplasia, mild, with joint laxity and advanced bone age OMIM:618870; skeletal dysplasia, mild, with joint laxity and advanced bone age MONDO:0030029
Congenital disorders of glycosylation v2.21 CSGALNACT1 Eleanor Williams Publications for gene: CSGALNACT1 were set to 31705726; 31325655
Congenital disorders of glycosylation v2.20 CSGALNACT1 Eleanor Williams edited their review of gene: CSGALNACT1: Changed publications: 27599773, 31325655, 31705726; Changed phenotypes: Skeletal dysplasia, mild, with joint laxity and advanced bone age OMIM:618870, skeletal dysplasia, mild, with joint laxity and advanced bone age MONDO:0030029
Congenital disorders of glycosylation v2.20 CSGALNACT1 Eleanor Williams reviewed gene: CSGALNACT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.45 CSGALNACT1 Eleanor Williams Classified gene: CSGALNACT1 as Amber List (moderate evidence)
Skeletal dysplasia v2.45 CSGALNACT1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with recommendation for green rating following GMS review as there are now 4 cases reported of biallelic variants in this gene in patients with mild skeletal dysplasia.
Skeletal dysplasia v2.45 CSGALNACT1 Eleanor Williams Gene: csgalnact1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.44 CSGALNACT1 Eleanor Williams edited their review of gene: CSGALNACT1: Changed rating: GREEN
Skeletal dysplasia v2.44 CSGALNACT1 Eleanor Williams Phenotypes for gene: CSGALNACT1 were changed from Desbuquois dysplasia with mild joint laxity; non-proportionate short stature to Desbuquois dysplasia with mild joint laxity; non-proportionate short stature; Skeletal dysplasia, mild, with joint laxity and advanced bone age OMIM:618870; skeletal dysplasia, mild, with joint laxity and advanced bone age MONDO:0030029
Skeletal dysplasia v2.43 CSGALNACT1 Eleanor Williams Publications for gene: CSGALNACT1 were set to 27599773; 31325655
Skeletal dysplasia v2.42 CSGALNACT1 Eleanor Williams edited their review of gene: CSGALNACT1: Changed publications: 27599773, 31325655, 31705726
Skeletal dysplasia v2.42 CSGALNACT1 Eleanor Williams reviewed gene: CSGALNACT1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia, mild, with joint laxity and advanced bone age OMIM:618870, skeletal dysplasia, mild, with joint laxity and advanced bone age MONDO:0030029; Mode of inheritance: None
Paediatric disorders - additional genes v1.71 VIM Eleanor Williams gene: VIM was added
gene: VIM was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: VIM was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: VIM were set to 32066935
Phenotypes for gene: VIM were set to lipodystrophy HP:0009125; Craniofacial dysostosis HP:0004439; Thoracic scoliosis HP:0002943; amyotrophy
Review for gene: VIM was set to RED
Added comment: Previously variants in this gene have been associated with cataracts (PMID: 26694549, 19126778). Cogne et al 2020 (PMID: 32066935) - report a de novo heterozygous variant in VIM (c.1160 T > C; p.(Leu387Pro)) causing a syndromic disorder affecting craniofacial development, peripheral nervous system, and adipose and ectodermal tissues in a 39 year old male. The variant was identified by WES. Both parents lacked the variant. Expression of human vimentin p.(Leu387Pro) in zebrafish resulted in a phenotype of perturbed body fat distribution, and craniofacial and peripheral nervous system development. Functional studies using patient-derived and transfected cells showed that the variant affects vimentin turnover and its ability to form filaments in the absence of wild-type vimentin.

Added gene to this panel on advice from Genomics England Clinical team.
Sources: Literature
Lipodystrophy - childhood onset v2.8 VIM Eleanor Williams gene: VIM was added
gene: VIM was added to Lipodystrophy - childhood onset. Sources: Literature
Mode of inheritance for gene: VIM was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: VIM were set to 32066935
Phenotypes for gene: VIM were set to lipodystrophy HP:0009125
Review for gene: VIM was set to RED
Added comment: Previously variants in this gene have been associated with cataracts (PMID: 26694549, 19126778). Cogne et al 2020 (PMID: 32066935) - report a de novo heterozygous variant in VIM (c.1160 T > C; p.(Leu387Pro)) causing a syndromic disorder affecting craniofacial development, peripheral nervous system, and adipose and ectodermal tissues in a 39 year old male. The variant was identified by WES. Both parents lacked the variant. Expression of human vimentin p.(Leu387Pro) in zebrafish resulted in a phenotype of perturbed body fat distribution, and craniofacial and peripheral nervous system development. Functional studies using patient-derived and transfected cells showed that the variant affects vimentin turnover and its ability to form filaments in the absence of wild-type vimentin.
Sources: Literature
Hereditary neuropathy v1.381 PNKP Dmitrijs Rots changed review comment from: In PMID: 30039206 reported a homozygous nonsense variant in a large Costa Rican family segregating with CMT2 phenotype. Additional 5 cases with compound heterozygous nonsense variants and CMT2 phenotype also reported. Some patients have Ataxia, but not oculomotor apraxia or Microcephaly, seizures, and developmental delay.; to: In PMID: 30039206 reported a homozygous nonsense variant in a large Costa Rican family segregating with CMT2 phenotype. Additional 5 cases with compound heterozygous nonsense variants and CMT2 phenotype also reported. Some patients have Ataxia, but not oculomotor apraxia or Microcephaly, seizures, and developmental delay.
Hereditary neuropathy or pain disorder v1.19 PNKP Dmitrijs Rots reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30039206; Phenotypes: Polyneuropathy, ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary neuropathy v1.381 PNKP Dmitrijs Rots reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30039206; Phenotypes: Polyneuropathy, ataxia; Mode of inheritance: None; Current diagnostic: yes
Likely inborn error of metabolism v2.44 NUS1 Eleanor Williams Classified gene: NUS1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.44 NUS1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber on advice from Genomics England clinical team. 1 case plus some functional data.
Likely inborn error of metabolism v2.44 NUS1 Eleanor Williams Gene: nus1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.43 NUS1 Eleanor Williams Publications for gene: NUS1 were set to 25066056
Likely inborn error of metabolism v2.42 NUS1 Eleanor Williams Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa 617082 to ?Congenital disorder of glycosylation, type 1aa OMIM:617082; congenital disorder of glycosylation, type IAA MONDO:0014904
Likely inborn error of metabolism v2.42 NUS1 Eleanor Williams Publications for gene: NUS1 were set to
Likely inborn error of metabolism v2.41 NUS1 Eleanor Williams edited their review of gene: NUS1: Added comment: Provisionally associated with ?Congenital disorder of glycosylation, type 1aa #617082 (AR) in OMIM based on family reported in Park et al 2014 (PMID: 25066056). They describe a family of Roma origin in which 2 out of 4 siblings presented with congenital scoliosis, severe neurological impairment, refractory epilepsy, hearing deficit and visual impairment with discrete bilateral macular lesions. A homozgyous missense mutation, R290H, was found in NUS1 (called NGBR in the paper) by exome sequencing. It segregated with the disease in the family. Patient fibroblasts showed reduced dolichol profiles and enhanced accumulation of free cholesterol as do fibroblasts from mice lacking NgBR.; Changed publications: 25066056; Changed phenotypes: ?Congenital disorder of glycosylation, type 1aa OMIM:617082, congenital disorder of glycosylation, type IAA MONDO:0014904
Likely inborn error of metabolism v2.41 NUS1 Eleanor Williams reviewed gene: NUS1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Congenital disorder of glycosylation, type 1aa 617082 AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.702 NUS1 Eleanor Williams edited their review of gene: NUS1: Changed rating: GREEN
Intellectual disability v3.702 NUS1 Eleanor Williams Added comment: Comment on mode of inheritance: The mode of inheritance should be considered for change to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal in line with its classification on the Genetic Epilepsy Syndromes panel.
Intellectual disability v3.702 NUS1 Eleanor Williams Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.701 NUS1 Eleanor Williams Classified gene: NUS1 as Amber List (moderate evidence)
Intellectual disability v3.701 NUS1 Eleanor Williams Added comment: Comment on list classification: Due to further reported cases, and review on the Genetic epilepsy syndromes by Helen Lord this gene should be considered for a green rating as GMS review.
Intellectual disability v3.701 NUS1 Eleanor Williams Gene: nus1 has been classified as Amber List (Moderate Evidence).
Distal myopathies v1.29 LRIF1 Eleanor Williams Classified gene: LRIF1 as Amber List (moderate evidence)
Distal myopathies v1.29 LRIF1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, and there is one case plus some functional data.
Distal myopathies v1.29 LRIF1 Eleanor Williams Gene: lrif1 has been classified as Amber List (Moderate Evidence).
Distal myopathies v1.28 LRIF1 Eleanor Williams gene: LRIF1 was added
gene: LRIF1 was added to Distal myopathies. Sources: Literature
Mode of inheritance for gene: LRIF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRIF1 were set to 32467133
Phenotypes for gene: LRIF1 were set to Facioscapulohumeral muscular dystrophy
Review for gene: LRIF1 was set to AMBER
Added comment: Review from Bryony Thompson (Royal Melbourne Hospital) on gene in PanelApp Australia.
https://panelapp.agha.umccr.org/panels/328/gene/LRIF1/:
A single consanguineous case with a homozygous truncating variant, and D4Z4 repeat of 13 units on a 4qA haplotype (permissive haplotype). DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.15 LRIF1 Eleanor Williams Classified gene: LRIF1 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.15 LRIF1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, and there is one case plus some functional data.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.15 LRIF1 Eleanor Williams Gene: lrif1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.14 LRIF1 Eleanor Williams gene: LRIF1 was added
gene: LRIF1 was added to Limb girdle muscular dystrophy. Sources: Literature
Mode of inheritance for gene: LRIF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRIF1 were set to 32467133
Phenotypes for gene: LRIF1 were set to Facioscapulohumeral muscular dystrophy
Review for gene: LRIF1 was set to AMBER
Added comment: Review from Bryony Thompson (Royal Melbourne Hospital) on gene in PanelApp Australia.
https://panelapp.agha.umccr.org/panels/328/gene/LRIF1/:
A single consanguineous case with a homozygous truncating variant, and D4Z4 repeat of 13 units on a 4qA haplotype (permissive haplotype). DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature
Monogenic hearing loss v2.145 GJB3 Eleanor Williams Classified gene: GJB3 as Green List (high evidence)
Monogenic hearing loss v2.145 GJB3 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green for now, but with recommendation of review at the next GMS update.
Monogenic hearing loss v2.145 GJB3 Eleanor Williams Gene: gjb3 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.144 GJB3 Eleanor Williams Tag for-review tag was added to gene: GJB3.
Monogenic hearing loss v2.144 GJB3 Eleanor Williams changed review comment from: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen.

A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell

Monoallelic cases:
PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER).

PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss.

PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects.

PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene.

PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed.

PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed.

PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant.

PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31.

PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed.

PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype.

PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr.

Biallelic cases:
PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del.

Functional studies:
PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.; to: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen.

A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in to the cell surface in a similar way to wild type protein.

Monoallelic cases:
PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER).

PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss.

PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects.

PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene.

PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed.

PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed.

PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant.

PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31.

PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed.

PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype.

PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr.

Biallelic cases:
PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del.

Functional studies:
PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WT Cx31.
Monogenic hearing loss v2.144 GJB3 Eleanor Williams changed review comment from: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen.

A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in many cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535) . 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell

Monoallelic cases:
PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER).

PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss.

PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects.

PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene.

PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed.

PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed.

PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant.

PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31.

PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed.

PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype.

PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr.

Biallelic cases:
PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del.

Functional studies:
PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.; to: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen.

A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell

Monoallelic cases:
PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER).

PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss.

PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects.

PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene.

PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed.

PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed.

PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant.

PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31.

PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed.

PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype.

PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr.

Biallelic cases:
PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del.

Functional studies:
PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.
Ectodermal dysplasia v1.15 LSS Eleanor Williams Classified gene: LSS as Amber List (moderate evidence)
Ectodermal dysplasia v1.15 LSS Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber for now, but with a recommendation for consideration for a green rating following GMS review, if appropriate for the panel.
Ectodermal dysplasia v1.15 LSS Eleanor Williams Gene: lss has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.14 LSS Eleanor Williams gene: LSS was added
gene: LSS was added to Ectodermal dysplasia. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 32101538; 30401459; 30723320; 29016354
Phenotypes for gene: LSS were set to Hypotrichosis 14 OMIM:618275; hypotrichosis 14 MONDO:0032649
Review for gene: LSS was set to GREEN
Added comment: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30723320 - Besnard et al 2019 - report 7 unrelated families (11 individuals) with variants in LSS who present with alopecia (11/11), intellectual disability (10 mod/severe, 1 mild) and epilepsy (7/11). Segregation data shown for 6 families.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.

PMID: 29016354 - Chen and Lui 2017 - report a pediatric patient with congenital cataract, small penis, baldness and absence of eyebrows and compound heterozygous variants in LSS.
Sources: Literature
Non-syndromic hypotrichosis v1.7 LSS Eleanor Williams Publications for gene: LSS were set to 32101538; 30401459
Non-syndromic hypotrichosis v1.6 LSS Eleanor Williams edited their review of gene: LSS: Changed publications: 32101538, 30401459, 30723320, 29016354
Non-syndromic hypotrichosis v1.6 LSS Eleanor Williams Classified gene: LSS as Green List (high evidence)
Non-syndromic hypotrichosis v1.6 LSS Eleanor Williams Added comment: Comment on list classification: After consultation with Genomics England clinicians, promoting this gene from red to green as there are > 3 cases (some syndromic, some non-syndromic).
Non-syndromic hypotrichosis v1.6 LSS Eleanor Williams Gene: lss has been classified as Green List (High Evidence).
Holoprosencephaly - NOT chromosomal v2.14 STAG2 Sarah Leigh Tag for-review tag was added to gene: STAG2.
Holoprosencephaly - NOT chromosomal v2.14 STAG2 Sarah Leigh edited their review of gene: STAG2: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 6 variants reported in unrelated cases, together with supporting in situ and functional evidence (PMID 31334757).; Changed rating: GREEN; Changed publications: 31334757
Holoprosencephaly - NOT chromosomal v2.14 STAG2 Sarah Leigh Classified gene: STAG2 as Amber List (moderate evidence)
Holoprosencephaly - NOT chromosomal v2.14 STAG2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Holoprosencephaly - NOT chromosomal v2.14 STAG2 Sarah Leigh Gene: stag2 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly - NOT chromosomal v2.13 STAG2 Sarah Leigh Phenotypes for gene: STAG2 were changed from holoprosencephaly to Holoprosencephaly 13, X-linked OMIM:301043
Congenital myopathy v2.18 KY Sarah Leigh Classified gene: KY as Amber List (moderate evidence)
Congenital myopathy v2.18 KY Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital myopathy v2.18 KY Sarah Leigh Gene: ky has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.17 KY Sarah Leigh Tag for-review tag was added to gene: KY.
Congenital myopathy v2.17 KY Sarah Leigh reviewed gene: KY: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital myopathy v2.17 KY Sarah Leigh Phenotypes for gene: KY were changed from congenital myopathy to Myopathy, myofibrillar 7 OMIM:617114
Congenital myopathy v2.16 KY Sarah Leigh Publications for gene: KY were set to 27484770
Congenital myopathy v2.15 HNRNPA2B1 Sarah Leigh Tag watchlist tag was added to gene: HNRNPA2B1.
Tag for-review tag was added to gene: HNRNPA2B1.
Congenital myopathy v2.15 HNRNPA2B1 Sarah Leigh Publications for gene: HNRNPA2B1 were set to
Congenital myopathy v2.14 HNRNPA2B1 Sarah Leigh Mode of inheritance for gene: HNRNPA2B1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v2.13 HNRNPA2B1 Sarah Leigh Classified gene: HNRNPA2B1 as Amber List (moderate evidence)
Congenital myopathy v2.13 HNRNPA2B1 Sarah Leigh Added comment: Comment on list classification: De novo terminating variants clustered in the C-terminus of the protein have been reported in six unrelated families all with a distinct class of dominantly-acting heterozygous variants in hnRNPA2B1 with a unique clinical phenotype of early childhood-onset progressive muscle weakness, ophthalmoplegia, ptosis, dysphagia, and variable degrees of respiratory insufficiency but no dementia (https://www.nmd-journal.com/article/S0960-8966(20)30203-0/fulltext). This source is a meeting abstract an there is no peer reviewed source at this time.
Congenital myopathy v2.13 HNRNPA2B1 Sarah Leigh Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Tag watchlist tag was added to gene: HNRNPA2B1.
Tag for-review tag was added to gene: HNRNPA2B1.
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Publications for gene: HNRNPA2B1 were set to
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Classified gene: HNRNPA2B1 as Amber List (moderate evidence)
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Added comment: Comment on list classification: De novo terminating variants clustered in the C-terminus of the protein have been reported in six unrelated families all with a distinct class of dominantly-acting heterozygous variants in hnRNPA2B1 with a unique clinical phenotype of early childhood-onset progressive muscle weakness, ophthalmoplegia, ptosis, dysphagia, and variable degrees of respiratory insufficiency but no dementia (https://www.nmd-journal.com/article/S0960-8966(20)30203-0/fulltext).
This source is a meeting abstract an there is no peer reviewed source at this time.
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.27 NF2 Eleanor Williams Classified gene: NF2 as Red List (low evidence)
Structural eye disease v1.27 NF2 Eleanor Williams Added comment: Comment on list classification: Leaving this gene for red now, but flagging for review by the GMS as ocular manifestations other than cataracts are seen in some patients.
Structural eye disease v1.27 NF2 Eleanor Williams Gene: nf2 has been classified as Red List (Low Evidence).
Structural eye disease v1.26 NF2 Eleanor Williams Phenotypes for gene: NF2 were changed from Neurofibromatosis, Type II, 101000 to Neurofibromatosis, type 2 OMIM:101000; neurofibromatosis type 2 MONDO:0007039
Structural eye disease v1.25 NF2 Eleanor Williams Publications for gene: NF2 were set to
Structural eye disease v1.24 NF2 Eleanor Williams edited their review of gene: NF2: Changed rating: AMBER; Changed publications: 33075808, 31089872, 29923868, 9246269, 12210058; Changed phenotypes: Neurofibromatosis, type 2 OMIM:101000, neurofibromatosis type 2 MONDO:0007039; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v1.24 NF2 Eleanor Williams Tag for review tag was added to gene: NF2.
Structural eye disease v1.24 NF2 Eleanor Williams changed review comment from: PMID: 33075808 - Sun et al 2020 - mouse model of Nf2 inactivation in embryonic eyes shows increased retinal pigmented epithelium proliferation which they propose cause defects resulting in persistent coloboma.; to: PMID: 33075808 - Sun et al 2020 - mouse model of Nf2 inactivation in embryonic eyes shows increased retinal pigmented epithelium proliferation which they propose cause defects resulting in persistent coloboma.

Additional papers supporting association of variants in NF2 and eye abnormalities

PMID: 31089872 - Waisberg et al 2019 - report on the eye examination of 8 unrelated NF2 patients from Brazil. 6 had germline variants (nonsense, frameshift, or splice site) in NF2. Ophthalmological features were present in all patients and varied from subtle retinal changes to a severe ocular phenotype preset at birth. Of those 6 with NF2 variants: cataracts 4/6, Hamartoma 4/6, Flame-shaped ERM 5/6, Strabismus 3/6, Retinal Tuft 2/6 and Choroidal nodules 3/6.

PMID: 29923868 - Painter et al 2019 - reviewed longitudinal ophthalmological data of 83 patients with NF2 who had a mutation present on blood testing, or identical mutations found in 2 or more tissue samples, or they met the updated Manchester modified criteria for a clinical diagnosis of NF2. Mutations in NF2 associated with severe systemic disease were found to result in greater visual morbidity at an earlier age.

PMID: 12210058 - Chan et al 2002 - looked at 40 ocular lesions from four NF2 patients, from three unrelated families. All had germline nonsense mutations in NF2. Cataracts were evident by pseudophakia in seven eyes, iris naevoid hyperplasia at the anterior surface in two eyes of two patients, and retinal lesions in all eyes.

PMID: 9246269 - Ragge et al 1997 - report 5 unrelated cases of patients with Neurofibromatosis 2 to illustrate the diverse ocular phenotypes seen in patients. Molecular analysis not given. The authors note that ocular manifestations are often the first sign of disease.
Retinal disorders v2.120 HK1 Ivone Leong commented on gene: HK1
Retinal disorders v2.120 HK1 Ivone Leong Tag for-review tag was added to gene: HK1.
Retinal disorders v2.120 HK1 Ivone Leong Publications for gene: HK1 were set to 25190649; 25316723
Retinal disorders v2.119 HK1 Ivone Leong Phenotypes for gene: HK1 were changed from Retinitis pigmentosa 79 617460 to Retinitis pigmentosa 79, OMIM:617460, MONDO:0044320
Differences in sex development v2.14 TSPYL1 Eleanor Williams Classified gene: TSPYL1 as Amber List (moderate evidence)
Differences in sex development v2.14 TSPYL1 Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber, but there are 3 cases now reported and so this gene should be reviewed at the next GMS update.
Differences in sex development v2.14 TSPYL1 Eleanor Williams Gene: tspyl1 has been classified as Amber List (Moderate Evidence).
Differences in sex development v2.13 TSPYL1 Eleanor Williams Phenotypes for gene: TSPYL1 were changed from Sudden infant death with dysgenesis of the testes syndrome 608800 to Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Differences in sex development v2.12 TSPYL1 Eleanor Williams Publications for gene: TSPYL1 were set to 15273283; 22137496; 19463995
Differences in sex development v2.11 TSPYL1 Eleanor Williams Tag for-review tag was added to gene: TSPYL1.
Differences in sex development v2.11 TSPYL1 Eleanor Williams reviewed gene: TSPYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32885560, 33075815; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome OMIM:608800, sudden infant death-dysgenesis of the testes syndrome MONDO:0012124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial non syndromic congenital heart disease v1.54 MYH6 Sarah Leigh Publications for gene: MYH6 were set to 15735645, 20656787
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.102 EZH2 Sarah Leigh Tag for-review tag was added to gene: EZH2.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.102 EZH2 Sarah Leigh Added comment: Comment on mode of inheritance: EZH2 is a epigene, where LOF or GOF variants result in a characteristic genome-wide, multilocus DNA methylation signature in the carrier. There does not appear to be evidence for allele specificity of this effect and so this gene should not be regarded as imprinted (PMID 32243864).
Therefore, the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.102 EZH2 Sarah Leigh Mode of inheritance for gene: EZH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Sudden death in young people v1.15 TSPYL1 Eleanor Williams Classified gene: TSPYL1 as Green List (high evidence)
Sudden death in young people v1.15 TSPYL1 Eleanor Williams Added comment: Comment on list classification: Promoting to green as there are now 3 independent cases of patients with plausible disease cause variants in this gene with SIDDT
Sudden death in young people v1.15 TSPYL1 Eleanor Williams Gene: tspyl1 has been classified as Green List (High Evidence).
Sudden death in young people v1.14 TSPYL1 Eleanor Williams Phenotypes for gene: TSPYL1 were changed from Sudden infant death with dysgenesis of the testes syndrome,608800; SIDDT to Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Sudden death in young people v1.13 TSPYL1 Eleanor Williams Publications for gene: TSPYL1 were set to
Sudden death in young people v1.12 TSPYL1 Eleanor Williams reviewed gene: TSPYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32885560, 33075815, 15273283, 25449952, 16418600, 19463995, 22137496; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome OMIM:608800, sudden infant death-dysgenesis of the testes syndrome MONDO:0012124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.118 NEUROD1 Ivone Leong Mode of inheritance for gene: NEUROD1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.117 HARS Ivone Leong commented on gene: HARS
Retinal disorders v2.117 HARS Ivone Leong Tag for-review tag was added to gene: HARS.
Retinal disorders v2.117 HARS Ivone Leong Publications for gene: HARS were set to
Retinal disorders v2.116 CTSF Ivone Leong changed review comment from: Comment on list classification: This gene is associated with Ceroid lipofuscinosis, neuronal, 13, Kufs type (also known as Kufs disease or Adult neuronal ceroid lipofuscinosis) in OMIM but not in Gene2Phenotype.

While neuronal ceroid lipofuscinosis are characterized by lysosomal lipopigment storage in neurons, and usually the eye, and cause progressive neurological impairment, motor and intellectual deterioration, seizures, visual failure, and early death, Kufs disease is different. For Kufs disease the retina is not involvolved and the onset is in adulthood (PMID: 21549341). Because of this CTSF has been given a Red rating.; to: Comment on list classification: This gene is associated with Ceroid lipofuscinosis, neuronal, 13, Kufs type (also known as Kufs disease or Adult neuronal ceroid lipofuscinosis) in OMIM but not in Gene2Phenotype.

While neuronal ceroid lipofuscinosis are characterized by lysosomal lipopigment storage in neurons, and usually the eye, and cause progressive neurological impairment, motor and intellectual deterioration, seizures, visual failure, and early death, Kufs disease is different. For Kufs disease the retina is not involvolved and the onset is in adulthood (PMID: 21549341). Based on the phenotype, this gene has been given a Red rating as the phenotype does not fit this panel.
Retinal disorders v2.116 CTSF Ivone Leong Classified gene: CTSF as Red List (low evidence)
Retinal disorders v2.116 CTSF Ivone Leong Added comment: Comment on list classification: This gene is associated with Ceroid lipofuscinosis, neuronal, 13, Kufs type (also known as Kufs disease or Adult neuronal ceroid lipofuscinosis) in OMIM but not in Gene2Phenotype.

While neuronal ceroid lipofuscinosis are characterized by lysosomal lipopigment storage in neurons, and usually the eye, and cause progressive neurological impairment, motor and intellectual deterioration, seizures, visual failure, and early death, Kufs disease is different. For Kufs disease the retina is not involvolved and the onset is in adulthood (PMID: 21549341). Because of this CTSF has been given a Red rating.
Retinal disorders v2.116 CTSF Ivone Leong Gene: ctsf has been classified as Red List (Low Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 TLK2 Arina Puzriakova Phenotypes for gene: TLK2 were changed from AD MR type 57 - 618050 to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837
Intellectual disability v3.700 TLK2 Arina Puzriakova Phenotypes for gene: TLK2 were changed from intellectual disability to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but may be promoted to Green at the next GMS panel update (added for-review' tag).

Sufficient number of unrelated cases (3) with microcephaly of relevant severity to this panel (more than -3 SD). Truncating variants appear to be associated with a more severe disease presentation (PMID: 33397746).
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.66 ZNF526 Arina Puzriakova gene: ZNF526 was added
gene: ZNF526 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: ZNF526.
Mode of inheritance for gene: ZNF526 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF526 were set to 33397746
Phenotypes for gene: ZNF526 were set to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Review for gene: ZNF526 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last updated on 09/12/2011), but has a 'possible' disease confidence rating for 'Autosomal Recessive Mental Retardation' in Gene2Phenotype.

- PMID: 33397746 (2021) - Five individuals from four unrelated families with homozygous ZNF526 variants. Four harboured truncating variants, and were all affected by profound DD and severe ID, microcephaly (ranging from -4 SD to -8 SD), bilateral progressive cataracts, hypertonic-dystonic movements, epilepsy and brain MRI anomalies. The fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe ID, and normal brain MRI. Zebrafish model demonstrated brain and eye malformations resembling findings seen in the human holoprosencephaly spectrum
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.56 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.56 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added for-review' tag).

At least 5 individuals from 4 unrelated families all presenting bilateral ocular cataracts, among other features (PMID: 33397746)
Bilateral congenital or childhood onset cataracts v2.56 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.55 ZNF526 Arina Puzriakova gene: ZNF526 was added
gene: ZNF526 was added to Cataracts. Sources: Literature
for-review tags were added to gene: ZNF526.
Mode of inheritance for gene: ZNF526 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF526 were set to 33397746
Phenotypes for gene: ZNF526 were set to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Review for gene: ZNF526 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last updated on 09/12/2011), but has a 'possible' disease confidence rating for 'Autosomal Recessive Mental Retardation' in Gene2Phenotype.

- PMID: 33397746 (2021) - Five individuals from four unrelated families with homozygous ZNF526 variants. Four harboured truncating variants, and were all affected by profound DD and severe ID, microcephaly (ranging from -4 SD to -8 SD), bilateral progressive cataracts, hypertonic-dystonic movements, epilepsy and brain MRI anomalies. The fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe ID, and normal brain MRI. Zebrafish model demonstrated brain and eye malformations resembling findings seen in the human holoprosencephaly spectrum
Sources: Literature
Retinal disorders v2.115 CIB2 Ivone Leong commented on gene: CIB2
Intellectual disability v3.699 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
Intellectual disability v3.699 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but can be rated Green at the next GMS panel update (added 'for-review' tag).

Truncating variants associated with a more severe disease presentation; however, ID is the universal feature among individuals with biallelic variants in this gene.
Intellectual disability v3.699 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.115 CIB2 Ivone Leong Tag for-review tag was added to gene: CIB2.
Intellectual disability v3.698 ZNF526 Arina Puzriakova Phenotypes for gene: ZNF526 were changed from Non-syndromic autosomal recessive intellectual disability to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Intellectual disability v3.697 ZNF526 Arina Puzriakova Publications for gene: ZNF526 were set to 21937992; 27012031
Intellectual disability v3.696 ZNF526 Arina Puzriakova Tag for-review tag was added to gene: ZNF526.
Retinal disorders v2.115 ROM1 Ivone Leong Phenotypes for gene: ROM1 were changed from Retinitis pigmentosa 7, digenic; Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis pigmentosa; Retinitis pigmentosa 7, digenic, 608133 to Retinitis pigmentosa 7, digenic, OMIM:608133
Retinal disorders v2.114 ROM1 Ivone Leong Publications for gene: ROM1 were set to 8595413; 32716032
Intellectual disability v3.696 ZNF526 Arina Puzriakova reviewed gene: ZNF526: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 25558065, 33397746; Phenotypes: Intellectual disability, Microcephaly, Cataracts, Epilepsy, Hypertonia, Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.113 PNPLA6 Ivone Leong commented on gene: PNPLA6: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at the next review.
Retinal disorders v2.113 PNPLA6 Ivone Leong Mode of inheritance for gene: PNPLA6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.112 PNPLA6 Ivone Leong Tag for-review tag was added to gene: PNPLA6.
Retinal disorders v2.112 PNPLA6 Ivone Leong Phenotypes for gene: PNPLA6 were changed from to Boucher-Neuhauser syndrome, OMIM:215470; Oliver-McFarlane syndrome, OMIM:275400; ?Laurence-Moon syndrome, OMIM:245800
Retinal disorders v2.111 PNPLA6 Ivone Leong Publications for gene: PNPLA6 were set to
Retinal disorders v2.110 TUBGCP6 Ivone Leong commented on gene: TUBGCP6: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Retinal disorders v2.110 TUBGCP6 Ivone Leong Added comment: Comment on publications: PMID: 31077665 extra case
Retinal disorders v2.110 TUBGCP6 Ivone Leong Publications for gene: TUBGCP6 were set to 22279524; 25344692
Retinal disorders v2.109 TUBGCP6 Ivone Leong Mode of inheritance for gene: TUBGCP6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.108 TUBGCP6 Ivone Leong Tag for-review tag was added to gene: TUBGCP6.
Retinal disorders v2.108 TUBGCP6 Ivone Leong Phenotypes for gene: TUBGCP6 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 1, OMIM:251270; microcephaly and chorioretinopathy 1, MONDO:0009624
Retinal disorders v2.107 TUBGCP6 Ivone Leong Publications for gene: TUBGCP6 were set to
Anophthalmia or microphthalmia v1.35 PLK4 Ivone Leong Classified gene: PLK4 as Amber List (moderate evidence)
Anophthalmia or microphthalmia v1.35 PLK4 Ivone Leong Gene: plk4 has been classified as Amber List (Moderate Evidence).
Anophthalmia or microphthalmia v1.34 PLK4 Ivone Leong gene: PLK4 was added
gene: PLK4 was added to Anophthalmia or microphthalmia. Sources: Literature
watchlist tags were added to gene: PLK4.
Mode of inheritance for gene: PLK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK4 were set to 25344692; 25320347; 27650967
Phenotypes for gene: PLK4 were set to Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171; microcephaly and chorioretinopathy 2, MONDO:0014516
Review for gene: PLK4 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25344692 describes 3 unrelated families with affected individuals who have biallelic variants in PLK4. All affected individuals have impaired growth/short stature. In one family 3 out of 7 affected individuals have an eye phenotype (ranging from microcornea, microphthalmia and cataract). Family 2 had retinopathy and family 3 did not have an eye exam performed.

PMID: 27650967 describes a case where the affected individual has bilateral microphthalmia and persistant hyperplastic primary vitreous of the left eye. The affected individual also has growth impairment.

PMID: 25320347 describes a case where the affected individuals have retinopathy and impaired growth.

As there are 2 unrelated cases there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Sources: Literature
Structural eye disease v1.24 PLK4 Ivone Leong Classified gene: PLK4 as Amber List (moderate evidence)
Structural eye disease v1.24 PLK4 Ivone Leong Gene: plk4 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.23 PLK4 Ivone Leong gene: PLK4 was added
gene: PLK4 was added to Structural eye disease. Sources: Literature
watchlist tags were added to gene: PLK4.
Mode of inheritance for gene: PLK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK4 were set to 25344692; 25320347; 27650967
Phenotypes for gene: PLK4 were set to Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171; microcephaly and chorioretinopathy 2, MONDO:0014516
Review for gene: PLK4 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25344692 describes 3 unrelated families with affected individuals who have biallelic variants in PLK4. All affected individuals have impaired growth/short stature. In one family 3 out of 7 affected individuals have an eye phenotype (ranging from microcornea, microphthalmia and cataract). Family 2 had retinopathy and family 3 did not have an eye exam performed.

PMID: 27650967 describes a case where the affected individual has bilateral microphthalmia and persistant hyperplastic primary vitreous of the left eye. The affected individual also has growth impairment.

PMID: 25320347 describes a case where the affected individuals have retinopathy and impaired growth.

As there are 2 unrelated cases there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Sources: Literature
Retinal disorders v2.106 PLK4 Ivone Leong commented on gene: PLK4: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Retinal disorders v2.106 PLK4 Ivone Leong Tag for-review tag was added to gene: PLK4.
Retinal disorders v2.106 TMEM216 Ivone Leong Publications for gene: TMEM216 were set to
Retinal disorders v2.105 TMEM216 Ivone Leong Mode of inheritance for gene: TMEM216 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.104 PLK4 Ivone Leong Mode of inheritance for gene: PLK4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.103 PLK4 Ivone Leong Phenotypes for gene: PLK4 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171; microcephaly and chorioretinopathy 2, MONDO:0014516
Retinal disorders v2.102 PLK4 Ivone Leong Publications for gene: PLK4 were set to
Retinal disorders v2.101 PEX6 Ivone Leong Phenotypes for gene: PEX6 were changed from Heimler syndrome 2, MIM# 616617 to Heimler syndrome 2, OMIM:616617, MONDO:0014709
Retinal disorders v2.100 P3H2 Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.; to: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. The GMS specialist group should review whether the phenotype for this gene is relevant for inclusion in this panel.
Retinal disorders v2.100 P3H2 Ivone Leong Classified gene: P3H2 as Amber List (moderate evidence)
Retinal disorders v2.100 P3H2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.
Retinal disorders v2.100 P3H2 Ivone Leong Gene: p3h2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.99 P3H2 Ivone Leong Tag for-review tag was added to gene: P3H2.
Retinal disorders v2.99 P3H2 Ivone Leong Mode of inheritance for gene: P3H2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.98 P3H2 Ivone Leong Phenotypes for gene: P3H2 were changed from Myopia, high, with cataract and vitreoretinal degeneration, 614292 -3 to Myopia, high, with cataract and vitreoretinal degeneration, OMIM:614292, MONDO:0013670
Retinal disorders v2.97 P3H2 Ivone Leong Publications for gene: P3H2 were set to
Intellectual disability v3.696 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957
Early onset or syndromic epilepsy v2.255 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957; 25326637
Hereditary ataxia with onset in adulthood v2.20 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Complex cortical dysplasia with other brain malformations 5, 615763 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Early onset or syndromic epilepsy v2.254 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Cortical dysplasia, complex, with other brain malformations 5, 615763; infantile-onset epilepsy to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Retinal disorders v2.96 NEUROD1 Ivone Leong Phenotypes for gene: NEUROD1 were changed from to Retinitis pigmentosa; Retinopathy; Permanent neonatal diabetes
Intellectual disability v3.695 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 5 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Retinal disorders v2.95 NEUROD1 Ivone Leong Publications for gene: NEUROD1 were set to
Fetal anomalies v1.136 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 5 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Cerebral vascular malformations v2.8 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Cerebral Malformation Disorders to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Malformations of cortical development v2.24 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Cortical dysplasia, complex, with other brain malformations 5 615763 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Retinal disorders v2.94 MTTP Ivone Leong Classified gene: MTTP as Amber List (moderate evidence)
Retinal disorders v2.94 MTTP Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases listed in OMIM. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.94 MTTP Ivone Leong Gene: mttp has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.23 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957
Retinal disorders v2.93 MTTP Ivone Leong Tag for-review tag was added to gene: MTTP.
Retinal disorders v2.93 MTTP Ivone Leong Mode of inheritance for gene: MTTP was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.92 MTTP Ivone Leong Phenotypes for gene: MTTP were changed from Eye Disorders to Abetalipoproteinemia, OMIM:200100, MONDO:0008692
Retinal disorders v2.91 MSTO1 Ivone Leong Classified gene: MSTO1 as Amber List (moderate evidence)
Retinal disorders v2.91 MSTO1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and not in Gene2Phenotype. There are at least 7 unrelated cases who are biallelic for variants in this gene and 1 family of patients (4 affected) who are monoallelic for variants in this gene.

For patients who are biallelic, there are 3 cases that reported pigmentary retinopathy. 5 out of 7 cases had growth impairments. For patients who are monoallelic there are no ophthalmological findings and growth impairment was only reported for 1 affected individual.

As not all affected individuals with biallelic variants showed a retinal disorder this gene has been given an Amber rating. Whether there is enough evidence to support a gene-disease association and for this gene to be rated Green should be reviewed by the GMS specialist group.
Retinal disorders v2.91 MSTO1 Ivone Leong Gene: msto1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.90 MSTO1 Ivone Leong Tag for-review tag was added to gene: MSTO1.
Retinal disorders v2.90 MSTO1 Ivone Leong Publications for gene: MSTO1 were set to 29339779; 28544275
Retinal disorders v2.89 MSTO1 Ivone Leong Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia MIM#617675 to Myopathy, mitochondrial, and ataxia, OMIM:617675
Retinal disorders v2.88 MMACHC Ivone Leong Classified gene: MMACHC as Amber List (moderate evidence)
Retinal disorders v2.88 MMACHC Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 cases in the literature; therefore, there is enough evidence to support a gene-disease association. This gene has been rated Amber and should be given Green status at the next review.
Retinal disorders v2.88 MMACHC Ivone Leong Gene: mmachc has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.87 MMACHC Ivone Leong Tag for-review tag was added to gene: MMACHC.
Retinal disorders v2.87 MMACHC Ivone Leong Phenotypes for gene: MMACHC were changed from Methylmalonic aciduria and homocystinuria, cblC type MIM#277400 to Methylmalonic aciduria and homocystinuria, cblC type, OMIM:277400, MONDO:0010184
Retinal disorders v2.86 MMACHC Ivone Leong Publications for gene: MMACHC were set to 28481040
Albinism or congenital nystagmus v1.10 LAMA1 Ivone Leong Classified gene: LAMA1 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.10 LAMA1 Ivone Leong Gene: lama1 has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v1.9 LAMA1 Ivone Leong gene: LAMA1 was added
gene: LAMA1 was added to Albinism or congenital nystagmus. Sources: Literature
for-review tags were added to gene: LAMA1.
Mode of inheritance for gene: LAMA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA1 were set to 25105227; 28283601; 33251915; 29167897; 328840387; 32195884
Phenotypes for gene: LAMA1 were set to Poretti-Boltshauser syndrome, OMIM:615960
Review for gene: LAMA1 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases of this affected gene in patients who have an eye phenotype, 6 out of 11 cases have nystagmus. There is enough evidence to support a gene-disease association and this gene should be considered for Green status at the next review.
Sources: Literature
Retinal disorders v2.85 LAMA1 Ivone Leong changed review comment from: This gene is associated with an relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases and therefore enough evidence to support a gene-disease association. This gene should be given a Green status at the next review.; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases and therefore enough evidence to support a gene-disease association. This gene should be given a Green status at the next review.
Retinal disorders v2.85 LAMA1 Ivone Leong commented on gene: LAMA1: This gene is associated with an relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases and therefore enough evidence to support a gene-disease association. This gene should be given a Green status at the next review.
Retinal disorders v2.85 LAMA1 Ivone Leong Tag for-review tag was added to gene: LAMA1.
Retinal disorders v2.85 LAMA1 Ivone Leong Publications for gene: LAMA1 were set to 25105227
Retinal disorders v2.84 LAMA1 Ivone Leong Publications for gene: LAMA1 were set to
Retinal disorders v2.83 LAMA1 Ivone Leong Mode of inheritance for gene: LAMA1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.82 LAMA1 Ivone Leong Phenotypes for gene: LAMA1 were changed from to Poretti-Boltshauser syndrome, OMIM:615960
Retinal disorders v2.81 IFT81 Ivone Leong Phenotypes for gene: IFT81 were changed from to Short-rib thoracic dysplasia 19 with or without polydactyly, OMIM:617895,MONDO:0033485
Retinal disorders v2.80 IFT81 Ivone Leong Mode of inheritance for gene: IFT81 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.79 IFT81 Ivone Leong Publications for gene: IFT81 were set to
Ophthalmological ciliopathies v1.15 IFT74 Ivone Leong Publications for gene: IFT74 were set to 27486776
Ophthalmological ciliopathies v1.14 IFT74 Ivone Leong Classified gene: IFT74 as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.14 IFT74 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 32144365 is the second case for this gene. Taken together there are 2 cases and an animal model. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.
Ophthalmological ciliopathies v1.14 IFT74 Ivone Leong Gene: ift74 has been classified as Amber List (Moderate Evidence).
Bardet Biedl syndrome v1.9 IFT74 Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.; to: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 32144365 is the second case for this gene. Taken together there are 2 cases and an animal model. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.
Ophthalmological ciliopathies v1.13 IFT74 Ivone Leong Tag for-review tag was added to gene: IFT74.
Rare multisystem ciliopathy disorders v1.132 IFT74 Ivone Leong Publications for gene: IFT74 were set to 27486776
Rare multisystem ciliopathy disorders v1.131 IFT74 Ivone Leong Classified gene: IFT74 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.131 IFT74 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 32144365 is the second case for this gene. Taken together there are 2 cases and an animal model. There is enough evidence to support a gene-disease association.
Rare multisystem ciliopathy disorders v1.131 IFT74 Ivone Leong Gene: ift74 has been classified as Green List (High Evidence).
Bardet Biedl syndrome v1.9 IFT74 Ivone Leong Publications for gene: IFT74 were set to 27486776
Bardet Biedl syndrome v1.8 IFT74 Ivone Leong Classified gene: IFT74 as Amber List (moderate evidence)
Bardet Biedl syndrome v1.8 IFT74 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.
Bardet Biedl syndrome v1.8 IFT74 Ivone Leong Gene: ift74 has been classified as Amber List (Moderate Evidence).
Bardet Biedl syndrome v1.7 IFT74 Ivone Leong Tag for-review tag was added to gene: IFT74.
Retinal disorders v2.78 IFT74 Ivone Leong Classified gene: IFT74 as Amber List (moderate evidence)
Retinal disorders v2.78 IFT74 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.
Retinal disorders v2.78 IFT74 Ivone Leong Gene: ift74 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.77 IFT74 Ivone Leong Tag for-review tag was added to gene: IFT74.
Retinal disorders v2.77 IFT74 Ivone Leong Phenotypes for gene: IFT74 were changed from Bardet-Biedl syndrome 20, MIM# 617119 to ?Bardet-Biedl syndrome 20, OMIM:617119
Retinal disorders v2.76 IFT27 Ivone Leong Phenotypes for gene: IFT27 were changed from to ?Bardet-Biedl syndrome 19, OMIM:615996
Retinal disorders v2.75 IFT27 Ivone Leong Publications for gene: IFT27 were set to
Retinal disorders v2.74 IFT172 Ivone Leong commented on gene: IFT172: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough data to support a gene-disease association. This gene should be made Green at the next review (tagged with "for-review").

This gene is also Green on the following panels:
- Ophthalmological ciliopathies (Version 1.13)
- Skeletal ciliopathies (Version 1.4)
- Rare multisystem ciliopathy disorders (Version 1.130)
Retinal disorders v2.74 IFT172 Ivone Leong Tag for-review tag was added to gene: IFT172.
Retinal disorders v2.74 IFT172 Ivone Leong Mode of inheritance for gene: IFT172 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.73 IFT172 Ivone Leong Phenotypes for gene: IFT172 were changed from to Retinitis pigmentosa 71, OMIM:616394, MONDO:0014618
Retinal disorders v2.72 IFT172 Ivone Leong Publications for gene: IFT172 were set to
Early onset or syndromic epilepsy v2.253 GRN Ivone Leong Classified gene: GRN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.253 GRN Ivone Leong Gene: grn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.252 GRN Ivone Leong gene: GRN was added
gene: GRN was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 31855245; 28404863; 30922528
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; neuronal ceroid lipofuscinosis 1, MONDO:0013866
Review for gene: GRN was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Biallic variants in GRN cause Ceroid lipofuscinosis, neuronal, 11, which is characterised by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. There is enough evidence to support a gene-disease association. This gene has been promoted to Amber and should be considered for Green status at the next review.

This gene is also on the Retinal disorders panel (Version 2.71), with the following review:
"Multiple individuals reported with bi-allelic variants and CLN phenotype. Please also note literature regarding retinal abnormalities in those with mono-allelic variants.
Zornitza Stark (Australian Genomics), 11 Oct 2020"
Sources: Literature
Retinal disorders v2.71 GRN Ivone Leong Classified gene: GRN as Amber List (moderate evidence)
Retinal disorders v2.71 GRN Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been promoted to Amber and should be made Green at the next review.
Retinal disorders v2.71 GRN Ivone Leong Gene: grn has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.70 GRN Ivone Leong Tag for-review tag was added to gene: GRN.
Hereditary neuropathy or pain disorder v1.19 NUDT2 Zornitza Stark reviewed gene: NUDT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33058507, 27431290, 30059600, 33058507; Phenotypes: Muscular hypotonia, Global developmental delay, Intellectual disability, Polyneuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset neurodegenerative disorder v2.37 UQCRC1 Zornitza Stark gene: UQCRC1 was added
gene: UQCRC1 was added to Neurodegenerative disorders - adult onset. Sources: Literature
Mode of inheritance for gene: UQCRC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UQCRC1 were set to 33141179; 33248804
Phenotypes for gene: UQCRC1 were set to 33141179; 33248804
Review for gene: UQCRC1 was set to AMBER
Added comment: Three unrelated families reported in PMID 33141179 with some functional data, however PMID 33248804 failed to identify significant variants in this gene in a large PD cohort.
Sources: Literature
Early onset or syndromic epilepsy v2.251 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 33131106
Phenotypes for gene: CELF2 were set to Developmental and epileptic encephalopathy
Review for gene: CELF2 was set to GREEN
Added comment: Five unrelated individuals reported. Four with de novo variants, and one inherited from a mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal.
Sources: Literature
Intellectual disability v3.694 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
gene: FGF13 was marked as current diagnostic
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Skeletal dysplasia v2.42 SCUBE3 Zornitza Stark reviewed gene: SCUBE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33308444; Phenotypes: Short stature, skeletal abnormalities, craniofacial abnormalities, dental anomalies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.694 UBR7 Zornitza Stark reviewed gene: UBR7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33340455; Phenotypes: Intellectual disability, epilepsy, hypothyroidism, congenital anomalies, dysmorphic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.251 RALGAPB Zornitza Stark gene: RALGAPB was added
gene: RALGAPB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RALGAPB were set to 32853829
Phenotypes for gene: RALGAPB were set to Neurodevelopmental disorders, autism
Review for gene: RALGAPB was set to AMBER
Added comment: PMID: 32853829 - 2 patients with de novo missense variants, 1 patient with a de novo PTC with autism spectrum disorder from a large cohort.
Reviews previous publications and identifies 10 de novo variants (5 PTCs, 5 missense, epilepsy only present in 2/10 and ID in 1/10.

Variants in this gene cause a neurodevelopmental disorder, but autism seems to be the most prominent feature.
Sources: Literature
Intellectual disability v3.694 RNU7-1 Zornitza Stark gene: RNU7-1 was added
gene: RNU7-1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like
Review for gene: RNU7-1 was set to GREEN
gene: RNU7-1 was marked as current diagnostic
Added comment: Review originally submitted by Ming Wong
- 16 affected individuals from 11 families
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.18 RPL3L Zornitza Stark gene: RPL3L was added
gene: RPL3L was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL3L were set to 32514796; 32870709
Phenotypes for gene: RPL3L were set to Neonatal dilated cardiomyopathy
Review for gene: RPL3L was set to GREEN
gene: RPL3L was marked as current diagnostic
Added comment: PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype.
Sources: Literature
Intellectual disability v3.694 DPH2 Zornitza Stark gene: DPH2 was added
gene: DPH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH2 were set to 32576952; 27421267
Phenotypes for gene: DPH2 were set to Diphthamide-deficiency syndrome
Review for gene: DPH2 was set to AMBER
Added comment: One 19 month old reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency (gross motor delay, not walking, fine motor and expressive language delays, macrocephaly)

Another family (sibs) was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative. Patients had ID and microcephaly (in contrast to the 19 month old above).

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
Intellectual disability v3.694 FBRSL1 Zornitza Stark gene: FBRSL1 was added
gene: FBRSL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBRSL1 were set to 32424618
Phenotypes for gene: FBRSL1 were set to Intellectual disability; congenital anomalies
Review for gene: FBRSL1 was set to GREEN
gene: FBRSL1 was marked as current diagnostic
Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. 2/3 had heart defects, cleft palate and hearing impairement.
Supported by Xenopus oocyte functional studies
Sources: Literature
Severe microcephaly v2.65 CAMK2B Zornitza Stark gene: CAMK2B was added
gene: CAMK2B was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CAMK2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK2B were set to 32875707
Phenotypes for gene: CAMK2B were set to microcephaly; intellectual disability; behavioural problems
Review for gene: CAMK2B was set to GREEN
Added comment: 5 individuals in review of literature with same de novo monoallelic variant reported with microcephaly
Sources: Literature
Structural eye disease v1.22 CRYAA Zornitza Stark reviewed gene: CRYAA: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32791987; Phenotypes: Anterior segment dysgenesis, microphthalmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bilateral congenital or childhood onset cataracts v2.54 COL6A3 Zornitza Stark gene: COL6A3 was added
gene: COL6A3 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: COL6A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COL6A3 were set to 33304895
Phenotypes for gene: COL6A3 were set to Peters anomaly
Review for gene: COL6A3 was set to AMBER
Added comment: Not sure if this is the right panel for Peters anomaly.

Variants in this gene are associated with neurological phenotypes (myopathy, dystonia). Two families reported with bi-allelic missense variants in this gene and Peters anomaly, limited functional data.
Sources: Literature
Ocular coloboma v1.41 FZD5 Zornitza Stark gene: FZD5 was added
gene: FZD5 was added to Ocular coloboma. Sources: Literature
Mode of inheritance for gene: FZD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FZD5 were set to 32737437; 26908622
Phenotypes for gene: FZD5 were set to Coloboma
Review for gene: FZD5 was set to GREEN
gene: FZD5 was marked as current diagnostic
Added comment: Four unrelated families reported.
Sources: Literature
Primary ovarian insufficiency v1.19 NANOS3 Zornitza Stark reviewed gene: NANOS3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25054146, 24091668; Phenotypes: Primary ovarian insufficiency; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary ovarian insufficiency v1.19 MSH5 Zornitza Stark reviewed gene: MSH5: Rating: AMBER; Mode of pathogenicity: None; Publications: 28175301, 9916805, 24970489; Phenotypes: Premature ovarian failure 13 MIM#617442; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary ovarian insufficiency v1.19 FANCM Zornitza Stark gene: FANCM was added
gene: FANCM was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: FANCM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCM were set to 30075111; 29895858; 28837162
Phenotypes for gene: FANCM were set to Premature ovarian failure
Review for gene: FANCM was set to GREEN
Added comment: 2 Finnish sisters with non-syndromic POI with a homozygous mutation (p.Gln1701*), and supporting functional assays. 1 case with 2 truncating variants (phase unknown) and non-syndromic POI and MMC chromosome-induced breakage. 3/5 women with homozygous truncating variants and breast cancer also reported early menopause or ovarian insufficiency. Null mouse model demonstrates significant reduction in ovarian follicles.
Sources: Literature
Primary ovarian insufficiency v1.19 EIF4ENIF1 Zornitza Stark reviewed gene: EIF4ENIF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31810472, 23902945, 33095795; Phenotypes: 31810472, 23902945, 33095795; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary ovarian insufficiency v1.19 DIAPH2 Zornitza Stark reviewed gene: DIAPH2: Rating: RED; Mode of pathogenicity: None; Publications: 9497258, 30689869, 26175800, 11129329; Phenotypes: Premature ovarian failure 2A MIM#300511; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hypogonadotropic hypogonadism (GMS) v1.11 CCDC141 Zornitza Stark gene: CCDC141 was added
gene: CCDC141 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Literature
Mode of inheritance for gene: CCDC141 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CCDC141 were set to 27014940; 28324054; 25192046
Phenotypes for gene: CCDC141 were set to Anosmic hypogonadotropic hypogonadism
Review for gene: CCDC141 was set to AMBER
Added comment: A consanguineous family had a homozygous nonsense variant, but also had a homozygous missense in FEZF1. 3 other families reported with heterozygous variants, but other variants in other genes present. In an olfactory mouse model, Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration.
Sources: Literature
Intellectual disability v3.694 CDC40 Zornitza Stark gene: CDC40 was added
gene: CDC40 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDC40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC40 were set to 33220177
Phenotypes for gene: CDC40 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disability
Review for gene: CDC40 was set to RED
Added comment: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.

Gene referred to as PRP17 in paper.
Sources: Literature
Intellectual disability v3.694 CCDC40 Zornitza Stark Deleted their comment
Intellectual disability v3.694 CCDC40 Zornitza Stark commented on gene: CCDC40: PMID 33220177, provided in error, refers to CDC40.
Intellectual disability v3.694 CCDC40 Zornitza Stark Deleted their comment
Intellectual disability v3.694 CCDC40 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: ID is not part of the phenotype.
Intellectual disability v3.694 CCDC40 Zornitza Stark edited their review of gene: CCDC40: Added comment: New publication: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.; Changed publications: 33220177
Intellectual disability v3.694 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disbility
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Neurological ciliopathies v1.11 RABL2A Eleanor Williams gene: RABL2A was added
gene: RABL2A was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: RABL2A was set to Unknown
Publications for gene: RABL2A were set to 33075816
Phenotypes for gene: RABL2A were set to neural tube defects
Review for gene: RABL2A was set to RED
Added comment: PMID: 33075816 - Ding et al 2020 - with the aim of identifying variants that affect male fertility, the authors report on mice expressing two RABL2A SNPs found to be rare (MAF between 2% and 0.02% in gnomAD, with a deleterious prediction from SIFT and PolyPhen-2, and to affect protein stability. Mice homozygous for these variants (p.L119F and p.V158F) were found to be show ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus.
Sources: Literature
Skeletal ciliopathies v1.4 RABL2A Eleanor Williams gene: RABL2A was added
gene: RABL2A was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: RABL2A was set to Unknown
Publications for gene: RABL2A were set to 33075816
Phenotypes for gene: RABL2A were set to polydactyly; growth retardation
Review for gene: RABL2A was set to RED
Added comment: PMID: 33075816 - Ding et al 2020 - with the aim of identifying variants that affect male fertility, the authors report on mice expressing two RABL2A SNPs found to be rare (MAF between 2% and 0.02% in gnomAD, with a deleterious prediction from SIFT and PolyPhen-2, and to affect protein stability. Mice homozygous for these variants (p.L119F and p.V158F) were found to be show ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus.
Sources: Literature
Structural eye disease v1.22 NF2 Eleanor Williams changed review comment from: PMID: 33075808 - Sun et al 2020 - mouse model of Nf2 inactivation in embryonic eyes shows increased retinal pigmented epithelium proliferation which they propose result defects leading to persistent coloboma.; to: PMID: 33075808 - Sun et al 2020 - mouse model of Nf2 inactivation in embryonic eyes shows increased retinal pigmented epithelium proliferation which they propose cause defects resulting in persistent coloboma.
Retinal disorders v2.70 GRN Ivone Leong Mode of inheritance for gene: GRN was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.69 GRN Ivone Leong Phenotypes for gene: GRN were changed from Eye Disorders to Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; neuronal ceroid lipofuscinosis 1, MONDO:0013866
Retinal disorders v2.68 GRN Ivone Leong Publications for gene: GRN were set to
Structural eye disease v1.22 NF2 Eleanor Williams reviewed gene: NF2: Rating: ; Mode of pathogenicity: None; Publications: 33075808; Phenotypes: ; Mode of inheritance: None
Retinal disorders v2.67 GNB3 Ivone Leong commented on gene: GNB3: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be given Green status at the next review.
Retinal disorders v2.67 GNB3 Ivone Leong Tag for-review tag was added to gene: GNB3.
Neurological segmental overgrowth v1.7 AKT1 Eleanor Williams Publications for gene: AKT1 were set to
Neurological segmental overgrowth v1.6 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.135 AKT1 Eleanor Williams Publications for gene: AKT1 were set to
Fetal anomalies v1.134 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Mosaic skin disorders - deep sequencing v1.5 AKT1 Eleanor Williams Publications for gene: AKT1 were set to 21793738
Mosaic skin disorders - deep sequencing v1.4 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Segmental overgrowth disorders - Deep sequencing v2.9 AKT1 Eleanor Williams Publications for gene: AKT1 were set to
Segmental overgrowth disorders - Deep sequencing v2.8 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Retinal disorders v2.67 GNB3 Ivone Leong Mode of inheritance for gene: GNB3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.66 GNB3 Ivone Leong Publications for gene: GNB3 were set to
Retinal disorders v2.65 GNB3 Ivone Leong Phenotypes for gene: GNB3 were changed from to Night blindness, congenital stationary, type 1H, OMIM:617024, MONDO:0014872
Retinal disorders v2.64 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Ceroid lipofuscinosis, neuronal, 13, Kufs type OMIM #615362 to Ceroid lipofuscinosis, neuronal, 13, Kufs type, OMIM:615362
Retinal disorders v2.63 CTNNA1 Ivone Leong commented on gene: CTNNA1: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 26691986a also describes a mouse model that mimics the human phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.63 CTNNA1 Ivone Leong Tag for-review tag was added to gene: CTNNA1.
Retinal disorders v2.63 CTNNA1 Ivone Leong Mode of inheritance for gene: CTNNA1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.62 CTNNA1 Ivone Leong Phenotypes for gene: CTNNA1 were changed from to Macular dystrophy, patterned, 2, OMIM:608970
Retinal disorders v2.61 CTNNA1 Ivone Leong Publications for gene: CTNNA1 were set to
Retinal disorders v2.60 CTC1 Ivone Leong Classified gene: CTC1 as Amber List (moderate evidence)
Retinal disorders v2.60 CTC1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.60 CTC1 Ivone Leong Gene: ctc1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.59 CTC1 Ivone Leong Tag for-review tag was added to gene: CTC1.
Retinal disorders v2.59 CTC1 Ivone Leong Phenotypes for gene: CTC1 were changed from Cerebroretinal microangiopathy with calcifications and cysts MIM#612199 to Cerebroretinal microangiopathy with calcifications and cysts, OMIM:612199
Monogenic hearing loss v2.144 CEP250 Ivone Leong Classified gene: CEP250 as Amber List (moderate evidence)
Monogenic hearing loss v2.144 CEP250 Ivone Leong Gene: cep250 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.143 CEP250 Ivone Leong gene: CEP250 was added
gene: CEP250 was added to Hearing loss. Sources: Literature
for-review tags were added to gene: CEP250.
Mode of inheritance for gene: CEP250 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP250 were set to 24780881; 29718797; 30459346
Phenotypes for gene: CEP250 were set to Cone-rod dystrophy and hearing loss 2, OMIM:618358, MONDO:0020780
Review for gene: CEP250 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be made considered for Green status at the next review.

This gene is also on the Retinal disorders panel (v2.58) with the following review from Zornitza Stark:
"Cone-rod dystrophy and hearing loss-2 (CRDHL2) is characterized by retinal dystrophy, with photophobia and progressive reduction in visual acuity, associated with sensorineural hearing loss. Three unrelated families reported.
Zornitza Stark (Australian Genomics), 10 Oct 2020"
Sources: Literature
Retinal disorders v2.58 CEP250 Ivone Leong commented on gene: CEP250: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be made Green at the next review.
Retinal disorders v2.58 CEP250 Ivone Leong Tag for-review tag was added to gene: CEP250.
Retinal disorders v2.58 CEP250 Ivone Leong Mode of inheritance for gene: CEP250 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.57 CEP250 Ivone Leong Phenotypes for gene: CEP250 were changed from to Cone-rod dystrophy and hearing loss 2, OMIM:618358, MONDO:0020780
Retinal disorders v2.56 CEP250 Ivone Leong Publications for gene: CEP250 were set to
Retinal disorders v2.55 ARL13B Ivone Leong Classified gene: ARL13B as Amber List (moderate evidence)
Retinal disorders v2.55 ARL13B Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been promoted to Amber and should be promoted to Green at the next review.
Retinal disorders v2.55 ARL13B Ivone Leong Gene: arl13b has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.54 ARL13B Ivone Leong Tag for-review tag was added to gene: ARL13B.
Retinal disorders v2.54 ARL13B Ivone Leong Phenotypes for gene: ARL13B were changed from Eye Disorders to Joubert syndrome 8, OMIM:612291, MONDO:0012855
Retinal disorders v2.53 ARL13B Ivone Leong Publications for gene: ARL13B were set to
Retinal disorders v2.52 AP3B2 Ivone Leong Classified gene: AP3B2 as Red List (low evidence)
Retinal disorders v2.52 AP3B2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with an eye phenotype in Gene2Phenotype but not in OMIM. PMID:27889060 describes 1 out of 8 families where individuals who have variants in this gene had retinitis pigmentosa and mild optic disc pallor. This gene is also Amber on the Optic neuropathy panel (Version 2.29).

Therefore, there is currently not enough evidence to support a gene-disease association, this gene has been given a Red rating.
Retinal disorders v2.52 AP3B2 Ivone Leong Gene: ap3b2 has been classified as Red List (Low Evidence).
Retinal disorders v2.51 AP3B2 Ivone Leong Phenotypes for gene: AP3B2 were changed from Early-onset epileptic encephalopathy with optic atrophy to Developmental and epileptic encephalopathy 48, OMIM:617276, MONDO:0015000
Optic neuropathy v2.29 AP3B2 Ivone Leong Phenotypes for gene: AP3B2 were changed from Epileptic encephalopathy, early infantile, 48, 617276 to Developmental and epileptic encephalopathy 48, OMIM:617276, MONDO:0015000
Optic neuropathy v2.28 AP3B2 Ivone Leong Tag for-review was removed from gene: AP3B2.
Tag watchlist tag was added to gene: AP3B2.
Optic neuropathy v2.28 AP3B2 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark. AP3B2 is associated with a relevant disease in OMIM and probably associated with a relevant disease in Gene2Phenotype. There is enough evidence for this gene to be Green; however, until the next major review this gene will be rated as Amber for now.; to: Comment on list classification: New gene added by Zornitza Stark. AP3B2 is associated with a relevant disease in OMIM and probably associated with a relevant disease in Gene2Phenotype. PMID:27889060 describes 2 out of 8 families where individuals who have variants in this gene had optic disc/nerve pallor. Therefore, there is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Retinal disorders v2.50 ALPK1 Ivone Leong Classified gene: ALPK1 as Amber List (moderate evidence)
Retinal disorders v2.50 ALPK1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association; therefore, this gene has been given an Amber rating and should be promoted to Green at the next review.
Retinal disorders v2.50 ALPK1 Ivone Leong Gene: alpk1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.49 ALPK1 Ivone Leong Tag for-review tag was added to gene: ALPK1.
Retinal disorders v2.49 ALPK1 Ivone Leong Phenotypes for gene: ALPK1 were changed from ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache to ROSAH syndrome, OMIM:614979
Retinal disorders v2.48 CIB2 Ivone Leong Publications for gene: CIB2 were set to
Retinal disorders v2.47 CA4 Ivone Leong commented on gene: CA4: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the external reviews and available evidence the rating of this gene should be re-reviewed by the GMS specialist group at the next review. Have tagged with "for-review".
Retinal disorders v2.47 CA4 Ivone Leong Tag for-review tag was added to gene: CA4.
Retinal disorders v2.47 CA4 Ivone Leong Publications for gene: CA4 were set to 15563508; 17652713; 15090652
Retinal disorders v2.46 CA4 Ivone Leong Phenotypes for gene: CA4 were changed from Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis pigmentosa; Retinitis pigmentosa 17, 600852 to Retinitis pigmentosa 17, OMIM:600852, MONDO:0010945
Retinal disorders v2.45 AFG3L2 Ivone Leong commented on gene: AFG3L2: This gene is associated with a relevant phenotype in OMIM, but it is not associated with an eye phenotype in Gene2Phenotype. Based on the available information there is enough evidence to support a gene-disease association. This gene has been tagged with "for-review" and should be promoted to Green at the next review.
Retinal disorders v2.45 AFG3L2 Ivone Leong Tag for-review tag was added to gene: AFG3L2.
Retinal disorders v2.45 AFG3L2 Ivone Leong Mode of inheritance for gene: AFG3L2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.44 AFG3L2 Ivone Leong Publications for gene: AFG3L2 were set to
Retinal disorders v2.43 AFG3L2 Ivone Leong Phenotypes for gene: AFG3L2 were changed from to Optic atrophy 12, OMIM:618977, MONDO:0033549
Retinal disorders v2.42 ACBD5 Ivone Leong Tag watchlist tag was added to gene: ACBD5.
Retinal disorders v2.42 ACBD5 Ivone Leong Classified gene: ACBD5 as Amber List (moderate evidence)
Retinal disorders v2.42 ACBD5 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. As there are only 2 reported cases there is not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Retinal disorders v2.42 ACBD5 Ivone Leong Gene: acbd5 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.41 ACBD5 Ivone Leong Added comment: Comment on publications: Previous Publications comment:
Abu-Safieh et al Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013 Feb;23(2):236-47 PMID: 23105016
Retinal disorders v2.41 ACBD5 Ivone Leong Publications for gene: ACBD5 were set to Abu-Safieh et al Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013 Feb; 23(2):236-47 PMID: 23105016
Retinal disorders v2.40 ACBD5 Ivone Leong Added comment: Comment on phenotypes: Previous Phenotypes comment: No OMIM disease ID; novel variant reported in PMID: 23105016 in family with cone-rod dystrophyand psychomotor delay associated with significant white matter involvement
Retinal disorders v2.40 ACBD5 Ivone Leong Phenotypes for gene: ACBD5 were changed from No OMIM disease ID; novel variant reported in PMID: 23105016 in family with cone-rod dystrophyand psychomotor delay associated with significant white matter involvement to Retinal dystrophy with leukodystrophy, OMIM:618863, MONDO:0030026
Retinal disorders v2.39 ACBD5 Ivone Leong Mode of inheritance for gene: ACBD5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Primary ciliary disorders v1.27 MCIDAS Ivone Leong Phenotypes for gene: MCIDAS were changed from Too new - not yet linked to the PCD mutations publication to Ciliary dyskinesia, primary, 42, OMIM:618695,MONDO:0032872
Respiratory ciliopathies including non-CF bronchiectasis v1.42 MCIDAS Ivone Leong Phenotypes for gene: MCIDAS were changed from to Ciliary dyskinesia, primary, 42, OMIM:618695,MONDO:0032872
Retinal disorders v2.38 GDF6 Mehdi Montazer reviewed gene: GDF6: 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: https://doi.org/10.1038/s41431-020-0678-9; Phenotypes: kidney hypodysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.42 NPR2 Mehdi Montazer reviewed gene: NPR2: 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: https://doi.org/10.1038/s10038-020-00871-0; Phenotypes: Acromesomelic dysplasia, Maroteaux type (OMIM: # 602875); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset hereditary spastic paraplegia v1.16 AP4E1 Arina Puzriakova Tag for-review tag was added to gene: AP4E1.
Adult onset hereditary spastic paraplegia v1.16 AP4E1 Arina Puzriakova Publications for gene: AP4E1 were set to 21620353; 23472171
Adult onset hereditary spastic paraplegia v1.15 AP4E1 Arina Puzriakova commented on gene: AP4E1
Adult onset hereditary spastic paraplegia v1.15 AP4B1 Arina Puzriakova changed review comment from: Review of literature did not reveal any adult onset published cases.

Tagged 'for-review' to highlight that this is a childhood onset condition and therefore AP4B1 should be downgraded to Red on this panel at the next GMS panel update. This gene is already Green on the 'Hereditary spastic paraplegia - childhood onset v.1.12' panel.; to: Review of literature did not reveal any adult onset published cases.

Tagged 'for-review' to highlight that this is a childhood onset condition and therefore AP4B1 should be downgraded to Red on this panel at the next GMS panel update. This gene is already Green on the 'Hereditary spastic paraplegia - childhood onset v.2.18' panel.
Severe microcephaly v2.65 AP4E1 Arina Puzriakova Publications for gene: AP4E1 were set to 20972249; 21620353; 21937992
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Tag for-review tag was added to gene: AP4E1.
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Classified gene: AP4E1 as Amber List (moderate evidence)
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but details regarding head circumference were mostly unavailable. At least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Gene: ap4e1 has been classified as Amber List (Moderate Evidence).
Ocular coloboma v1.41 SIX3 Sarah Leigh changed review comment from: Comment on mode of inheritance: The gene was previously listed as an imprinted gene, with maternal expression. It would appear that this is not the case, although there is variable penetrance of the Holoprosencephaly 2 157170 phenotype in at least three unrelated families (PMID 17001667;19353631;19346217).; to: Comment on mode of inheritance: SIX3 was previously listed as an imprinted gene, with maternal expression. It would appear that this is not the case, although there is variable penetrance of the Holoprosencephaly 2 157170 phenotype in at least three unrelated families (PMID 17001667;19353631;19346217).
Ocular coloboma v1.41 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 21976454; 28670735
Ocular coloboma v1.40 SIX3 Sarah Leigh Added comment: Comment on mode of inheritance: The gene was previously listed as an imprinted gene, with maternal expression. It would appear that this is not the case, although there is variable penetrance of the Holoprosencephaly 2 157170 phenotype in at least three unrelated families (PMID 17001667;19353631;19346217).
Ocular coloboma v1.40 SIX3 Sarah Leigh Mode of inheritance for gene: SIX3 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.63 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, MIM# 613744 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Intellectual disability v3.694 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 4 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Fetal anomalies v1.134 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 4 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Adult onset neurodegenerative disorder v2.37 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Adult onset hereditary spastic paraplegia v1.15 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Childhood onset hereditary spastic paraplegia v2.23 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Hereditary spastic paraplegia v1.219 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Intellectual disability v3.693 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 5 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Fetal anomalies v1.133 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 5 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Adult onset neurodegenerative disorder v2.36 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Childhood onset hereditary spastic paraplegia v2.22 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Hereditary spastic paraplegia v1.218 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Adult onset hereditary spastic paraplegia v1.14 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Adult onset hereditary spastic paraplegia v1.13 AP4B1 Arina Puzriakova Tag for-review tag was added to gene: AP4B1.
Adult onset hereditary spastic paraplegia v1.13 AP4B1 Arina Puzriakova commented on gene: AP4B1
White matter disorders and cerebral calcification - narrow panel v1.30 AP4B1 Arina Puzriakova Tag for-review tag was added to gene: AP4B1.
White matter disorders and cerebral calcification - narrow panel v1.30 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive MIM#614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
White matter disorders and cerebral calcification - narrow panel v1.29 AP4B1 Arina Puzriakova Publications for gene: AP4B1 were set to 29193663
White matter disorders and cerebral calcification - narrow panel v1.28 AP4B1 Arina Puzriakova Classified gene: AP4B1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.28 AP4B1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag).

Literature search revealed at least 24 unrelated published families with biallelic variants in this gene. Disorder mainly characterised by HSP but white matter loss is reported in over half of patients (see Publications list)
White matter disorders and cerebral calcification - narrow panel v1.28 AP4B1 Arina Puzriakova Gene: ap4b1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.62 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, MIM# 614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Severe microcephaly v2.61 AP4B1 Arina Puzriakova Publications for gene: AP4B1 were set to 21620353; 22290197; 24700674; 24781758
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Classified gene: AP4B1 as Amber List (moderate evidence)
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but will be flagged for review at the next GMS panel update to assess whether clinical utility is sufficient for inclusion as Green (added 'for-review' tag).

Literature search revealed at least 24 unrelated published cases with biallelic variants in this gene. Microcephaly is commonly reported but often mild, and particularly in the context of other more prominent/universal features (ID, HSP, etc) this disorder may be better represented by other panels.

Nonetheless, microcephaly of relevant severity to this panel (OFC ≤ -3 SD) has been recorded in at least 8 unrelated families which reaches the threshold for inclusion (PMIDs: 21620353; 29193663; 30337681; 32166732)
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Gene: ap4b1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.59 AP4B1 Arina Puzriakova Tag for-review tag was added to gene: AP4B1.
Severe microcephaly v2.59 C7orf43 Arina Puzriakova Phenotypes for gene: C7orf43 were changed from Microcephaly 25, primary, autosomal recessive, MIM# 618351 to Microcephaly 25, primary, autosomal recessive, OMIM:618351; Microcephaly 25, primary, autosomal recessive, MONDO:0032694
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Tag new-gene-name tag was added to gene: C7orf43.
Severe microcephaly v2.58 C7orf43 Arina Puzriakova commented on gene: C7orf43: Added new-gene-name tag, new approved HGNC gene symbol for C7orf43 is MAP11
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Classified gene: C7orf43 as Amber List (moderate evidence)
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM (MIM# 618351) but not yet in Gene2Phenotype.

Three individuals from one family with severe ID and primary microcephaly of relevant severity (-5 SD to -6 SD). Zebrafish model recapitulates human microcephaly phenotype.

Rating Amber as additional cases required prior to inclusion on a diagnostic panel.
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Gene: c7orf43 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.5 PLVAP Zornitza Stark gene: PLVAP was added
gene: PLVAP was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, MIM# 618183
Review for gene: PLVAP was set to GREEN
gene: PLVAP was marked as current diagnostic
Added comment: Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients.

Four unrelated families reported.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 NEUROG3 Zornitza Stark gene: NEUROG3 was added
gene: NEUROG3 was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: NEUROG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROG3 were set to 16855267; 32574610; 28724572; 21490072
Phenotypes for gene: NEUROG3 were set to Diarrhoea 4, malabsorptive, congenital, MIM# 610370
Review for gene: NEUROG3 was set to GREEN
Added comment: Multiple families reported with malabsorptive diarrhoea +/- neonatal diabetes.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 TMPRSS15 Zornitza Stark gene: TMPRSS15 was added
gene: TMPRSS15 was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: TMPRSS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS15 were set to 11719902; 33061943
Phenotypes for gene: TMPRSS15 were set to Enterokinase deficiency, MIM# 226200
Review for gene: TMPRSS15 was set to GREEN
gene: TMPRSS15 was marked as current diagnostic
Added comment: Deficiency of enterokinase, a sequence-specific protease that activates trypsinogen and has a major role in protein digestion, is an autosomal recessive disorder characterised by severe protein malabsorption in early infancy, with failure to thrive, chronic diarrhoea, and generalized oedema. In adulthood, patients have normal body weight and no gastrointestinal symptoms, even when pancreatic enzyme supplements are discontinued. Three unrelated families reported with molecularly confirmed diagnosis.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 WNT2B Zornitza Stark gene: WNT2B was added
gene: WNT2B was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: WNT2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT2B were set to 29909964
Phenotypes for gene: WNT2B were set to Diarrhoea 9, MIM# 618168
Review for gene: WNT2B was set to GREEN
gene: WNT2B was marked as current diagnostic
Added comment: Diarrhoea-9 is a form of neonatal-onset chronic diarrhoea characterized by an osmotic diarrhoea that is not substrate specific, abnormal crypt and villus architecture, and significant fat malabsorption. Three probands from two unrelated families and functional data suggesting severe intestinal dysregulation due to decreased intestinal stem cell number and function.

Borderline Green/Amber.
Sources: Expert Review
Ocular coloboma v1.39 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 21976454
Paediatric or syndromic cardiomyopathy v1.18 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Dilated Cardiomyopathy and conduction defects v1.67 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Dilated and arrhythmogenic cardiomyopathy v1.11 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from arrythmogenic cardiomyopathy; Cardiomyopathy, familial hypertrophic, 26; Cardiomyopathy, familial restrictive 5; Myopathy, myofibrillar, 5 to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.13 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Myopathy, myofibrillar, 5 609524 to Myopathy, distal, 4, OMIM:614065; Distal myopathy with posterior leg and anterior hand involvement, MONDO:0013550; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Congenital myopathy v2.12 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Myopathy, myofibrillar, 5, 609524; early-onset restrictive cardiomyopathy and congenital myopathy to Myopathy, distal, 4, OMIM:614065; Distal myopathy with posterior leg and anterior hand involvement, MONDO:0013550; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Arrhythmogenic right ventricular cardiomyopathy v2.13 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Arrhythmogenic cardiomyopathy; Cardiomyopathy, familial restrictive 5 (617047); Myopathy, distal, 4 (614065); Myopathy, myofibrillar, 5 (609524) to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883
Hypertrophic cardiomyopathy v2.16 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883
Distal myopathies v1.27 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from myofibrillar myopathy 5, 609524; Distal myopathy 4, 614065 to Myopathy, distal, 4, OMIM:614065; Distal myopathy with posterior leg and anterior hand involvement, MONDO:0013550; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Arthrogryposis v3.42 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Myopathy, myofibrillar, 5, 609524 to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883; Myopathy, distal, 4, OMIM:614065; Distal myopathy with posterior leg and anterior hand involvement, MONDO:0013550; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Arthrogryposis v3.41 FLNC Arina Puzriakova Classified gene: FLNC as Amber List (moderate evidence)
Arthrogryposis v3.41 FLNC Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but should be promoted to Green at the next GMS panel update (added 'for-review' tag). PMID: 29858533 reports on 3 unrelated individuals who presented at birth with arthrogryposis. This was evident prior to other FLNC-related features such as muscle weakness and cardiomyopathy, and so it is plausible that these cases may be tested in the context of this clinical indication.
Arthrogryposis v3.41 FLNC Arina Puzriakova Gene: flnc has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.40 FLNC Arina Puzriakova Publications for gene: FLNC were set to
Arthrogryposis v3.39 FLNC Arina Puzriakova Mode of inheritance for gene: FLNC was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.692 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum 617193 to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Early onset or syndromic epilepsy v2.251 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, 617193; seizures; West syndrome to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Fetal anomalies v1.132 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Early-Onset Neurodegenerative Encephalopathy to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Arthrogryposis v3.38 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Arthrogryposis v3.37 TBCD Arina Puzriakova Publications for gene: TBCD were set to
Arthrogryposis v3.36 TBCD Arina Puzriakova Classified gene: TBCD as Red List (low evidence)
Arthrogryposis v3.36 TBCD Arina Puzriakova Added comment: Comment on list classification: Maintaining the Red rating on this panel as curation of published literature revealed only a single report of an individual with multiple arthrogryposis (individual II-2 from PMID:27666374). This disorder is better represented by other panels for which this gene is already Green (Genetic epilepsy syndromes, Intellectual disability, etc).
Arthrogryposis v3.36 TBCD Arina Puzriakova Gene: tbcd has been classified as Red List (Low Evidence).
Arthrogryposis v3.35 TBCD Arina Puzriakova Mode of inheritance for gene: TBCD was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric motor neuronopathies v1.35 TRIP4 Arina Puzriakova Phenotypes for gene: TRIP4 were changed from Spinal muscular atrophy with congenital bone fractures 1 616866 to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806
Fetal anomalies v1.131 TRIP4 Arina Puzriakova Publications for gene: TRIP4 were set to
Fetal anomalies v1.130 TRIP4 Arina Puzriakova Phenotypes for gene: TRIP4 were changed from Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806; ?Muscular dystrophy, congenital, Davignon-Chauveau type, OMIM:617066; Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, MONDO:0014896
Congenital myopathy v2.11 TRIP4 Arina Puzriakova Phenotypes for gene: TRIP4 were changed from severe congenital myopathy with congenital bone fractures, 616866; Spinal muscular atrophy with congenital bone fractures 1, 616866 to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806; ?Muscular dystrophy, congenital, Davignon-Chauveau type, OMIM:617066; Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, MONDO:0014896
Arthrogryposis v3.34 TRIP4 Arina Puzriakova Phenotypes for gene: TRIP4 were changed from Spinal muscular atrophy with congenital bone fractures 1, 616866 to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806
Arthrogryposis v3.33 TRIP4 Arina Puzriakova Classified gene: TRIP4 as Amber List (moderate evidence)
Arthrogryposis v3.33 TRIP4 Arina Puzriakova Added comment: Comment on list classification: Three families with multiple congenital contractures among other features associated with variants in this gene (PMID: 26924529). However, a founder effect was suspected in the two Kosovo families and therefore this can only be considered as 2 cases total. Maintaining Amber rating, awaiting further cases/clinical evidence.
Arthrogryposis v3.33 TRIP4 Arina Puzriakova Gene: trip4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.388 GIMAP6 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Boaz Palterer. Biallelic variant identified in a patient with lymphopenia and recurrent infections. The same variant was detected in an asymptomatic older sibling and although authors state that GIMAP6 was the best candidate to explain the clinical phenotype in the affected individual, homozygous variants were also identified in 8 other genes. Therefore, there is only enough evidence for a Red rating at present.; to: Comment on list classification: New gene added by Boaz Palterer. Biallelic variant identified in a patient with lymphopenia and recurrent infections. The same variant was detected in an asymptomatic older sibling and although authors state that GIMAP6 was the best candidate to explain the clinical phenotype in the affected individual, homozygous variants were also identified in 8 other genes (PMID: 33328581). Therefore, there is only enough evidence for a Red rating at present.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.388 GIMAP6 Arina Puzriakova Classified gene: GIMAP6 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.388 GIMAP6 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Biallelic variant identified in a patient with lymphopenia and recurrent infections. The same variant was detected in an asymptomatic older sibling and although authors state that GIMAP6 was the best candidate to explain the clinical phenotype in the affected individual, homozygous variants were also identified in 8 other genes. Therefore, there is only enough evidence for a Red rating at present.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.388 GIMAP6 Arina Puzriakova Gene: gimap6 has been classified as Red List (Low Evidence).
Rare anaemia v1.9 ADH5 Arina Puzriakova Phenotypes for gene: ADH5 were changed from Aplastic anaemia; myelodysplasia; short stature to Aplastic anaemia; Mental retardation; Skin hyperpigmentation, Short stature; Microcephaly
Rare anaemia v1.8 ADH5 Arina Puzriakova Publications for gene: ADH5 were set to 33147438
Rare anaemia v1.7 ADH5 Arina Puzriakova Classified gene: ADH5 as Amber List (moderate evidence)
Rare anaemia v1.7 ADH5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient unrelated cases (>3) with relevant phenotype for this panel; however, as inheritance is digenic, this gene has been made Amber rather than Green and tagged 'digenic'.
Rare anaemia v1.7 ADH5 Arina Puzriakova Gene: adh5 has been classified as Amber List (Moderate Evidence).
Rare anaemia v1.6 ADH5 Arina Puzriakova Tag digenic tag was added to gene: ADH5.
Rare anaemia v1.6 ADH5 Arina Puzriakova reviewed gene: ADH5: Rating: ; Mode of pathogenicity: None; Publications: 33147438, 33355142; Phenotypes: Aplastic anaemia, Mental retardation, Skin hyperpigmentation, Short stature, Microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.250 CPA6 Zornitza Stark reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: 25875328, 21922598, 23105115; Phenotypes: Epilepsy, familial temporal lobe, 5 MIM#614417, Febrile seizures, familial, 11 MIM#614418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.387 TLR8 Boaz Palterer gene: TLR8 was added
gene: TLR8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TLR8 was set to Other
Publications for gene: TLR8 were set to 10.1182/blood.2020009620
Phenotypes for gene: TLR8 were set to neutropenia; lymphoproliferation; hypogammaglobulinemia; bone marrow failure
Penetrance for gene: TLR8 were set to unknown
Mode of pathogenicity for gene: TLR8 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: TLR8 was set to AMBER
Added comment: Aluri et al. (Blood 2020, 10.1182/blood.2020009620) identified six unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and bone marrow failure associated with three different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8).
The variants are functionally gain-of-function and all patients are males, it's unclear if heterozygous females are affected. Both germline and somatic variants have been identified, but somatic mutations appear to be prominent.
Sources: Literature
Intellectual disability v3.691 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from CORNELIA DE LANGE SYNDROME TYPE 2 (CDLS2) to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Early onset or syndromic epilepsy v2.250 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590; seizures; EPILEPTIC ENCEPHALOPATHY; Rett-like phenotype to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Clefting v2.13 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from CORNELIA DE LANGE SYNDROME 2; CDLS2 to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Skeletal dysplasia v2.42 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2 300590 to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370
Fetal anomalies v1.129 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from CORNELIA DE LANGE SYNDROME TYPE 2; EPILEPTIC ENCEPHALOPATHY to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Severe microcephaly v2.57 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590 (includes microcephaly) to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Limb disorders v2.19 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590; Cornelia de Lange syndrome 2 300590 to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370
IUGR and IGF abnormalities v1.35 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia De Lange to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370
Radial dysplasia v1.13 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590 to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370
Holoprosencephaly - NOT chromosomal v2.12 SMC1A Arina Puzriakova Tag for-review tag was added to gene: SMC1A.
Holoprosencephaly - NOT chromosomal v2.12 SMC1A Arina Puzriakova Classified gene: SMC1A as Amber List (moderate evidence)
Holoprosencephaly - NOT chromosomal v2.12 SMC1A Arina Puzriakova Added comment: Comment on list classification: New gene added by external reviewer. At least 6 unrelated females with holoprosencephaly, mostly commonly semi-lobar type, associated with de novo variants in this gene (PMIDs: 28166369 and 31334757). Likely represents the severe end of the spectrum of SMC1A-related disorders.

Sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag)
Holoprosencephaly - NOT chromosomal v2.12 SMC1A Arina Puzriakova Gene: smc1a has been classified as Amber List (Moderate Evidence).
Holoprosencephaly - NOT chromosomal v2.11 SMC1A Arina Puzriakova Publications for gene: SMC1A were set to PMID: 31334757
Holoprosencephaly - NOT chromosomal v2.10 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from holoprosencephaly; single central incisor to Developmental and epileptic encephalopathy 85, with midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Clefting v2.12 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS; Cleft palate to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Fetal anomalies v1.128 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome 170390 to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Skeletal muscle channelopathy v1.7 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome, 170390 to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222; Episodic weakness; Periodic paralysis
Paroxysmal central nervous system disorders v1.10 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome, 170390; Andersen cardiodysrhythmic periodic paralysis; Episodic weakness; Periodic paralysis; Hypokalemic Periodic Paralysis, Type 2 to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222; Episodic weakness; Periodic paralysis
Catecholaminergic polymorphic VT v2.7 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from catecholaminergic polymorphic ventricular tachycardia; Atrial fibrillation, familial, 9 (613980); Andersen syndrome (170390); Short QT syndrome 3 (609622) to Short QT syndrome 3, OMIM:609622; Short QT syndrome type 3, MONDO:0012314; Atrial fibrillation, familial, 9, OMIM:613980; Atrial fibrillation, familial, 9, MONDO:0013513; Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Long QT syndrome v2.22 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome (170390); Atrial fibrillation, familial, 9 (613980); ANDERSEN SYNDROME (170390); LONG QT SYNDROME 7 (170390); Short QT syndrome 3 (609622) to Short QT syndrome 3, OMIM:609622; Short QT syndrome type 3, MONDO:0012314; Atrial fibrillation, familial, 9, OMIM:613980; Atrial fibrillation, familial, 9, MONDO:0013513; Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Short QT syndrome v2.7 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Atrial fibrillation, familial, 9 (613980); Short QT syndrome 3 609622; Short QT syndrome 3 (609622); Andersen syndrome (170390); ventricular tacyarrhythmia; short qt; atrial fibrillation to Short QT syndrome 3, OMIM:609622; Short QT syndrome type 3, MONDO:0012314; Atrial fibrillation, familial, 9, OMIM:613980; Atrial fibrillation, familial, 9, MONDO:0013513; Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Skeletal Muscle Channelopathies v1.27 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Hypokalemic Periodic Paralysis, Type 2; Episodic weakness; Periodic paralysis; ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS; Andersen syndrome to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222; Episodic weakness; Periodic paralysis
Brain channelopathy v1.59 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome, MIM# 170390 to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222; Episodic weakness; Periodic paralysis
Brain channelopathy v1.58 KCNJ2 Arina Puzriakova Classified gene: KCNJ2 as Green List (high evidence)
Brain channelopathy v1.58 KCNJ2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Green as there are sufficient unrelated cases (>3) with monoallelic variants in this potassium channel gene. KCNJ2 is also Green on the 'Skeletal muscle channelopathy v1.6' GMS panel.
Brain channelopathy v1.58 KCNJ2 Arina Puzriakova Gene: kcnj2 has been classified as Green List (High Evidence).
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Tag watchlist tag was added to gene: SLC9A7.
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Classified gene: SLC9A7 as Amber List (moderate evidence)
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM and Gene2Phenotype. However, only 2 unrelated families reported at present (PMID: 30335141) and therefore only sufficient for an Amber rating, awaiting further publications/clinical evidence (added 'watchlist' tag)
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Gene: slc9a7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.689 SLC9A7 Arina Puzriakova Phenotypes for gene: SLC9A7 were changed from Intellectual developmental disorder, X-linked 108; OMIM #301024 to Intellectual developmental disorder, X-linked 108, OMIM:301024; Intellectual developmental disorder, X-linked 108, MONDO:0026723
Childhood onset dystonia, chorea or related movement disorder v1.70 MPI Arina Puzriakova Mode of inheritance for gene: MPI was changed from to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.69 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Primary lymphoedema v2.7 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Fetal anomalies v1.127 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Likely inborn error of metabolism v2.41 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation); Congenital disorder of glycosylation, type Ib 602579 to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation)
Likely inborn error of metabolism v2.40 MPI Arina Puzriakova Publications for gene: MPI were set to 10980531
Undiagnosed metabolic disorders v1.436 MPI Arina Puzriakova Publications for gene: MPI were set to 27604308
Undiagnosed metabolic disorders v1.435 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation); Congenital disorder of glycosylation, type Ib 602579; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation) to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.387 MPI Arina Puzriakova Mode of inheritance for gene: MPI was changed from to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.386 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Congenital disorders of glycosylation v2.20 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Congenital disorder of glycosylation, type Ib 602579; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation) to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation)
Congenital disorders of glycosylation v2.19 MPI Arina Puzriakova Publications for gene: MPI were set to 10980531
Cholestasis v1.76 MPI Arina Puzriakova Publications for gene: MPI were set to 12414827; 10980531; 9585601; 28108845
Cholestasis v1.75 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Congenital disorder of glycosylation, type Ib, OMIM:602579 to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
COVID-19 research v1.71 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Neonatal cholestasis v1.17 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Congenital disorder of glycosylation, type Ib 602579 to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Intellectual disability v3.688 MPI Arina Puzriakova Publications for gene: MPI were set to 9525984; 3080572; 9585601
Intellectual disability v3.687 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Intellectual disability v3.686 MPI Arina Puzriakova reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.686 MPI Arina Puzriakova Tag for-review tag was added to gene: MPI.
Intellectual disability v3.686 HDAC4 Arina Puzriakova commented on gene: HDAC4
Intellectual disability v3.686 HDAC4 Arina Puzriakova Tag for-review was removed from gene: HDAC4.
Intellectual disability v3.686 AGO2 Arina Puzriakova Classified gene: AGO2 as Amber List (moderate evidence)
Intellectual disability v3.686 AGO2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. All patients reported in PMID: 33199684 presented GDD/ID, while other features were relatively heterogenous. However, cognitive impairment was perhaps too mild in majority of cases. Tagged 'for-review' to assess whether there is sufficient evidence for a Green rating in light of the scope of the ID panel.
Intellectual disability v3.686 AGO2 Arina Puzriakova Gene: ago2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.685 AGO2 Arina Puzriakova Tag for-review tag was added to gene: AGO2.
Intellectual disability v3.685 AGO2 Arina Puzriakova reviewed gene: AGO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33199684; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.685 ZNF407 Arina Puzriakova Classified gene: ZNF407 as Amber List (moderate evidence)
Intellectual disability v3.685 ZNF407 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Some evidence linking both mono- and biallelic variants with disease but currently not sufficient for a Green rating. Further cases would help validate this gene-disease association (added 'watchlist' tag)
Intellectual disability v3.685 ZNF407 Arina Puzriakova Gene: znf407 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.684 SMG8 Arina Puzriakova Phenotypes for gene: SMG8 were changed from Intellectual disability; Microcephaly; Short stature; Facial dysmorphism Edit to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism
Intellectual disability v3.684 SMG8 Arina Puzriakova Phenotypes for gene: SMG8 were changed from Intellectual disability to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism Edit
Bilateral congenital or childhood onset cataracts v2.54 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.54 SMG8 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as although number of unrelated cases reaches threshold for inclusion (3), the phenotype is not fully penetrant and the disorder is better represented by other panels (e.g. ID, microcephaly etc). This may however we revised if further cases arise.
Bilateral congenital or childhood onset cataracts v2.54 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.53 SMG8 Arina Puzriakova gene: SMG8 was added
gene: SMG8 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: SMG8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMG8 were set to 31130284; 33242396
Phenotypes for gene: SMG8 were set to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism; Cataract
Review for gene: SMG8 was set to AMBER
Added comment: Currently not associated with any phenotype in OMIM or G2P.
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- PMID: 31130284 (2019) - One individual with cataract and a homozygous variant in this gene identified as part of a large candidate gene discovery study. Other features include microcephaly, ID, and neck hyperpigmentation. No further details were provided.

- PMID: 33242396 (2020) - Different biallelic variants in the SMG8 gene identified in 4 consanguineous families, of which 2 kindreds had 3 individuals with cataract. Authors reported congenital bilateral cataract in the two sibs, while the third patient had cataract operated at age 12yrs although the age of onset or any further information was not available. Other clinical features include GDD/ID, dysmorphic features, microcephaly, short stature, brain imaging anomalies and congenital heart disease. Some supportive functional data also provided.
Sources: Literature
Severe microcephaly v2.56 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
Severe microcephaly v2.56 SMG8 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but can be promoted to Green at the next GMS panel update (added 'for-review' tag).

At least 5 unrelated families with microcephaly and different homozygous variants in the SMG8 gene. OFC recorded for only 3 families, but each includes at least one microcephalic individual with severity relevant to this panel (more than -3 SD)
Severe microcephaly v2.56 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.55 SMG8 Arina Puzriakova gene: SMG8 was added
gene: SMG8 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: SMG8.
Mode of inheritance for gene: SMG8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMG8 were set to 31130284; 33242396
Phenotypes for gene: SMG8 were set to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism
Review for gene: SMG8 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM or G2P.
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- PMID: 31130284 (2019) - Two individuals with distinct homozygous variants in this gene identified as part of a large candidate gene discovery study. Phenotype in one patient included microcephaly, ID, cataract, and neck hyperpigmentation; while the other presented short stature, microcephaly, fine motor delay, ventricular septal defect, failure to thrive, and facial dysmorphism.

- PMID: 33242396 (2020) - 9 affected individuals from 4 consanguineous families with different biallelic variants in the SMG8 gene. Clinical features include GDD/ID (8/8), dysmorphic features (9/9) microcephaly (6/9), short stature (4/9), brain imaging anomalies (4/5), congenital heart disease (3/9) and cataract (3/8). Some supportive functional data also provided. Microcephaly was recorded in 3/4 families, ranging in severity from -2.5 SD to -4.1 SD.
Sources: Literature
Intellectual disability v3.683 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
Intellectual disability v3.683 SMG8 Arina Puzriakova Added comment: Comment on list classification: Additional cases reported in recent publication (PMID: 33242396) extend the total to at least 5 unrelated families with GDD/ID and different homozygous variants in the SMG8 gene. Also some supporting functional data provided.

Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.683 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.682 SMG8 Arina Puzriakova Publications for gene: SMG8 were set to 31130284
Intellectual disability v3.681 SMG8 Arina Puzriakova edited their review of gene: SMG8: Added comment: PMID: 33242396 (2020) - 9 affected individuals from 4 consanguineous families with different biallelic variants in the SMG8 gene. Clinical features include GDD (8/8), dysmorphic features (9/9) microcephaly (6/9), short stature (4/9), brain imaging anomalies (4/5), congenital heart disease (3/9) and cataract (3/8). Only two sibs from Family 2 had a formal ID diagnosis, but this can be inferred from the clinical reports of the other cases demonstrating severe language delays, difficulties to follow simple instructions or perform daily activities.
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Several features described here overlap with those in the previously reported cases from PMID: 31130284 (e.g. microcephaly, ID, cataract, VSD); Changed rating: GREEN; Changed publications: 31130284, 33242396
Rare anaemia v1.6 NHLRC2 Eleanor Williams changed review comment from: Comment on list classification: Changing rating from red to amber with recommendation of review by the GMS with regards to phenotypic fit for this panel. Sufficient cases to make green if appropriate.; to: Comment on list classification: On recommendation of Genomics England clinical team, changing rating from red to amber with recommendation of review by the GMS with regards to phenotypic fit for this panel. Sufficient cases to make green if appropriate.
Rare anaemia v1.6 NHLRC2 Eleanor Williams Classified gene: NHLRC2 as Amber List (moderate evidence)
Rare anaemia v1.6 NHLRC2 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber with recommendation of review by the GMS with regards to phenotypic fit for this panel. Sufficient cases to make green if appropriate.
Rare anaemia v1.6 NHLRC2 Eleanor Williams Gene: nhlrc2 has been classified as Amber List (Moderate Evidence).
Rare anaemia v1.5 NHLRC2 Eleanor Williams Tag for-review tag was added to gene: NHLRC2.
Rare anaemia v1.5 NHLRC2 Eleanor Williams gene: NHLRC2 was added
gene: NHLRC2 was added to Rare anaemia. Sources: Literature
Mode of inheritance for gene: NHLRC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NHLRC2 were set to 29423877; 32435055
Phenotypes for gene: NHLRC2 were set to FINCA syndrome OMIM:618278
Review for gene: NHLRC2 was set to GREEN
Added comment: PMID: 29423877 Uusimaa et al 2018 - report 3 patients from 2 unrelated non-consanguineous Finnish families in which the children were born asymptomatic but by 2 months of age they had developed a progressive multi-organ disorder. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. All three patients were found using WES to be compound heterozygous for NM_198514:c.442G>T, p.Asp148Tyr and c.601_602delAG, p.Arg201GlyfsTer6. Segregation data for both families is provided. The family history of the two families, traced back 7–9 generations, showed that they did not have common ancestors. Both variants are rare in both Finnish (Sequencing Initiative Suomi - 0.003 and 0.0001 respectively) and non-Finnish populations (Exac). Patient fibroblasts expressed only mRNA with the c.442G>T missense variant, and at low levels. Development of Nhlrc2 null mice stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos showed that nhlrc2 has a role in cellular integrity of the central nervous system during development.

PMID: 32435055 - Brodsky et al 2020 - report a 2 year old Ukranian patient with FINCA syndrome who was found by WES to have compound heterozygous variants in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P). The c.428C>A variant is not found in the gnomAD database. Each parent was a carrier for one of the variants.
Sources: Literature
Paediatric disorders - additional genes v1.70 NHLRC2 Eleanor Williams Classified gene: NHLRC2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.70 NHLRC2 Eleanor Williams Added comment: Comment on list classification: Changing the rating of this gene from red to amber, but with a green rating recommendation for GMS review. 3 cases reported, plus mouse and zebrafish models and functional data from patient fibroblasts.
Paediatric disorders - additional genes v1.70 NHLRC2 Eleanor Williams Gene: nhlrc2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.69 NHLRC2 Eleanor Williams gene: NHLRC2 was added
gene: NHLRC2 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: NHLRC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NHLRC2 were set to 29423877; 32435055
Phenotypes for gene: NHLRC2 were set to FINCA syndrome OMIM:618278
Review for gene: NHLRC2 was set to GREEN
Added comment: PMID: 29423877 Uusimaa et al 2018 - report 3 patients from 2 unrelated non-consanguineous Finnish families in which the children were born asymptomatic but by 2 months of age they had developed a progressive multi-organ disorder. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. All three patients were found using WES to be compound heterozygous for NM_198514:c.442G>T, p.Asp148Tyr and c.601_602delAG, p.Arg201GlyfsTer6. Segregation data for both families is provided. The family history of the two families, traced back 7–9 generations, showed that they did not have common ancestors. Both variants are rare in both Finnish (Sequencing Initiative Suomi - 0.003 and 0.0001 respectively) and non-Finnish populations (Exac). Patient fibroblasts expressed only mRNA with the c.442G>T missense variant, and at low levels. Development of Nhlrc2 null mice stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos showed that nhlrc2 has a role in cellular integrity of the central nervous system during development.

PMID: 32435055 - Brodsky et al 2020 - report a 2 year old Ukranian patient with FINCA syndrome who was found by WES to have compound heterozygous variants in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P). The c.428C>A variant is not found in the gnomAD database. Each parent was a carrier for one of the variants.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.68 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to
Childhood onset dystonia, chorea or related movement disorder v1.67 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886
Early onset or syndromic epilepsy v2.249 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from ?Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Early onset or syndromic epilepsy v2.248 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 26195193; 27567911; 29545233; 27567911
Monogenic hearing loss v2.142 KCNMA1 Arina Puzriakova Classified gene: KCNMA1 as Red List (low evidence)
Monogenic hearing loss v2.142 KCNMA1 Arina Puzriakova Added comment: Comment on list classification: Multiple individuals with KCNMA1-related channelopathy characterised by a variety of neurologic symptoms, with both mono- and biallelic cases reported. Only a single patient described by Liang et al., 2019 (PMID: 31152168) with hearing impairment and therefore a Red rating on this panel is appropriate.
Monogenic hearing loss v2.142 KCNMA1 Arina Puzriakova Gene: kcnma1 has been classified as Red List (Low Evidence).
Monogenic hearing loss v2.141 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to
Monogenic hearing loss v2.140 KCNMA1 Arina Puzriakova Mode of inheritance for gene: KCNMA1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.681 LSS Eleanor Williams changed review comment from: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; to: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS, as agreed with Genomics England clinicians. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.
Intellectual disability v3.681 LSS Eleanor Williams Tag for-review tag was added to gene: LSS.
Intellectual disability v3.681 LSS Eleanor Williams edited their review of gene: LSS: Added comment: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; Changed rating: GREEN
Paroxysmal central nervous system disorders v1.9 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to
Paroxysmal central nervous system disorders v1.8 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276
Brain channelopathy v1.57 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM# 609446 to Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276
Brain channelopathy v1.56 KCNMA1 Arina Puzriakova Classified gene: KCNMA1 as Green List (high evidence)
Brain channelopathy v1.56 KCNMA1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Green as there are sufficient unrelated cases (3) with early-onset paroxysmal nonkinesigenic dyskinesia associated with monoallelic variants in this potassium channel gene. KCNMA1 is also Green on the 'Paroxysmal central nervous system disorders v1.7' GMS panel.
Brain channelopathy v1.56 KCNMA1 Arina Puzriakova Gene: kcnma1 has been classified as Green List (High Evidence).
Intellectual disability v3.681 KCNMA1 Arina Puzriakova changed review comment from: Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity to this panel has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel.

Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.; to: Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel in context of the severe intellectual impairment that may be observed.

Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.
Intellectual disability v3.681 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Intellectual disability v3.680 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 31427379; 31152168; 27567911; 29545233; 26195193
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Classified gene: KCNMA1 as Amber List (moderate evidence)
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Gene: kcnma1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.678 KCNMA1 Arina Puzriakova Tag for-review tag was added to gene: KCNMA1.
Intellectual disability v3.678 KCNMA1 Arina Puzriakova reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26195193, 27567911, 29330545, 29545233, 31152168, 31427379; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643, Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551, Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446, Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276, Liang-Wang syndrome, OMIM:618729, Liang-Wang syndrome, MONDO:0032886, {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596, Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.678 LIAS Eleanor Williams commented on gene: LIAS
Intellectual disability v3.678 LIAS Eleanor Williams Tag for-review tag was added to gene: LIAS.
Non-syndromic hypotrichosis v1.5 LSS Eleanor Williams changed review comment from: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30723320 - Besnard et al 2019 - report 7 unrelated families (11 individuals) with variants in LSS who present with alopecia (11/11), intellectual disability (10 mod/severe, 1 mild) and epilepsy (7/11). Segregation data shown for 6 families.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.
Sources: Literature; to: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30723320 - Besnard et al 2019 - report 7 unrelated families (11 individuals) with variants in LSS who present with alopecia (11/11), intellectual disability (10 mod/severe, 1 mild) and epilepsy (7/11). Segregation data shown for 6 families.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.

PMID: 29016354 - Chen and Lui 2017 - report a pediatric patient with congenital cataract, small penis, baldness and absence of eyebrows and compound heterozygous variants in LSS.

Sources: Literature
Non-syndromic hypotrichosis v1.5 LSS Eleanor Williams changed review comment from: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.
Sources: Literature; to: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30723320 - Besnard et al 2019 - report 7 unrelated families (11 individuals) with variants in LSS who present with alopecia (11/11), intellectual disability (10 mod/severe, 1 mild) and epilepsy (7/11). Segregation data shown for 6 families.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.
Sources: Literature
Non-syndromic hypotrichosis v1.5 LSS Eleanor Williams changed review comment from: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental.
Sources: Literature; to: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.
Sources: Literature
Non-syndromic hypotrichosis v1.5 LSS Eleanor Williams gene: LSS was added
gene: LSS was added to Non-syndromic hypotrichosis. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 32101538; 30401459
Phenotypes for gene: LSS were set to Hypotrichosis 14 OMIM:618275; hypotrichosis 14 MONDO:0032649
Review for gene: LSS was set to GREEN
Added comment: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental.
Sources: Literature
Intellectual disability v3.678 GRIA1 Arina Puzriakova Classified gene: GRIA1 as Amber List (moderate evidence)
Intellectual disability v3.678 GRIA1 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as no new evidence has been published since previous review. Most commonly reported as a candidate gene in large screening studies with limited segregation/phenotype/functional data. Also variable penetrance of the ID phenotype. Therefore, there is currently not enough evidence to classify as Green.
Intellectual disability v3.678 GRIA1 Arina Puzriakova Gene: gria1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.139 GJB3 Eleanor Williams edited their review of gene: GJB3: Changed publications: 9843210, 12630965, 10790215, 12791041, 15131355, 17259707, 19744334, 22617145, 23638949, 25214170, 27610647, 10587579, 16077902
Monogenic hearing loss v2.139 GJB3 Eleanor Williams edited their review of gene: GJB3: Changed publications: 9843210, 12630965, 10790215, 12791041, 15131355, 17259707, 19744334, 22617145, 23638949, 25214170, 27610647, 10587579, 1607790279
Monogenic hearing loss v2.139 GJB3 Eleanor Williams reviewed gene: GJB3: Rating: AMBER; Mode of pathogenicity: None; Publications: 9843210, 12630965, 10790215, 12791041, 15131355, 17259707, 19744334, 22617145, 23638949, 25214170, 27610647, 105875, 1607790279; Phenotypes: Deafness, autosomal dominant 2B OMIM:612644; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.247 H3F3B Arina Puzriakova Publications for gene: H3F3B were set to
Early onset or syndromic epilepsy v2.246 H3F3B Arina Puzriakova Phenotypes for gene: H3F3B were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Early onset or syndromic epilepsy v2.245 H3F3B Arina Puzriakova Mode of inheritance for gene: H3F3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Classified gene: H3F3B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) in view of evidence in recent publication (PMID: 33268356)
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Gene: h3f3b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.243 H3F3B Arina Puzriakova Tag for-review tag was added to gene: H3F3B.
Early onset or syndromic epilepsy v2.243 H3F3B Arina Puzriakova reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Intellectual disability, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.677 H3F3B Arina Puzriakova changed review comment from: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).; to: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. One individual was reported to have a normal IQ at 15 years. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).
Intellectual disability v3.677 H3F3B Arina Puzriakova Publications for gene: H3F3B were set to
Intellectual disability v3.676 H3F3B Arina Puzriakova Phenotypes for gene: H3F3B were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Intellectual disability v3.675 H3F3B Arina Puzriakova Mode of inheritance for gene: H3F3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.674 H3F3B Arina Puzriakova Classified gene: H3F3B as Amber List (moderate evidence)
Intellectual disability v3.674 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (at least 12) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.674 H3F3B Arina Puzriakova Gene: h3f3b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.673 H3F3B Arina Puzriakova Tag for-review tag was added to gene: H3F3B.
Intellectual disability v3.673 H3F3B Arina Puzriakova reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Segmental overgrowth disorders - Deep sequencing v2.8 PADI6 Sarah Leigh Tag for-review tag was added to gene: PADI6.
Segmental overgrowth disorders - Deep sequencing v2.8 PADI6 Sarah Leigh edited their review of gene: PADI6: Added comment: PMID: 32928291 reports three variants associated with Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance in three cases. Five variants have also been associated with Preimplantation embryonic lethality 2, where they have been biallelic in the women affected (pmid 27545678). There is enough evidence for this gene to be reviewed at the next major review.; Changed publications: 32928291, 33221824, 27545678
Malformations of cortical development v2.22 H3F3A Arina Puzriakova commented on gene: H3F3A: Added new-gene-name tag, new approved HGNC gene symbol for H3F3A is H3-3A
Malformations of cortical development v2.22 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Malformations of cortical development v2.22 H3F3A Arina Puzriakova Added comment: Comment on list classification: New gene added as Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Malformations of cortical development v2.22 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.21 H3F3A Arina Puzriakova gene: H3F3A was added
gene: H3F3A was added to Malformations of cortical development. Sources: Literature
new-gene-name, for-review tags were added to gene: H3F3A.
Mode of inheritance for gene: H3F3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: H3F3A were set to 31942419; 33268356
Phenotypes for gene: H3F3A were set to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Review for gene: H3F3A was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM, but is listed in Gene2Phenotype with a 'confirmed' disease confidence rating for 'Craniofacial with neurodevelopment disorders'.

- PMID: 31942419 (2019) - De novo missense variant identified by trio exome sequencing in a girl with secondary microcephaly, severe DD and ID, growth retardation and dysmorphic features. Brain MRI demonstrated hypoplasia of corpus callosum and cerebellum as well as thin layer of frontal and parietal periventricular gliosis. No functional analyses of the variant or patient cells were performed.

- PMID: 33268356 (2020) - De novo missense variants identified in 33 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. 23/28 patients showed abnormalities on brain MRI including hypoplasia/agenesis of the corpus collosum (9), cortical atrophy (6) and impaired myelination (5). Variable seizure phenotypes were reported in 17/33 cases, all early-onset where specified, mostly during infancy (latest onset at 14 years of age).
Sources: Literature
Segmental overgrowth disorders - Deep sequencing v2.8 PADI6 Sarah Leigh gene: PADI6 was added
gene: PADI6 was added to Segmental overgrowth disorders. Sources: Literature
Mode of inheritance for gene: PADI6 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: PADI6 were set to 32928291; 33221824
Phenotypes for gene: PADI6 were set to Preimplantation embryonic lethality 2 OMIM:617234; Beckwith-Wiedemann syndrome
Review for gene: PADI6 was set to AMBER
Added comment: Sources: Literature
Early onset or syndromic epilepsy v2.243 H3F3A Arina Puzriakova Phenotypes for gene: H3F3A were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Early onset or syndromic epilepsy v2.242 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
Early onset or syndromic epilepsy v2.241 H3F3A Arina Puzriakova Mode of inheritance for gene: H3F3A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) in view of evidence in recent publication (PMID: 33268356)
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.239 H3F3A Arina Puzriakova Tag for-review tag was added to gene: H3F3A.
Early onset or syndromic epilepsy v2.239 H3F3A Arina Puzriakova reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Intellectual disability, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.673 H3F3A Arina Puzriakova Phenotypes for gene: H3F3A were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Intellectual disability v3.672 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
Intellectual disability v3.671 H3F3A Arina Puzriakova Mode of inheritance for gene: H3F3A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.670 H3F3A Arina Puzriakova Deleted their comment
Intellectual disability v3.670 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Intellectual disability v3.670 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (>30) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.670 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.670 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Intellectual disability v3.670 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (>30) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.670 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.669 H3F3A Arina Puzriakova Tag for-review tag was added to gene: H3F3A.
Intellectual disability v3.669 H3F3A Arina Puzriakova reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942419, 33268356; Phenotypes: Developmental delay, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.139 GJB6 Eleanor Williams commented on gene: GJB6: As reviewer Zornitza Stark reports this gene has Refuted status in association with hearing loss by ClinGen. However, leaving as amber, as there is still some evidence to support the possibility that SNV in this gene are associated with hearing loss (Grifa et al and Amritkumar et al).
Monogenic hearing loss v2.139 PMP22 Eleanor Williams Classified gene: PMP22 as Amber List (moderate evidence)
Monogenic hearing loss v2.139 PMP22 Eleanor Williams Added comment: Comment on list classification: After consultation with Genomics England clinical team leaving this gene as amber as the majority of patients do not have a hearing loss phenotype, and there are also issues around the potential predictive nature of the neurological aspects if this panel was applied to a paediatric hearing loss cohort.
Monogenic hearing loss v2.139 PMP22 Eleanor Williams Gene: pmp22 has been classified as Amber List (Moderate Evidence).
DDG2P v2.16 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
DDG2P v2.15 H3F3A Arina Puzriakova Classified gene: H3F3A as Green List (high evidence)
DDG2P v2.15 H3F3A Arina Puzriakova Added comment: Comment on list classification: Changed rating to Green as H3F3A is listed in Gene2Phenotype under the new gene name, H3-3A.

Associated with 'Craniofacial with neurodevelopment disorders' with a disease confidence rating of 'confirmed'
DDG2P v2.15 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Green List (High Evidence).
DDG2P v2.14 H3F3A Arina Puzriakova commented on gene: H3F3A
DDG2P v2.14 H3F3A Arina Puzriakova Tag new-gene-name tag was added to gene: H3F3A.
Monogenic hearing loss v2.138 SCD5 Eleanor Williams Classified gene: SCD5 as Red List (low evidence)
Monogenic hearing loss v2.138 SCD5 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to red. As outlined by the reviewer, one large Chinese family with autosomal dominant non syndromic hearing loss reported, in which a missense variant in the SCD5 gene (c.626G > C, p.W209S, NM_ 001037582) segregated perfectly cases with hearing loss.
Monogenic hearing loss v2.138 SCD5 Eleanor Williams Gene: scd5 has been classified as Red List (Low Evidence).
Monogenic hearing loss v2.137 SCD5 Eleanor Williams Phenotypes for gene: SCD5 were changed from Deafness, autosomal dominant 79, MIM#619086 to Deafness, autosomal dominant 79 OMIM:619086; deafness, autosomal dominant 79 MONDO:0033668
Intellectual disability v3.669 KDM4B Arina Puzriakova Tag for-review tag was added to gene: KDM4B.
Intellectual disability v3.669 KDM4B Arina Puzriakova Classified gene: KDM4B as Amber List (moderate evidence)
Intellectual disability v3.669 KDM4B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but may be promoted to Green at the next GMS panel update (added 'for-review' tag).

9 unrelated individuals reported at present (PMID: 33232677). Although all presented GDD, only 1 individual had severe ID (IQ = 50) and 3 had mild ID. Although ID is too mild in majority of cases, developmental delay was the universal feature amongst affected individuals and other phenotypes were heterogenous (e.g. seizures, brain malformations). Therefore, there may be value in inclusion on this panel for capturing this phenotype.
Intellectual disability v3.669 KDM4B Arina Puzriakova Gene: kdm4b has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.38 ABCC6 Ivone Leong edited their review of gene: ABCC6: Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the evidence and expert reviews, this gene should be promoted to Green at the next review.; Changed rating: GREEN
Retinal disorders v2.38 ABCC6 Ivone Leong Tag for-review tag was added to gene: ABCC6.
Retinal disorders v2.38 ABCC6 Ivone Leong Mode of inheritance for gene: ABCC6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.37 ABCC6 Ivone Leong Phenotypes for gene: ABCC6 were changed from to Pseudoxanthoma elasticum, OMIM:264800; inherited pseudoxanthoma elasticum, MONDO:0100091
Retinal disorders v2.36 USP45 Ivone Leong Classified gene: USP45 as Amber List (moderate evidence)
Retinal disorders v2.36 USP45 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.36 USP45 Ivone Leong Gene: usp45 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.35 USP45 Ivone Leong Tag for-review tag was added to gene: USP45.
Retinal disorders v2.35 USP45 Ivone Leong Phenotypes for gene: USP45 were changed from Lebers congenital amaurosis; retinal dystrophy; ?Leber congenital amaurosis 19, 618513 to Lebers congenital amaurosis; retinal dystrophy; ?Leber congenital amaurosis 19, OMIMM:618513
Skeletal Muscle Channelopathies v1.26 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, OMIM:255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140
Fetal anomalies v1.126 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from DYSSEGMENTAL DYSPLASIA SILVERMAN-HANDMAKER TYPE; SCHWARTZ-JAMPEL SYNDROME to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140
Skeletal dysplasia v2.41 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Dyssegmental dysplasia, Silverman-Handmaker type 224410; Schwartz-Jampel syndrome, type 1 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140
Arthrogryposis v3.32 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717
Paroxysmal central nervous system disorders v1.7 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800; Dyssegmental dysplasia, Silverman-Handmaker type, 224410 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140
Skeletal Muscle Channelopathies v1.25 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800
Intellectual disability v3.668 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717
Intellectual disability v3.667 HSPG2 Arina Puzriakova Classified gene: HSPG2 as Amber List (moderate evidence)
Intellectual disability v3.667 HSPG2 Arina Puzriakova Added comment: Comment on list classification: While there are sufficient cases to support a gene-disease association, DD/ID is part of a broader phenotype and cognitive impairment is unlikely to represent a main feature of the disease presentation.

Maintaining Amber rating as the disorder is better represented in other panels (e.g. Skeletal dysplasia, Arthrogryposis, etc) where this gene is already Green.
Intellectual disability v3.667 HSPG2 Arina Puzriakova Gene: hspg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Classified gene: CSNK1G1 as Amber List (moderate evidence)
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as now at least 5 unrelated individuals reported (PMID: 33009664). All present developmental delay of varying severity, although a formal ID assessment was not performed. Tagged 'for-review' to evaluate relevance of the phenotypes to this panel.
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Gene: csnk1g1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.665 CSNK1G1 Arina Puzriakova Tag for-review tag was added to gene: CSNK1G1.
Dilated and arrhythmogenic cardiomyopathy v1.10 SLC6A6 Ivone Leong Classified gene: SLC6A6 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.10 SLC6A6 Ivone Leong Gene: slc6a6 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.9 SLC6A6 Ivone Leong gene: SLC6A6 was added
gene: SLC6A6 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
watchlist tags were added to gene: SLC6A6.
Mode of inheritance for gene: SLC6A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034; 17875433; 20804595
Phenotypes for gene: SLC6A6 were set to Early retinal degeneration; cardiomyopathy
Review for gene: SLC6A6 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype.

There are 3 unrelated cases with early retinal degeneration and only 2 cases had DCM (PMID: 31903486 and 29886034). The case described in PMID: 29886034 did not report any segregation results for the affected individual with DCM. The case described in 29886034, affected individuals were treated with taurine for 2 years and the cardiomyopathy was corrected.
The mouse model (PMID: 20804595) is a KO taurine transporter showed a cardiac.
Sources: Literature
Skeletal dysplasia v2.40 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Skeletal dysplasia v2.40 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.39 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. After consulting the Genomics England Clinical Team, it was decided that this gene should be added to this panel with an Amber rating. The skeletal phenotype is relatively mild and the GMS specialist group should review whether this gene is appropriate for this panel.
Sources: Literature
Early onset or syndromic epilepsy v2.239 CSNK1G1 Arina Puzriakova Mode of inheritance for gene: CSNK1G1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.39 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.39 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.38 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Red List (low evidence)
Likely inborn error of metabolism v2.38 SHMT2 Arina Puzriakova Added comment: Comment on list classification: New gene added as Amber but can be promoted to Green at the next GMS panel update (added 'for-review' tag)
Likely inborn error of metabolism v2.38 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Red List (Low Evidence).
Likely inborn error of metabolism v2.37 SHMT2 Arina Puzriakova commented on gene: SHMT2: SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Likely inborn error of metabolism v2.37 SHMT2 Arina Puzriakova gene: SHMT2 was added
gene: SHMT2 was added to Inborn errors of metabolism. Sources: Literature
for-review tags were added to gene: SHMT2.
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Review for gene: SHMT2 was set to GREEN
Added comment: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

Clinical features include dysmorphism, congenital microcephaly, hypertrophic cardiomyopathy or atrial-septal defects, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy.

SHMT2 encodes the mitochondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

While plasma metabolites were within normal range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts, decrease in glycine/serine ratios, impaired folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.
Sources: Literature
CAKUT v1.157 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
CAKUT v1.157 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
CAKUT v1.156 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to CAKUT. Sources: Literature
watchlist tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene has been given an Amber rating.
Sources: Literature
Holoprosencephaly - NOT chromosomal v2.9 HS2ST1 Ivone Leong changed review comment from: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum (2/3), skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene should be considered for Green gene rating status at the next review.
Sources: Literature; to: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum (2/3), skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene has been given an Amber review.
Holoprosencephaly - NOT chromosomal v2.9 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Holoprosencephaly - NOT chromosomal v2.9 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly - NOT chromosomal v2.8 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Holoprosencephaly. Sources: Literature
watchlist tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum (2/3), skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene should be considered for Green gene rating status at the next review.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.17 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.17 SHMT2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Paediatric or syndromic cardiomyopathy v1.17 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.16 SHMT2 Arina Puzriakova changed review comment from: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5).

Other features include dysmorphism, congenital microcephaly, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy. Some functional data indicating variants result in impaired SHMT2 enzymatic function.
Sources: Literature; to: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Age of diagnosis of hypertrophic cardiomyopathy ranged from 3 years to 16 years of age.

Other features include dysmorphism, congenital microcephaly, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy. Some functional data indicating variants result in impaired SHMT2 enzymatic function.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.16 SHMT2 Arina Puzriakova commented on gene: SHMT2: SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Paediatric or syndromic cardiomyopathy v1.16 SHMT2 Arina Puzriakova gene: SHMT2 was added
gene: SHMT2 was added to Cardiomyopathies - including childhood onset. Sources: Literature
for-review tags were added to gene: SHMT2.
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Review for gene: SHMT2 was set to GREEN
Added comment: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5).

Other features include dysmorphism, congenital microcephaly, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy. Some functional data indicating variants result in impaired SHMT2 enzymatic function.
Sources: Literature
Likely inborn error of metabolism v2.36 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.36 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.35 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Inborn errors of metabolism. Sources: Literature
for-review tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene should be considered for Green gene rating status at the next review.
Sources: Literature
Undiagnosed metabolic disorders v1.434 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.434 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.433 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to GREEN
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism.

There is enough evidence to support a gene-disease association, so this gene has been rated Green.
Sources: Literature
Intellectual disability v3.665 SHMT2 Arina Puzriakova Tag for-review tag was added to gene: SHMT2.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Amber List (moderate evidence)
Intellectual disability v3.665 SHMT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Sufficient number of unrelated cases (>3) with ID of relevant severity to this panel. Some functional data indicating variants result in impaired SHMT2 enzymatic function. Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)

SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Amber List (Moderate Evidence).
Cytopenias and congenital anaemias v1.80 RAP1B Ivone Leong Classified gene: RAP1B as Amber List (moderate evidence)
Cytopenias and congenital anaemias v1.80 RAP1B Ivone Leong Gene: rap1b has been classified as Amber List (Moderate Evidence).
Cytopenias and congenital anaemias v1.79 RAP1B Ivone Leong gene: RAP1B was added
gene: RAP1B was added to Cytopenias and congenital anaemias. Sources: Literature
watchlist tags were added to gene: RAP1B.
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAP1B were set to 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability; cytopenia
Review for gene: RAP1B was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings. Cytopenia is not a feature for this patient.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v1.34 RAP1B Ivone Leong Classified gene: RAP1B as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.34 RAP1B Ivone Leong Gene: rap1b has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.33 RAP1B Ivone Leong gene: RAP1B was added
gene: RAP1B was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
watchlist tags were added to gene: RAP1B.
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAP1B were set to 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability; cytopenia
Review for gene: RAP1B was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings. Cytopenia is not a feature for this patient.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Sources: Literature
Intellectual disability v3.664 SHMT2 Arina Puzriakova Phenotypes for gene: SHMT2 were changed from Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Intellectual disability v3.663 ITFG2 Arina Puzriakova Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Intellectual disability v3.662 ITFG2 Arina Puzriakova Classified gene: ITFG2 as Amber List (moderate evidence)
Intellectual disability v3.662 ITFG2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as ITFG2 can only be classified as a possible candidate gene based present evidence. Clinical and pedigree details are limited and there is no supporting functional data. Additional cases required to corroborate this gene-disease association.
Intellectual disability v3.662 ITFG2 Arina Puzriakova Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.661 RAP1B Ivone Leong Tag watchlist tag was added to gene: RAP1B.
Intellectual disability v3.661 RAP1B Ivone Leong Classified gene: RAP1B as Amber List (moderate evidence)
Intellectual disability v3.661 RAP1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Intellectual disability v3.661 RAP1B Ivone Leong Gene: rap1b has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.52 CTDP1 Ivone Leong Classified gene: CTDP1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.52 CTDP1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the new review, this gene has been promoted to Amber and tagged with "for-review" for the next round of GMS panel reviews so the new rating can be considered.
Bilateral congenital or childhood onset cataracts v2.52 CTDP1 Ivone Leong Gene: ctdp1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.51 CTDP1 Ivone Leong Tag for-review tag was added to gene: CTDP1.
Skeletal dysplasia v2.38 COG4 Ivone Leong Classified gene: COG4 as Amber List (moderate evidence)
Skeletal dysplasia v2.38 COG4 Ivone Leong Gene: cog4 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.37 COG4 Ivone Leong gene: COG4 was added
gene: COG4 was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: COG4.
Mode of inheritance for gene: COG4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COG4 were set to 31949312; 30290151
Phenotypes for gene: COG4 were set to Saul-Wilson syndrome, OMIM:618150; microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407
Mode of pathogenicity for gene: COG4 was set to Other
Review for gene: COG4 was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. This gene was added to the Cataracts panel by Zornitza Stark (Australian Genomics).

"Saul-Wilson syndrome (AD): 14 patients reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like) All have a recurrent de novo heterozygous missense variant (p.Gly516Arg). Please note bi-allelic variants cause CDG. Sources: Expert list
Zornitza Stark (Australian Genomics), 7 Jul 2020"

PMID: 30290151 suggests that the Saul-Wilson syndrome variant is gain of function. Therefore, this gene should be considered to be Green at the next review.
Sources: Literature
Monogenic hearing loss v2.136 COG4 Ivone Leong Classified gene: COG4 as Amber List (moderate evidence)
Monogenic hearing loss v2.136 COG4 Ivone Leong Gene: cog4 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.135 COG4 Ivone Leong gene: COG4 was added
gene: COG4 was added to Hearing loss. Sources: Literature
for-review tags were added to gene: COG4.
Mode of inheritance for gene: COG4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COG4 were set to 31949312; 30290151
Phenotypes for gene: COG4 were set to Saul-Wilson syndrome, OMIM:618150; microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407
Mode of pathogenicity for gene: COG4 was set to Other
Review for gene: COG4 was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. This gene was added to the Cataracts panel by Zornitza Stark (Australian Genomics).

"Saul-Wilson syndrome (AD): 14 patients reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like) All have a recurrent de novo heterozygous missense variant (p.Gly516Arg). Please note bi-allelic variants cause CDG. Sources: Expert list
Zornitza Stark (Australian Genomics), 7 Jul 2020"

PMID: 30290151, many of the affected patients also have hearing loss and the authors suggest that the Saul-Wilson syndrome variant is gain of function. Therefore, this gene should be considered to be Green at the next review.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.51 COG4 Ivone Leong Added comment: Comment on mode of pathogenicity: PMID: 30290151 suggests that Saul-Wilson syndrome variant is gain of function.
Bilateral congenital or childhood onset cataracts v2.51 COG4 Ivone Leong Mode of pathogenicity for gene: COG4 was changed from None to Other
Bilateral congenital or childhood onset cataracts v2.50 COG4 Ivone Leong Tag for-review tag was added to gene: COG4.
Bilateral congenital or childhood onset cataracts v2.50 COG4 Ivone Leong Classified gene: COG4 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.50 COG4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Bilateral congenital or childhood onset cataracts v2.50 COG4 Ivone Leong Gene: cog4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.238 EXT2 Zornitza Stark edited their review of gene: EXT2: Changed publications: 26246518, 30288735, 30997052, 30075207; Changed phenotypes: Seizures, scoliosis, and macrocephaly syndrome, MIM# 616682
Intellectual disability v3.660 MPI Zornitza Stark reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: 12414827, 9585601, 10980531, 33098580, 33204592, 32905087, 32266963, 30242110; Phenotypes: Congenital disorder of glycosylation, type Ib, MIM# 602579, MPI-CDG MONDO:0011257; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.385 GIMAP6 Boaz Palterer gene: GIMAP6 was added
gene: GIMAP6 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: GIMAP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIMAP6 were set to 33328581
Phenotypes for gene: GIMAP6 were set to Lymphopenia; Sinopulmonary Infections
Penetrance for gene: GIMAP6 were set to unknown
Review for gene: GIMAP6 was set to RED
Added comment: Two siblings with an homozygous variant in GIMAP6 and absent protein expression. One with lymphopenia and recurrent sinopulmonary infections, the other clinically asymptomatic.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.66 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from Hyperlysinemia; Saccharopinuria, 268700 to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
DDG2P v2.14 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIA 238700 to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Likely inborn error of metabolism v2.34 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from Intellectual disability; Hyperlysinemia; Hyperlysinaemia (Disorders of histidine, tryptophan or lysine metabolism) to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Fetal anomalies v1.125 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIAHyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388 to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Fetal anomalies v1.124 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIA to HYPERLYSINEMIAHyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Undiagnosed metabolic disorders v1.432 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from Hyperlysinaemia (Disorders of histidine, tryptophan or lysine metabolism); Intellectual disability; Hyperlysinemia 238700 to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Intellectual disability v3.660 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIA to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Adult onset neurodegenerative disorder v2.35 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Hereditary ataxia with onset in adulthood v2.19 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from CMT 2N 613287; EIEE29, 616339 to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Hereditary neuropathy or pain disorder v1.19 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Charcot Marie Tooth disease, axonal, type 2N, 613287; Charcot-Marie-Tooth, Type 2 to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Intellectual disability v3.659 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from EARLY-ONSET EPILEPTIC ENCEPHALOPATHY WITH PERSISTENT MYELINATION DEFECT. to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Hereditary neuropathy v1.381 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Charcot-Marie-Tooth, Type 2 ; Charcot Marie Tooth disease, axonal, type 2N, 613287; Charcot-Marie-Tooth, Type 2 to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Early onset or syndromic epilepsy v2.238 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Fetal anomalies v1.123 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from EARLY-ONSET EPILEPTIC ENCEPHALOPATHY WITH PERSISTENT MYELINATION DEFECT. to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Severe microcephaly v2.54 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29, MIM# 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Hereditary ataxia v1.207 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Retinal disorders v2.34 SLC6A6 Ivone Leong Phenotypes for gene: SLC6A6 were changed from Early retinal degeneration; Dilated cardiomyopathy to Early retinal degeneration; cardiomyopathy
Retinal disorders v2.33 SLC6A6 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 2 unrelated cases with early retinal degeneration and a mouse model that replicates the human phenotype. Therefore, there is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 2 unrelated cases with early retinal degeneration and a mouse model that replicates the human phenotype. PMID: 29886034 did not look at the eyes of patients so therefore unsure if the affected individual with a variant in SLC6A6 has an eye phenotype.

Therefore, there is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - narrow panel v2.35 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
White matter disorders and cerebral calcification - narrow panel v1.27 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29, MIM# 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Childhood onset dystonia, chorea or related movement disorder v1.65 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Hereditary ataxia with onset in adulthood v2.18 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550; Triple A syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Fetal anomalies v1.122 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from ACHALASIA-ADDISONIANISM-ALACRIMA SYNDROME to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Adult onset neurodegenerative disorder v2.34 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Retinal disorders v2.33 SLC6A6 Ivone Leong Phenotypes for gene: SLC6A6 were changed from Early retinal degeneration; cardiomyopathy to Early retinal degeneration; Dilated cardiomyopathy
Hereditary ataxia v1.206 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Ataxia and cerebellar anomalies - narrow panel v2.34 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Familial dysautonomia v1.9 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Congenital adrenal hypoplasia v2.4 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Triple A syndrome (Addisons, achalasia, alacrima), 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Intellectual disability v3.658 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Retinal disorders v2.32 SLC6A6 Ivone Leong Classified gene: SLC6A6 as Amber List (moderate evidence)
Retinal disorders v2.32 SLC6A6 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 2 unrelated cases with early retinal degeneration and a mouse model that replicates the human phenotype. Therefore, there is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Retinal disorders v2.32 SLC6A6 Ivone Leong Gene: slc6a6 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.31 SLC6A6 Ivone Leong Tag for-review tag was added to gene: SLC6A6.
Retinal disorders v2.31 SLC6A6 Ivone Leong Added comment: Comment on publications: PMID: 17875433 slc6a6-/- mouse develop retinal degenerative disease.
Retinal disorders v2.31 SLC6A6 Ivone Leong Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034
Retinal disorders v2.30 AHR Ivone Leong commented on gene: AHR: This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association so this gene will remain Amber.
Retinal disorders v2.30 AHR Ivone Leong Tag watchlist tag was added to gene: AHR.
Retinal disorders v2.30 AHR Ivone Leong Publications for gene: AHR were set to
Retinal disorders v2.29 AHR Ivone Leong Phenotypes for gene: AHR were changed from ?Retinitis pigmentosa 85, OMIM:618345 to ?Retinitis pigmentosa 85, OMIM:618345; Retinal dystrophy
Retinal disorders v2.28 AHR Ivone Leong Phenotypes for gene: AHR were changed from to ?Retinitis pigmentosa 85, OMIM:618345
Retinal disorders v2.27 AHR Ivone Leong Mode of inheritance for gene: AHR was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.657 GOT2 Arina Puzriakova Tag watchlist was removed from gene: GOT2.
Intellectual disability v3.657 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Early onset or syndromic epilepsy v2.237 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Intellectual disability v3.656 GOT2 Arina Puzriakova Classified gene: GOT2 as Amber List (moderate evidence)
Intellectual disability v3.656 GOT2 Arina Puzriakova Added comment: Comment on list classification: ID of relevant severity to this panel (severe-to-profound) is reported in 4/4 individuals (PMID:31422819). However, intellectual impairment was secondary to epilepsy and there is no evidence of neurodevelopmental delay preceding the onset of seizures. Therefore, maintaining Amber rating on this panel (GOT2 is already Green on the Genetic epilepsy syndromes (v2.236) panel)
Intellectual disability v3.656 GOT2 Arina Puzriakova Gene: got2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.655 GOT2 Arina Puzriakova commented on gene: GOT2
Intellectual disability v3.655 GATA6 Arina Puzriakova Classified gene: GATA6 as Amber List (moderate evidence)
Intellectual disability v3.655 GATA6 Arina Puzriakova Added comment: Comment on list classification: Developmental delay has been reported in some patients with GATA6 variants. However, in view of the pancreatic and cardiac abnormalities that constitute the main phenotypes, cognitive impairment is unlikely to represent a key feature of the disease presentation.

Maintaining Amber rating as the disorder is better represented in other panels (e.g. Diabetes, Severe Paediatric Disorders, etc) where this gene is already Green.
Intellectual disability v3.655 GATA6 Arina Puzriakova Gene: gata6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.654 HS2ST1 Ivone Leong Tag watchlist tag was added to gene: HS2ST1.
Intellectual disability v3.654 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Intellectual disability v3.654 HS2ST1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Therefore, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.654 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.385 TBX21 Arina Puzriakova Classified gene: TBX21 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.385 TBX21 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Rating Red as only single patient reported at present with homozygous variants in the TBX21 gene resulting clinically in MSMD. Additional cases required to support pathogenicity and inclusion on a diagnostic panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.385 TBX21 Arina Puzriakova Gene: tbx21 has been classified as Red List (Low Evidence).
Intellectual disability v3.653 BICRA Ivone Leong Classified gene: BICRA as Amber List (moderate evidence)
Intellectual disability v3.653 BICRA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.653 BICRA Ivone Leong Gene: bicra has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.652 BICRA Ivone Leong Tag for-review tag was added to gene: BICRA.
Intellectual disability v3.652 EMC10 Ivone Leong Classified gene: EMC10 as Red List (low evidence)
Intellectual disability v3.652 EMC10 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. As there is only 1 case, this gene has been given a Red rating.
Intellectual disability v3.652 EMC10 Ivone Leong Gene: emc10 has been classified as Red List (Low Evidence).
Bilateral congenital or childhood onset cataracts v2.49 CTDP1 Ivone Leong Tag founder-effect tag was added to gene: CTDP1.
Bilateral congenital or childhood onset cataracts v2.49 CTDP1 Ivone Leong Publications for gene: CTDP1 were set to 14517542; 24690360; 14517542
Bilateral congenital or childhood onset cataracts v2.48 CTDP1 Ivone Leong Phenotypes for gene: CTDP1 were changed from Congenital cataracts, facial dysmorphism, and neuropathy, 604168 to Congenital cataracts, facial dysmorphism, and neuropathy, OMIM:604168, MONDO:0011402
Bilateral congenital or childhood onset cataracts v2.47 CTDP1 Ivone Leong Publications for gene: CTDP1 were set to
Bilateral congenital or childhood onset cataracts v2.46 POLG Ivone Leong Tag for-review tag was added to gene: POLG.
Bilateral congenital or childhood onset cataracts v2.46 POLG Ivone Leong Classified gene: POLG as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.46 POLG Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with the relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence for this gene to be Green; however, the inclusion of this gene to the panel should be reviewed by the GMS specialist group.
Bilateral congenital or childhood onset cataracts v2.46 POLG Ivone Leong Gene: polg has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.45 ABHD12 Ivone Leong Classified gene: ABHD12 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.45 ABHD12 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association; however, the GMS specialist group should review whether this gene should be included in the panel.
Bilateral congenital or childhood onset cataracts v2.45 ABHD12 Ivone Leong Gene: abhd12 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.44 ABHD12 Ivone Leong Tag for-review tag was added to gene: ABHD12.
Skeletal dysplasia v2.36 MIA3 Aleš Maver changed review comment from: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature; to: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Skeletal dysplasia v2.36 MIA3 Aleš Maver changed review comment from: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publications reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature; to: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Skeletal dysplasia v2.36 MIA3 Aleš Maver gene: MIA3 was added
gene: MIA3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIA3 were set to 32101163
Phenotypes for gene: MIA3 were set to short stature; skeletal dysplasia; amelogenesis
Penetrance for gene: MIA3 were set to unknown
Review for gene: MIA3 was set to RED
Added comment: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publications reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.44 ABHD12 Ivone Leong Publications for gene: ABHD12 were set to
Bilateral congenital or childhood onset cataracts v2.43 ABHD12 Ivone Leong Phenotypes for gene: ABHD12 were changed from Polyneuropathy, Hearing Loss, Ataxia, Retinitis Pigmentosa and Cataract (PHARC); Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, 612674 to Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, OMIM:612674; PHARC syndrome, MONDO:0012984
Bilateral congenital or childhood onset cataracts v2.42 PLOD3 Ivone Leong Classified gene: PLOD3 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.42 PLOD3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence for a gene-disease association. Therefore, this gene should be Green at the next review.
Bilateral congenital or childhood onset cataracts v2.42 PLOD3 Ivone Leong Gene: plod3 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.41 PLOD3 Ivone Leong Tag for-review tag was added to gene: PLOD3.
Bilateral congenital or childhood onset cataracts v2.41 SLC16A12 Ivone Leong Classified gene: SLC16A12 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.41 SLC16A12 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-disease association. This gene should be rated Green at the next review.
Bilateral congenital or childhood onset cataracts v2.41 SLC16A12 Ivone Leong Gene: slc16a12 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.40 SLC16A12 Ivone Leong Added comment: Comment on publications: This was originally in the Publications section:
Kloeckener-Gruissem et al (2008) Am J Hum Genet 82:772-779 - a nonsense variant in SLC16A12 was identified in a Swiss family with autosomal dominant juvenile cataract, microcornea, and renal glucosuria. High SLC16A12 transcript expression levels in the eye and kidney was observed (PMID: 18304496);
Functional study: Castorino et al (2011) IOVS 52:6774 PMID: 21778275 - reports the variant causes a defect in protein trafficking;
A 5'UTR SNP was identified in one patient with age-related cataract, and caused increased expression in luciferase assays PMID: 20181839
Bilateral congenital or childhood onset cataracts v2.40 SLC16A12 Ivone Leong Publications for gene: SLC16A12 were set to Kloeckener-Gruissem et al (2008) Am J Hum Genet 82:772-779 - a nonsense variant in SLC16A12 was identified in a Swiss family with autosomal dominant juvenile cataract, microcornea, and renal glucosuria. High SLC16A12 transcript expression levels in the eye and kidney was observed; Functional study: Castorino et al (2011) IOVS 52:6774 PMID: 21778275 - reports the variant causes a defect in protein trafficking; A 5'UTR SNP was identified in one patient with age-related cataract, and caused increased expression in luciferase assays PMID: 20181839
Bilateral congenital or childhood onset cataracts v2.39 SLC16A12 Ivone Leong Phenotypes for gene: SLC16A12 were changed from Cataract, juvenile, with microcornea and glucosuria, 612018 to Cataract 47, juvenile, with microcornea, OMIM:612018; juvenile cataract-microcornea-renal glucosuria syndrome, MONDO:0012786
Bilateral congenital or childhood onset cataracts v2.38 COG4 Ivone Leong Phenotypes for gene: COG4 were changed from Saul-Wilson syndrome, OMIM #618150 to Saul-Wilson syndrome, OMIM:618150; microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407
Bilateral congenital or childhood onset cataracts v2.37 EED Ivone Leong reviewed gene: EED: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v2.37 EED Ivone Leong Tag for-review tag was added to gene: EED.
Bilateral congenital or childhood onset cataracts v2.37 EED Ivone Leong Phenotypes for gene: EED were changed from Cohen-Gibson syndrome 617561 to Cohen-Gibson syndrome, OMIM:617561,MONDO:0060510
Congenital myopathy v2.10 GFER Ivone Leong Classified gene: GFER as Amber List (moderate evidence)
Congenital myopathy v2.10 GFER Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association and this gene should be considered Green at the next review. This gene has been promoted to Amber and tagged with "for-review".
Congenital myopathy v2.10 GFER Ivone Leong Gene: gfer has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.9 GFER Ivone Leong Publications for gene: GFER were set to 19409522
Bilateral congenital or childhood onset cataracts v2.36 GFER Ivone Leong Classified gene: GFER as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.36 GFER Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to promote this gene from Red to Green. This gene should be made Green at the next review.
Bilateral congenital or childhood onset cataracts v2.36 GFER Ivone Leong Gene: gfer has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.35 GFER Ivone Leong Phenotypes for gene: GFER were changed from Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay, OMIM:613076 to Myopathy, mitochondrial progressive, with congenital cataract and developmental delay, OMIM:613076
Bilateral congenital or childhood onset cataracts v2.34 GFER Ivone Leong Tag for-review tag was added to gene: GFER.
Bilateral congenital or childhood onset cataracts v2.34 GFER Ivone Leong Phenotypes for gene: GFER were changed from Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay, 613076 to Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay, OMIM:613076
Bilateral congenital or childhood onset cataracts v2.33 GFER Ivone Leong Publications for gene: GFER were set to Di Fonzo et al (2009) Am J Hum Genet 84:594-604
Bilateral congenital or childhood onset cataracts v2.32 GEMIN4 Ivone Leong Tag watchlist tag was added to gene: GEMIN4.
Bilateral congenital or childhood onset cataracts v2.32 GEMIN4 Ivone Leong Publications for gene: GEMIN4 were set to 27878435; 25558065
Bilateral congenital or childhood onset cataracts v2.31 GEMIN4 Ivone Leong edited their review of gene: GEMIN4: Added comment: On re-reviewing this gene, the mouse model was not a knockout gene model of GEMIN4. PMID: 30237576 is a new publication that describes another case with the same variant as that reported by PMID: 25558065. The affected individual is from the same region as the previous publication. Therefore, there is insufficient evidence to support a gene-disease status and this gene should be downgraded from Green to Amber at the next review.; Changed rating: AMBER; Changed publications: 30237576
Bilateral congenital or childhood onset cataracts v2.31 GEMIN4 Ivone Leong Tag for-review tag was added to gene: GEMIN4.
Cutaneous photosensitivity with a likely genetic cause v1.7 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Cutaneous photosensitivity with a likely genetic cause v1.7 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Cutaneous photosensitivity with a likely genetic cause v1.6 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Cutaneous photosensitivity with a likely genetic cause. Sources: Expert Review
for-review tags were added to gene: ANAPC1.
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). This gene was suggested to be added to this panel as Amber by the Genomics England Clinical Team. The publication did not mention any affected individuals having photosensitivity; however, as it is a mimic of RECQL4, this gene may be appropriate for this panel.

This gene has been tagged with "for-review" so that the GMS specialist group could review this gene for whether it is appropriate for this panel or not.
Sources: Expert Review
Skeletal dysplasia v2.36 ANAPC1 Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating.
Sources: Literature; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating.

Have tagged with "for-review" so that GMS could review whether this gene is appropriate for the panel or not.
Sources: Literature
Skeletal dysplasia v2.36 ANAPC1 Ivone Leong Tag for-review tag was added to gene: ANAPC1.
Skeletal dysplasia v2.36 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Skeletal dysplasia v2.36 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.35 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating.
Sources: Literature
Ectodermal dysplasia without a known gene mutation v1.21 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Green List (high evidence)
Ectodermal dysplasia without a known gene mutation v1.21 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Green List (High Evidence).
Ectodermal dysplasia without a known gene mutation v1.20 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Ectodermal dysplasia without a known gene mutation. Sources: Literature
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). All affected individuals have poikiloderma. 9/10 patients had sparse or absent hair, eyebrows, or eyelashes. 5/10 had abnormal teeth and 4/10 had abnormal nails. There is enough evidence to support a gene-disease association.
Sources: Literature
Ectodermal dysplasia v1.13 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Ectodermal dysplasia v1.13 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.12 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Ectodermal dysplasia. Sources: Literature
for-review tags were added to gene: ANAPC1.
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). All affected individuals have poikiloderma. 9/10 patients had sparse or absent hair, eyebrows, or eyelashes. 5/10 had abnormal teeth and 4/10 had abnormal nails. There is enough evidence to support a gene-disease association. This gene should be rated Green pending review from GMS.
Sources: Literature
Corneal dystrophy v1.6 VSX1 Ivone Leong Classified gene: VSX1 as Red List (low evidence)
Corneal dystrophy v1.6 VSX1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence to support a gene-disease association for this gene; however, this gene has been given a Red rating as it does not fit in the scope of the clinical indication for this panel.
Corneal dystrophy v1.6 VSX1 Ivone Leong Gene: vsx1 has been classified as Red List (Low Evidence).
Corneal dystrophy v1.5 VSX1 Ivone Leong Phenotypes for gene: VSX1 were changed from Keratoconus 1, MIM# 148300 to Keratoconus 1, OMIM:148300, MONDO:0007851
Intellectual disability v3.651 CSNK1G1 Ivone Leong Phenotypes for gene: CSNK1G1 were changed from severe non-syndromic early-onset epilepsy to severe non-syndromic early-onset epilepsy; Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of the face; Abnormality of limbs
Intellectual disability v3.650 CSNK1G1 Ivone Leong Publications for gene: CSNK1G1 were set to 24463883
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 TBX21 Boaz Palterer gene: TBX21 was added
gene: TBX21 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TBX21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBX21 were set to 33296702
Phenotypes for gene: TBX21 were set to Defects with susceptibility to mycobacterial infection (MSMD); Defects in Intrinsic and Innate Immunity
Penetrance for gene: TBX21 were set to unknown
Review for gene: TBX21 was set to RED
Added comment: One patient from consanguineous parents with homozygous indel. Corroborated by in vitro and mouse model.
Sources: Literature
Pigmentary skin disorders v1.9 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Pigmentary skin disorders v1.9 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v1.8 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Pigmentary skin disorders. Sources: Literature
for-review tags were added to gene: ANAPC1.
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome 1. All affected individuals have Poikiloderma. There is enough evidence to support a gene-disease association. This gene should be rated Green at next review.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.31 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.31 ANAPC1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at next review.
Bilateral congenital or childhood onset cataracts v2.31 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.30 ANAPC1 Ivone Leong Tag for-review tag was added to gene: ANAPC1.
Bilateral congenital or childhood onset cataracts v2.30 ANAPC1 Ivone Leong Phenotypes for gene: ANAPC1 were changed from Rothmund Thomson syndrome type 1, OMIM 618625 to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Optic neuropathy v2.28 INTS8 Ivone Leong gene: INTS8 was added
gene: INTS8 was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene: INTS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS8 were set to 28542170
Phenotypes for gene: INTS8 were set to Optic atrophy
Review for gene: INTS8 was set to RED
Added comment: PMID: 28542170 describes one Dutch family with 3 affected siblings. All three are compound heterozygous for variants in this gene. Optic atrophy was listed as a phenotype for 2/3 siblings.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.29 INTS1 Ivone Leong Classified gene: INTS1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.29 INTS1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be made Green at the next review.
Bilateral congenital or childhood onset cataracts v2.29 INTS1 Ivone Leong Gene: ints1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.28 INTS1 Ivone Leong Tag for-review tag was added to gene: INTS1.
Bilateral congenital or childhood onset cataracts v2.28 INTS1 Ivone Leong Phenotypes for gene: INTS1 were changed from Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, MIM# 618571 to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:618571, MONDO:0032817
Bilateral congenital or childhood onset cataracts v2.27 PIK3C2A Ivone Leong Tag for-review tag was added to gene: PIK3C2A.
Bilateral congenital or childhood onset cataracts v2.27 PIK3C2A Ivone Leong Classified gene: PIK3C2A as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.27 PIK3C2A Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene should be Green at the next review.
Bilateral congenital or childhood onset cataracts v2.27 PIK3C2A Ivone Leong Gene: pik3c2a has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.26 PIK3C2A Ivone Leong Phenotypes for gene: PIK3C2A were changed from Oculoskeletodental syndrome, 618440 to Oculoskeletodental syndrome, OMIM:618440, MONDO:0034145
Bilateral congenital or childhood onset cataracts v2.25 PANK4 Ivone Leong Classified gene: PANK4 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.25 PANK4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in Gene2Phenotype but not OMIM. There is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Bilateral congenital or childhood onset cataracts v2.25 PANK4 Ivone Leong Gene: pank4 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.24 PANK4 Ivone Leong Tag watchlist tag was added to gene: PANK4.
Bilateral congenital or childhood onset cataracts v2.24 NACC1 Ivone Leong Classified gene: NACC1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.24 NACC1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Bilateral congenital or childhood onset cataracts v2.24 NACC1 Ivone Leong Gene: nacc1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.23 NACC1 Ivone Leong Tag for-review tag was added to gene: NACC1.
Bilateral congenital or childhood onset cataracts v2.23 NACC1 Ivone Leong Phenotypes for gene: NACC1 were changed from Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination, OMIM:617393, MONDO:0044306 to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, OMIM:617393, MONDO:0044306
Bilateral congenital or childhood onset cataracts v2.22 NACC1 Ivone Leong Phenotypes for gene: NACC1 were changed from Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination (MIM# 617393) to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination, OMIM:617393, MONDO:0044306
Bilateral congenital or childhood onset cataracts v2.21 SREBF1 Ivone Leong Classified gene: SREBF1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.21 SREBF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Bilateral congenital or childhood onset cataracts v2.21 SREBF1 Ivone Leong Gene: srebf1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.20 SREBF1 Ivone Leong Tag for-review tag was added to gene: SREBF1.
Intellectual disability v3.649 GATA6 Ivone Leong Publications for gene: GATA6 were set to
Bilateral congenital or childhood onset cataracts v2.20 SREBF1 Ivone Leong Phenotypes for gene: SREBF1 were changed from Mucoepithelial dysplasia, hereditary, MIM#158310 to Mucoepithelial dysplasia, hereditary, OMIM:158310, MONDO:0008017
Bilateral congenital or childhood onset cataracts v2.19 PSMC3 Ivone Leong Classified gene: PSMC3 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.19 PSMC3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association; therefore, this gene has been given an Amber rating.
Bilateral congenital or childhood onset cataracts v2.19 PSMC3 Ivone Leong Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Anophthalmia or microphthalmia v1.33 FAT1 Ivone Leong Publications for gene: FAT1 were set to 30862798; 26905694
Anophthalmia or microphthalmia v1.32 FAT1 Ivone Leong Classified gene: FAT1 as Green List (high evidence)
Anophthalmia or microphthalmia v1.32 FAT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence for this gene to be Green on this panel.

This is also a Green gene on the GMS Structural eye disease (Version 1.22) with the following review:
"DB Lahrouchi: five families; Ciani mouse mouse model
Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust), 19 Jun 2019"
Anophthalmia or microphthalmia v1.32 FAT1 Ivone Leong Gene: fat1 has been classified as Green List (High Evidence).
Bardet Biedl syndrome v1.7 C8orf37 Ivone Leong Classified gene: C8orf37 as Amber List (moderate evidence)
Bardet Biedl syndrome v1.7 C8orf37 Ivone Leong Added comment: Comment on list classification: This gene has been promoted from Red to Amber as there are 2 cases.
Bardet Biedl syndrome v1.7 C8orf37 Ivone Leong Gene: c8orf37 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v1.13 C8orf37 Ivone Leong Classified gene: C8orf37 as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.13 C8orf37 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Ophthalmological ciliopathies v1.13 C8orf37 Ivone Leong Gene: c8orf37 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v1.12 C8orf37 Ivone Leong Tag for-review tag was added to gene: C8orf37.
Ophthalmological ciliopathies v1.12 C8orf37 Ivone Leong Publications for gene: C8orf37 were set to 26854863; 27008867
Retinal disorders v2.26 C8orf37 Ivone Leong Phenotypes for gene: C8orf37 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Eye Disorders; Retinitis pigmentosa 64, 614500Cone-rod dystrophy 16, 614500; Retinitis pigmentosa; Retinitis Pigmentosa, Recessive to Bardet-Biedl syndrome 21, OMIM:617406, MONDO:0044308; Cone-rod dystrophy 16, OMIM:614500, MONDO:0013786; Retinitis pigmentosa 64, OMIM:614500, MONDO:0019200
Bardet Biedl syndrome v1.6 C8orf37 Ivone Leong Phenotypes for gene: C8orf37 were changed from Bardet-Biedl syndrome 21, 617406; Cone-rod dystrophy 16; Retinitis pigmentosa 64, 614500 to Bardet-Biedl syndrome 21, OMIM:617406, MONDO:0044308; Cone-rod dystrophy 16, OMIM:614500, MONDO:0013786; Retinitis pigmentosa 64, OMIM:614500, MONDO:0019200
Ophthalmological ciliopathies v1.11 C8orf37 Ivone Leong Phenotypes for gene: C8orf37 were changed from Bardet-Biedl syndrome 21, 617406 to Bardet-Biedl syndrome 21, OMIM:617406, MONDO:0044308; Cone-rod dystrophy 16, OMIM:614500, MONDO:0013786; Retinitis pigmentosa 64, OMIM:614500, MONDO:0019200
Retinal disorders v2.25 KIF3B Ivone Leong Classified gene: KIF3B as Amber List (moderate evidence)
Retinal disorders v2.25 KIF3B Ivone Leong Gene: kif3b has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.24 KIF3B Ivone Leong gene: KIF3B was added
gene: KIF3B was added to Retinal disorders. Sources: Expert list,Literature
watchlist tags were added to gene: KIF3B.
Mode of inheritance for gene: KIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF3B were set to 32386558
Phenotypes for gene: KIF3B were set to hepatic fibrosis; Retinitis pigmentosa 89, OMIM:618955, MONDO:0030071; postaxial polydactyly
Review for gene: KIF3B was set to AMBER
Added comment: New gene added by Zornitza Stark (Australian Genomics) to the Ophthalmological ciliopathies (Version 1.10). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association so this gene has been given an Amber rating.

"Two unrelated families with a ciliopathy phenotype including RP and some functional data. Sources: Literature
Zornitza Stark (Australian Genomics), 3 Jun 2020"
Sources: Expert list, Literature
Ophthalmological ciliopathies v1.10 KIF3B Ivone Leong Classified gene: KIF3B as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.10 KIF3B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Ophthalmological ciliopathies v1.10 KIF3B Ivone Leong Gene: kif3b has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v1.9 KIF3B Ivone Leong Tag watchlist tag was added to gene: KIF3B.
Severe microcephaly v2.53 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Severe microcephaly v2.53 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Severe microcephaly v2.53 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.53 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.52 NARS Arina Puzriakova gene: NARS was added
gene: NARS was added to Severe microcephaly. Sources: Literature
new-gene-name, for-review tags were added to gene: NARS.
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225; 32788587
Phenotypes for gene: NARS were set to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Review for gene: NARS was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous variants (PMIDs: 32738225). Microcephaly was observed in the majority of cases (90%), with severity relevant to this panel (≥ 3 SD). These cases predominantly presented with primary microcephaly; however, secondary microcephaly was also noted. Other features include GDD/ID, seizures, ataxia, and dysmorphism. Supportive functional data.
Sources: Literature
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Tag new-gene-name tag was added to gene: NARS.
Tag for-review tag was added to gene: NARS.
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.235 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.648 NARS Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.
Ophthalmological ciliopathies v1.9 KIF3B Ivone Leong Phenotypes for gene: KIF3B were changed from hepatic fibrosis; retinitis pigmentosa; postaxial polydactyly to hepatic fibrosis; Retinitis pigmentosa 89, OMIM:618955, MONDO:0030071; postaxial polydactyly
Intellectual disability v3.648 NARS Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 6 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.
Early onset or syndromic epilepsy v2.235 NARS Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Early onset or syndromic epilepsy v2.234 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
Intellectual disability v3.648 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Intellectual disability v3.648 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Intellectual disability v3.648 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.648 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.647 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Leber hereditary optic neuropathy v1.5 PRICKLE3 Ivone Leong Classified gene: PRICKLE3 as Red List (low evidence)
Leber hereditary optic neuropathy v1.5 PRICKLE3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is currently not enough evidence to support a gene-disease association so this gene has been given a Red rating.
Leber hereditary optic neuropathy v1.5 PRICKLE3 Ivone Leong Gene: prickle3 has been classified as Red List (Low Evidence).
Intellectual disability v3.647 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
Intellectual disability v3.646 NARS Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Intellectual disability v3.645 ATP2A2 Ivone Leong reviewed gene: ATP2A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Clefting v2.11 MED25 Eleanor Williams Phenotypes for gene: MED25 were changed from BASEL-VANAGAITE-SMIRIN-YOSEF SYNDROME; BVSYS to Basel-Vanagait-Smirin-Yosef syndrome OMIM:616449
Clefting v2.10 MED25 Eleanor Williams Publications for gene: MED25 were set to 25792360
Clefting v2.9 MED25 Eleanor Williams Classified gene: MED25 as Amber List (moderate evidence)
Clefting v2.9 MED25 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as Amber for now, but there are sufficient cases with clefting to promote this gene to green on this panel after the next GMS review.
Clefting v2.9 MED25 Eleanor Williams Gene: med25 has been classified as Amber List (Moderate Evidence).
Clefting v2.8 MED25 Eleanor Williams Tag for-review tag was added to gene: MED25.
Clefting v2.8 MED25 Eleanor Williams reviewed gene: MED25: Rating: ; Mode of pathogenicity: None; Publications: 31602195, 32324310, 32816121; Phenotypes: Basel-Vanagait-Smirin-Yosef syndrome OMIM:616449; Mode of inheritance: None
Intellectual disability v3.645 ISCA-37418-Loss Arina Puzriakova Phenotypes for Region: ISCA-37418-Loss were changed from Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities to Smith-Magenis syndrome, OMIM:182290; Smith-Magenis syndrome, MONDO:0008434
Intellectual disability v3.644 RAP1B Zornitza Stark gene: RAP1B was added
gene: RAP1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability
Review for gene: RAP1B was set to GREEN
Added comment: Three unrelated individuals reported with de novo variants, some functional data. One of them described as Kabuki-like but lacks typical facial gestalt.
Sources: Literature
Intellectual disability v3.644 EMC10 Zornitza Stark gene: EMC10 was added
gene: EMC10 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858
Phenotypes for gene: EMC10 were set to Intellectual disability
Review for gene: EMC10 was set to RED
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD.
WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.
Sources: Literature
Early onset or syndromic epilepsy v2.233 FBXO28 Zornitza Stark gene: FBXO28 was added
gene: FBXO28 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO28 were set to 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy
Review for gene: FBXO28 was set to GREEN
Added comment: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature
Laterality disorders and isomerism v1.20 CFAP52 Zornitza Stark gene: CFAP52 was added
gene: CFAP52 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: CFAP52 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP52 were set to 25469542; 33139725
Phenotypes for gene: CFAP52 were set to Heterotaxy
Review for gene: CFAP52 was set to GREEN
Added comment: Five unrelated families and functional data.
Sources: Literature
Laterality disorders and isomerism v1.20 CFAP45 Zornitza Stark gene: CFAP45 was added
gene: CFAP45 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: CFAP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP45 were set to 33139725
Phenotypes for gene: CFAP45 were set to Situs inversus; asthenospermia
Review for gene: CFAP45 was set to GREEN
Added comment: Three unrelated individuals reported with bi-alleic LOF variants, mouse model recapitulated phenotype.
Sources: Literature
Fetal anomalies v1.121 GDF6 Zornitza Stark reviewed gene: GDF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32737436; Phenotypes: Syndromic CAKUT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Proteinuric renal disease v2.33 DAAM2 Zornitza Stark gene: DAAM2 was added
gene: DAAM2 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: DAAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAAM2 were set to 33232676
Phenotypes for gene: DAAM2 were set to Steroid-resistant nephrotic syndrome (SRNS)
Review for gene: DAAM2 was set to GREEN
Added comment: - steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis on histologic analysis of kidney biopsies and foot process effacement shown by electron microscopy (authors have suggested the term nephrotic syndrome type 22 (NPHS22))
- 4 unrelated families, 3 of which were consanguineous
- 4 unique missense and 1 stop
- in vitro studies for the missense variants
Sources: Literature
Intellectual disability v3.644 BICRA Zornitza Stark gene: BICRA was added
gene: BICRA was added to Intellectual disability. Sources: Literature
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 Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features
Review for gene: BICRA was set to GREEN
Added comment: 12 individuals reported, 11 de novo (1 not resolved), with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features. Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association.
Sources: Literature
Neuronal ceroid lipofuscinosis v1.4 CLCN6 Zornitza Stark reviewed gene: CLCN6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25794116, 21107136, 33217309; Phenotypes: Neurodegeneration, Benign partial epilepsy, febrile seizures, NCL; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.644 HS2ST1 Zornitza Stark gene: HS2ST1 was added
gene: HS2ST1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to GREEN
Added comment: Four affected individuals from 3 unrelated families. 3 unique missense and 2 PTCs. Clinical features included developmental delay, corpus callosum hypoplasia or aplasia, and skeletal and renal abnormalities as well as joint contractures/arthrogryposis.
Sources: Literature
Intellectual disability v3.644 KDM4B Zornitza Stark gene: KDM4B was added
gene: KDM4B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria.

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Congenital myopathy v2.8 UNC45B Zornitza Stark gene: UNC45B was added
gene: UNC45B was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: UNC45B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45B were set to 33217308
Phenotypes for gene: UNC45B were set to Progressive Myopathy with Eccentric Cores
Review for gene: UNC45B was set to GREEN
Added comment: 10 individuals from 8 families reported with biallelic variants clinically manifesting with childhood-onset, progressive proximal and axial muscle weakness and various degrees of respiratory insufficiency. 4 missense variants and a +5 splice variant reported, p.Arg754Gln is recurrent. Functional studies support pathogenicity.
Sources: Literature
Intellectual disability v3.644 SMG8 Zornitza Stark edited their review of gene: SMG8: Added comment: Four more families reported in PMID 33242396. Some functional data also provided.; Changed rating: GREEN; Changed publications: 31130284, 33242396
Hereditary ataxia with onset in adulthood v2.17 RFC1 Zornitza Stark edited their review of gene: RFC1: Added comment: A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families reported in PMID 33103729. Both of these need to be added as STRs but I haven't quite figured out how to do it!; Changed publications: 30926972, 33103729
Ataxia and cerebellar anomalies - narrow panel v2.33 MINPP1 Zornitza Stark gene: MINPP1 was added
gene: MINPP1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Review for gene: MINPP1 was set to GREEN
Added comment: 8 individuals from 6 unrelated families reported with bi-allelic LOF variants. All presented with almost complete absence of motor and cognitive development, progressive or congenital microcephaly, spastic tetraplegia or dystonia, and vision impairments. For most, the first symptoms included neonatal severe axial hypotonia and epilepsy that started during the first months or years of life. Prenatal symptoms of microcephaly associated with increased thalami echogenicity were detected in one, while the seven other individuals presented with progressive microcephaly. Some exhibited rapidly progressive phenotype and the affected children died in their infancy or middle-childhood. Strikingly, all the affected children had a unique brain MRI showing a mild to severe PCH, fluid-filled posterior fossa, with dilated lateral ventricles. In addition, severe atrophy at the level of the basal ganglia or thalami often associated with typical T2 hypersignal were identified in all the patients MRI.

Supportive functional data showing accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions.
Sources: Literature
Severe microcephaly v2.51 RRP7A Zornitza Stark gene: RRP7A was added
gene: RRP7A was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: RRP7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRP7A were set to 33199730
Phenotypes for gene: RRP7A were set to Microcephaly
Review for gene: RRP7A was set to AMBER
Added comment: 10 affected individuals from a single large consanguineous family where bi-allelic variant segregated with severe microcephaly (-6-8SD), variable ID. Supportive functional data from mouse and zebrafish.
Sources: Literature
Intellectual disability v3.644 AGO2 Zornitza Stark gene: AGO2 was added
gene: AGO2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AGO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGO2 were set to 33199684
Phenotypes for gene: AGO2 were set to Intellectual disability; regression; seizures
Review for gene: AGO2 was set to GREEN
Added comment: 21 individuals reported, five variants (p.L192P, p.G201V, p.T357M, p.M364T, p.C751Y) were recurrent. Variable ID.
Sources: Literature
Skeletal dysplasia v2.34 HHAT Zornitza Stark gene: HHAT was added
gene: HHAT was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HHAT were set to 24784881; 30912300
Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome 600092
Review for gene: HHAT was set to AMBER
Added comment: Two unrelated families reported. Clinical features include progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia.
Sources: Literature
Intellectual disability v3.644 H3F3B Zornitza Stark reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.644 H3F3A Zornitza Stark reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.51 YIPF5 Zornitza Stark gene: YIPF5 was added
gene: YIPF5 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Neonatal diabetes; microcephaly; seizures
Review for gene: YIPF5 was set to GREEN
Added comment: Six individuals from 5 unrelated consanguineous families reported with bi-allelic variants in this gene and neonatal/early-onset diabetes, severe microcephaly, and epilepsy. Functional data supports gene-disease association.
Sources: Literature
Mitochondrial disorders v2.12 COX16 Zornitza Stark Deleted their comment
Mitochondrial disorders v2.12 COX16 Zornitza Stark edited their review of gene: COX16: Added comment: 2 unrelated patients with the same homozygous (non-consanguineous) nonsense variant c.244C>T (p.Arg82*), and isolated complex IV deficiency present in both patient fibroblasts/skeletal muscle biopsy. COX16 is involved in the biogenesis of complex IV, the terminal complex of the mitochondrial respiratory chain.; Changed rating: AMBER; Changed publications: 33169484; Changed phenotypes: Hypertrophic cardiomyopathy, encephalopathy, severe fatal lactic acidosis; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v2.7 CHD4 Zornitza Stark gene: CHD4 was added
gene: CHD4 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: CHD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD4 were set to 31474762
Phenotypes for gene: CHD4 were set to Moya Moya; Sifrim-Hitz-Weiss syndrome, MIM# 617159
Review for gene: CHD4 was set to RED
Added comment: 5 individuals reported with Moya Moya and ID, but only in one was de novo inheritance confirmed. 4 missense variants and one canonical splice.
Sources: Literature
Cerebral vascular malformations v2.7 SETD5 Zornitza Stark gene: SETD5 was added
gene: SETD5 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: SETD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD5 were set to 31474762
Phenotypes for gene: SETD5 were set to Moya Moya; Mental retardation, autosomal dominant 23, MIM# 615761
Review for gene: SETD5 was set to RED
Added comment: Single family reported with de novo SETD5 frameshift in a child with ID and Moya Moya. 2 other families with novel missense and concordant phenotypes but no parental segregation performed.
Sources: Literature
Cerebral vascular malformations v2.7 CNOT3 Zornitza Stark gene: CNOT3 was added
gene: CNOT3 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: CNOT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNOT3 were set to 31474762
Phenotypes for gene: CNOT3 were set to Moya Moya; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, MIM# 618672
Review for gene: CNOT3 was set to AMBER
Added comment: 2 families with de novo variants (one nonsense and one missense) in individuals with ID and Moya Moya
Sources: Literature
Intellectual disability v3.644 HDAC4 Zornitza Stark edited their review of gene: HDAC4: Added comment: New report of 4 different missense present in the 14-3-3 binding site, identified de novo in 7 individuals with an intellectual disability syndrome, and supporting in vitro functional assays.; Changed rating: GREEN; Changed publications: 24715439, 20691407, 31209962, https://doi.org/10.1016/j.xhgg.2020.100015
Neurological ciliopathies v1.10 TMEM218 Zornitza Stark gene: TMEM218 was added
gene: TMEM218 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 25161209; https://doi.org/10.1016/j.xhgg.2020.100016
Phenotypes for gene: TMEM218 were set to Joubert syndrome; retinal dystrophy; polycystic kidneys; occipital encephalocele
Review for gene: TMEM218 was set to GREEN
Added comment: 11 individuals in 6 families with homozygous or compound heterozygous missense and nonsense (1) variants, with a Joubert/Meckel syndrome phenotype. Clinical features included the molar tooth sign (N=2), occipital encephalocele (N=5, all fetuses), retinal dystrophy (N=4, all living individuals), polycystic kidneys (N=2), and polydactyly (N=2), without liver involvement. A null mouse model had nephronophthisis and retinal degeneration.
Sources: Literature
Congenital disorders of glycosylation v2.18 SSR3 Zornitza Stark gene: SSR3 was added
gene: SSR3 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: SSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SSR3 were set to 30945312
Phenotypes for gene: SSR3 were set to Congenital disorder of glycosylation, type Iu, MIM#615042
Review for gene: SSR3 was set to AMBER
Added comment: Single individual reported with an unsolved type I CDG, intellectual disability, homozygous LOF variant in SSR3, supportive functional evidence.
Sources: Literature
Congenital disorders of glycosylation v2.18 DPM2 Zornitza Stark reviewed gene: DPM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23109149, 33129689; Phenotypes: Congenital disorder of glycosylation, type Iu, MIM#615042; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.121 MYL9 Zornitza Stark reviewed gene: MYL9: Rating: AMBER; Mode of pathogenicity: None; Publications: 29453416, 33031641; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.33 MTCL1 Zornitza Stark gene: MTCL1 was added
gene: MTCL1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: MTCL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTCL1 were set to 30548255; 28283581; 32961396
Phenotypes for gene: MTCL1 were set to slowly progressive cerebellar ataxia; mild intellectual disability; seizures; episodic pain; spinocerebellar ataxia
Review for gene: MTCL1 was set to GREEN
Added comment: Two families reported with bi-allelic LOF variants, early onset ataxia and a supportive null mouse model.
Single family with mono-allelic variant in two individuals and adult-onset ataxia (not pertinent to this panel, and less compelling).
Sources: Literature
Rare anaemia v1.4 ADH5 Zornitza Stark gene: ADH5 was added
gene: ADH5 was added to Rare anaemia. Sources: Literature
Mode of inheritance for gene: ADH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADH5 were set to 33147438
Phenotypes for gene: ADH5 were set to Aplastic anaemia; myelodysplasia; short stature
Review for gene: ADH5 was set to GREEN
Added comment: 7 individuals reported with bi-allelic variants in this gene and a Fanconi syndrome-like phenotype. All had aplastic anaemia, 4 developed a myelodysplastic syndrome, and one developed AML. Short stature and abnormal skin pigmentation were additional features.

Note, all also had the ALDH2*2 allele, which is common in East Asian populations, and may be contributory.

Extensive experimental data.
Sources: Literature
Mitochondrial disorders v2.12 NDUFB10 Zornitza Stark edited their review of gene: NDUFB10: Added comment: Second family reported, including more functional data.; Changed rating: GREEN; Changed publications: 28040730, 32025618, 33169436; Changed phenotypes: fatal infantile lactic acidosis, cardiomyopathy, Mitochondrial complex I deficiency nuclear type 35 (MC1DN35), MIM#619003
Monogenic hearing loss v2.134 SCD5 Zornitza Stark gene: SCD5 was added
gene: SCD5 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: SCD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCD5 were set to 31972369
Phenotypes for gene: SCD5 were set to Deafness, autosomal dominant 79, MIM#619086
Review for gene: SCD5 was set to RED
Added comment: Single 5-generation family reported with a missense variant segregating in 19 affected individuals. Variant is found at a low frequency in ExAC.
Sources: Literature
Intellectual disability v3.644 ATP2A2 Ivone Leong Publications for gene: ATP2A2 were set to 19250991; 20456342
Intellectual disability v3.643 SMARCA2 Arina Puzriakova Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, 601358; COFFIN SIRIS to Nicolaides-Baraitser syndrome, OMIM:601358; Coffin-siris syndrome; Blepharophimosis intellectual disability syndrome
Intellectual disability v3.642 SMARCA2 Arina Puzriakova Publications for gene: SMARCA2 were set to
Monogenic hearing loss v2.134 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
Monogenic hearing loss v2.134 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Furthermore, some cases with hearing loss would not be tested for other panels related to this phenotype (e.g. ID, severe microcephaly) as they did not exhibit the relevant features.

Therefore, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag).
Monogenic hearing loss v2.134 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.133 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688 to Sensorineural hearing loss; Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Monogenic hearing loss v2.132 MORC2 Arina Puzriakova gene: MORC2 was added
gene: MORC2 was added to Hearing loss. Sources: Literature
for-review tags were added to gene: MORC2.
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to 32693025
Phenotypes for gene: MORC2 were set to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Review for gene: MORC2 was set to GREEN
Added comment: MORC2 variants have commonly been associated with CMT, presenting axonal neuropathy with progressive weakness, muscle cramps and sensory impairment. However, Sacoto et al (2020) (PMID: 32693025) present a cohort of 20 individuals (19 kindreds) with a neurodevelopmental disorder characterised by DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. Hearing loss was observed in 11/19 subjects, primarily SNHL.
Sources: Literature
Severe microcephaly v2.51 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
Severe microcephaly v2.51 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Inclusion on this panel would be of value for detecting such cases, and so this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.51 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.50 MORC2 Arina Puzriakova gene: MORC2 was added
gene: MORC2 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: MORC2.
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to 32693025
Phenotypes for gene: MORC2 were set to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Review for gene: MORC2 was set to GREEN
Added comment: MORC2 variants have commonly been associated with CMT, presenting axonal neuropathy with progressive weakness, muscle cramps and sensory impairment. However, Sacoto et al (2020) (PMID: 32693025) present a cohort of 20 individuals (19 kindreds) with a neurodevelopmental disorder characterised by DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. Severity of microcephaly relevant to this panel (≥ 3 SD) was observed in 7 subjects.
Sources: Literature
Congenital myopathy v2.8 HNRNPA2B1 Anna Sarkozy reviewed gene: HNRNPA2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: oculopharyngodistal myopathy, muscular dystrophy, congenital myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v2.8 HNRNPA2B1 Anna Sarkozy Deleted their review
Congenital muscular dystrophy v2.4 HNRNPA2B1 Anna Sarkozy gene: HNRNPA2B1 was added
gene: HNRNPA2B1 was added to Congenital muscular dystrophy. Sources: Other,Expert list,Research
Mode of inheritance for gene: HNRNPA2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HNRNPA2B1 were set to oculopharyngodistal myopathy, muscular dystrophy, congenital myopathy
Review for gene: HNRNPA2B1 was set to GREEN
Added comment: de novo variants in this gene have been reported in multiple unrelated families and presented at the World muscle society congress 2020, a full publication is currently in progress. see abstract:
https://www.nmd-journal.com/article/S0960-8966(20)30203-0/fulltext
Sources: Other, Expert list, Research
Congenital myopathy v2.8 HNRNPA2B1 Anna Sarkozy gene: HNRNPA2B1 was added
gene: HNRNPA2B1 was added to Congenital myopathy. Sources: Expert list,Literature
Mode of inheritance for gene: HNRNPA2B1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HNRNPA2B1 were set to oculopharyngodistal myopathy; muscular dystrophy; congenital myopathy
Review for gene: HNRNPA2B1 was set to GREEN
Added comment: variants in this gene have now been reported in several unrelated families
this was presented at the world muscle society conference in 2020 and it is currently submitted for full publication
https://doi.org/10.1016/j.nmd.2020.08.006
Sources: Expert list, Literature
Congenital myopathy v2.8 KY Anna Sarkozy edited their review of gene: KY: Added comment: recent reports at the WMS 2020 reported unrelated family with KY gene variants.
"Novel mutation in KY gene causes a novel congenital myopathy with early contractures" see
https://www.nmd-journal.com/article/S0960-8966(20)30298-4/fulltext; Changed rating: GREEN; Changed phenotypes: congenital myopathy
Intellectual disability v3.641 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Intellectual disability v3.640 MORC2 Arina Puzriakova Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Intellectual disability v3.639 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
Intellectual disability v3.639 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Inclusion on this panel would be of value for detecting such cases, and so this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.639 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.638 MORC2 Arina Puzriakova Tag for-review tag was added to gene: MORC2.
Intellectual disability v3.638 MORC2 Arina Puzriakova reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025; Phenotypes: Developmental delay, Intellectual disability, Growth retardation, Microcephaly, Craniofacial dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.638 LARS Arina Puzriakova commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Intellectual disability v3.638 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
Intellectual disability v3.638 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Developmental delay is prevalent among affected individuals, and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This may serve as a possible route for diagnostic testing as currently there are no relevant panels for detecting the hepatic phenotype of the disease presentation, and so there may be value in rating Green at the next major panel review (added 'for-review tag).
Intellectual disability v3.638 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.637 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Tag for-review tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Tag for-review tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Seizures are prevalent among affected individuals, often triggered by infections. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.637 NUS1 Arina Puzriakova Classified gene: NUS1 as Amber List (moderate evidence)
Intellectual disability v3.637 NUS1 Arina Puzriakova Gene: nus1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.636 NUS1 Arina Puzriakova Tag for-review tag was added to gene: NUS1.
Congenital hypothyroidism v2.4 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from GH,TSH, ACTH, LH, FSH deficiency, variable mental retardation, undescended posterior pituitary, anterior pituitary hypoplasia, or persistence of the craniopharyngeal canal to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
DDG2P v2.13 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from MENTAL RETARDATION X-LINKED WITH ISOLATED GROWTH HORMONE DEFICIENCY 300123; SEX REVERSAL TYPE 3 300833 to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Fetal anomalies v1.121 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from SEX REVERSAL TYPE 3; MENTAL RETARDATION X-LINKED WITH ISOLATED GROWTH HORMONE DEFICIENCY to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Hypogonadotropic hypogonadism (GMS) v1.11 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked to Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Hypogonadotropic hypogonadism v1.29 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked to Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
IUGR and IGF abnormalities v1.34 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked, 312000; Mental retardation, X-linked, with isolated growth hormone deficiency, 300123 to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Pituitary hormone deficiency v2.6 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked (312000); Mental retardation, X-linked, with isolated growth hormone deficiency (300123) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Familial hypoparathyroidism v2.5 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123; Panhypopituitarism, X-linked, 312000 to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Intellectual disability v3.636 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123Panhypopituitarism, X-linked, 312000; SEX REVERSAL TYPE 3 (SRXX3) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252
Intellectual disability v3.635 SOX3 Arina Puzriakova commented on gene: SOX3
Intellectual disability v3.635 SOX3 Arina Puzriakova Tag for-review tag was added to gene: SOX3.
Intellectual disability v3.635 PSAT1 Arina Puzriakova Publications for gene: PSAT1 were set to 17436247
Intellectual disability v3.634 PSAT1 Arina Puzriakova Phenotypes for gene: PSAT1 were changed from PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY to Phosphoserine aminotransferase deficiency, OMIM:610992; Neu-Laxova syndrome 2, OMIM:616038
Intellectual disability v3.633 PRKAR1A Arina Puzriakova Phenotypes for gene: PRKAR1A were changed from Gene2Phenotype confirmed gene with ID HPO to Acrodysostosis 1, with or without hormone resistance, OMIM:101800
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Classified gene: SH3PXD2B as Red List (low evidence)
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Gene: sh3pxd2b has been classified as Red List (Low Evidence).
Intellectual disability v3.631 SEC23B Arina Puzriakova Classified gene: SEC23B as Red List (low evidence)
Intellectual disability v3.631 SEC23B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.631 SEC23B Arina Puzriakova Gene: sec23b has been classified as Red List (Low Evidence).
Intellectual disability v3.630 SCN11A Arina Puzriakova Classified gene: SCN11A as Red List (low evidence)
Intellectual disability v3.630 SCN11A Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.630 SCN11A Arina Puzriakova Gene: scn11a has been classified as Red List (Low Evidence).
Intellectual disability v3.629 SCARF2 Arina Puzriakova Classified gene: SCARF2 as Red List (low evidence)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Gene: scarf2 has been classified as Red List (Low Evidence).
Intellectual disability v3.628 SBDS Arina Puzriakova Classified gene: SBDS as Red List (low evidence)
Intellectual disability v3.628 SBDS Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.628 SBDS Arina Puzriakova Gene: sbds has been classified as Red List (Low Evidence).
Intellectual disability v3.627 SALL4 Arina Puzriakova Classified gene: SALL4 as Red List (low evidence)
Intellectual disability v3.627 SALL4 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.627 SALL4 Arina Puzriakova Gene: sall4 has been classified as Red List (Low Evidence).
Intellectual disability v3.626 PRSS56 Arina Puzriakova Classified gene: PRSS56 as Red List (low evidence)
Intellectual disability v3.626 PRSS56 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.626 PRSS56 Arina Puzriakova Gene: prss56 has been classified as Red List (Low Evidence).
Intellectual disability v3.625 PROP1 Arina Puzriakova Classified gene: PROP1 as Red List (low evidence)
Intellectual disability v3.625 PROP1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.625 PROP1 Arina Puzriakova Gene: prop1 has been classified as Red List (Low Evidence).
Intellectual disability v3.624 PRDM12 Arina Puzriakova Classified gene: PRDM12 as Red List (low evidence)
Intellectual disability v3.624 PRDM12 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.624 PRDM12 Arina Puzriakova Gene: prdm12 has been classified as Red List (Low Evidence).
Intellectual disability v3.623 PPA2 Arina Puzriakova Classified gene: PPA2 as Red List (low evidence)
Intellectual disability v3.623 PPA2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.623 PPA2 Arina Puzriakova Gene: ppa2 has been classified as Red List (Low Evidence).
Intellectual disability v3.622 POLR1D Arina Puzriakova Classified gene: POLR1D as Red List (low evidence)
Intellectual disability v3.622 POLR1D Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.622 POLR1D Arina Puzriakova Gene: polr1d has been classified as Red List (Low Evidence).
Intellectual disability v3.621 POLD1 Arina Puzriakova Classified gene: POLD1 as Red List (low evidence)
Intellectual disability v3.621 POLD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.621 POLD1 Arina Puzriakova Gene: pold1 has been classified as Red List (Low Evidence).
Intellectual disability v3.620 POC1B Arina Puzriakova Classified gene: POC1B as Red List (low evidence)
Intellectual disability v3.620 POC1B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.620 POC1B Arina Puzriakova Gene: poc1b has been classified as Red List (Low Evidence).
Intellectual disability v3.619 PMS2 Arina Puzriakova Classified gene: PMS2 as Red List (low evidence)
Intellectual disability v3.619 PMS2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.619 PMS2 Arina Puzriakova Gene: pms2 has been classified as Red List (Low Evidence).
Intellectual disability v3.618 PLOD2 Arina Puzriakova Classified gene: PLOD2 as Red List (low evidence)
Intellectual disability v3.618 PLOD2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.618 PLOD2 Arina Puzriakova Gene: plod2 has been classified as Red List (Low Evidence).
Intellectual disability v3.617 PKHD1 Arina Puzriakova Classified gene: PKHD1 as Red List (low evidence)
Intellectual disability v3.617 PKHD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.617 PKHD1 Arina Puzriakova Gene: pkhd1 has been classified as Red List (Low Evidence).
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Classified gene: PKD1L1 as Red List (low evidence)
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Gene: pkd1l1 has been classified as Red List (Low Evidence).
Intellectual disability v3.615 PITX3 Arina Puzriakova Classified gene: PITX3 as Red List (low evidence)
Intellectual disability v3.615 PITX3 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.615 PITX3 Arina Puzriakova Gene: pitx3 has been classified as Red List (Low Evidence).
Intellectual disability v3.614 PITX2 Arina Puzriakova Classified gene: PITX2 as Red List (low evidence)
Intellectual disability v3.614 PITX2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.614 PITX2 Arina Puzriakova Gene: pitx2 has been classified as Red List (Low Evidence).
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Classified gene: PIK3R1 as Red List (low evidence)
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Gene: pik3r1 has been classified as Red List (Low Evidence).
Intellectual disability v3.612 POLR1C Arina Puzriakova Phenotypes for gene: POLR1C were changed from Treacher Collins syndrome 3, 248390 to Leukodystrophy, hypomyelinating, 11, OMIM:616494
Intellectual disability v3.611 POLR1C Arina Puzriakova Publications for gene: POLR1C were set to
Intellectual disability v3.610 POLR1C Arina Puzriakova Tag for-review tag was added to gene: POLR1C.
Intellectual disability v3.610 POLR1C Arina Puzriakova Classified gene: POLR1C as Amber List (moderate evidence)
Intellectual disability v3.610 POLR1C Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment (ID and/or cognitive regression) may be variable amongst affected individuals; however, there are sufficient unrelated cases (>3) for inclusion on this panel as Green.
Intellectual disability v3.610 POLR1C Arina Puzriakova Gene: polr1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.609 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; developmental delay; intellectual disability to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Early onset or syndromic epilepsy v2.232 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, MIM 614932 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Early onset or syndromic epilepsy v2.231 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.231 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Classified gene: PNPT1 as No list
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Gene: pnpt1 has been removed from the panel.
Early onset or syndromic epilepsy v2.229 PNPT1 Arina Puzriakova Tag for-review tag was added to gene: PNPT1.
Intellectual disability v3.608 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Intellectual disability v3.608 PNPT1 Arina Puzriakova Added comment: Comment on list classification: GDD/ID is a prominent feature of the disease presentation and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This is a possible route for diagnostic testing and so there may be value in classifying as Green - PNPT1 will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.608 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Classified gene: CEP85L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Gene: cep85l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.228 CEP85L Arina Puzriakova gene: CEP85L was added
gene: CEP85L was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CEP85L.
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CEP85L were set to 32097630; 32097629
Phenotypes for gene: CEP85L were set to Lissencephaly 10, OMIM:618873; Lissencephaly 10, MONDO:0030031
Review for gene: CEP85L was set to GREEN
Added comment: - PMID: 32097630 (2020) - 13 patients from 9 unrelated families with lissencephaly and heterozygous variants in the CEP85L gene. Seizures are part of the phenotype, present in all cases (except 1 unknown) which were intractable in most. Age of seizure onset was variable, ranging from 5 months to 14 years. Mouse model supports a role of CEP85L in neuronal migration. Gene-disease association included in OMIM.
Sources: Literature
Malformations of cortical development v2.20 CEP85L Arina Puzriakova Phenotypes for gene: CEP85L were changed from Lissencephaly, posterior predominant to Lissencephaly 10, OMIM:618873; Lissencephaly 10, MONDO:0030031
Malformations of cortical development v2.19 CEP85L Arina Puzriakova Publications for gene: CEP85L were set to 32097630
Malformations of cortical development v2.18 CEP85L Arina Puzriakova Tag for-review tag was added to gene: CEP85L.
Malformations of cortical development v2.18 CEP85L Arina Puzriakova Classified gene: CEP85L as Amber List (moderate evidence)
Malformations of cortical development v2.18 CEP85L Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).

At least 13 patients from 9 unrelated families with lissencephaly and heterozygous variants in the CEP85L gene. Mouse model supports a role in neuronal migration. Gene-disease association also included in OMIM.
Malformations of cortical development v2.18 CEP85L Arina Puzriakova Gene: cep85l has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.7 CCM2 Eleanor Williams Phenotypes for gene: CCM2 were changed from Cerebral Cavernous Malformation; Cerebral cavernous malformations 2; Cerebral Cavernous Malformations; Capillary malformation-arteriovenous malformation 608354 to Cerebral cavernous malformations-2 603284; Capillary malformation-arteriovenous malformation 608354
Cerebral vascular malformations v2.6 ACTA2 Eleanor Williams Phenotypes for gene: ACTA2 were changed from Moyamoya disease 5; Moyamoya Disease; Moyamoya disease 5,614042; Aortic aneurysm familial thoracic 6,611788; Multisystemic smooth muscle dysfunction syndrome,613834 to Moyamoya disease 5,614042; Aortic aneurysm familial thoracic 6,611788; Multisystemic smooth muscle dysfunction syndrome,613834
Intellectual disability v3.607 SCN1B Arina Puzriakova Classified gene: SCN1B as Amber List (moderate evidence)
Intellectual disability v3.607 SCN1B Arina Puzriakova Added comment: Comment on list classification: Biallelic variants associated with developmental epileptic encephalopathy characterised by early onset epileptic seizures followed by cognitive decline. At least 5 unrelated families in literature (PMIDs: 19710327; 23148524; 28218389).

Rating Amber as seizures are the prominent feature of the disease presentation, to which cognitive impairment is secondary. Cases would be detected via the epilepsy route (SCN1B is already Green on Genetic epilepsy syndromes panel).
Intellectual disability v3.607 SCN1B Arina Puzriakova Gene: scn1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.606 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from EPILEPSY, GENERALIZED, WITH FEBRILE SEIZURES PLUS, TYPE 1 to Developmental and epileptic encephalopathy 52, OMIM:617350; Developmental and epileptic encephalopathy, 52, MONDO:0033361
Intellectual disability v3.605 SCN1B Arina Puzriakova Publications for gene: SCN1B were set to 18464934
Intellectual disability v3.604 SCN1B Arina Puzriakova Mode of inheritance for gene: SCN1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Corneal dystrophy v1.4 MIR184 Ivone Leong reviewed gene: MIR184: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Corneal dystrophy v1.4 MIR184 Ivone Leong Tag for-review tag was added to gene: MIR184.
Corneal dystrophy v1.4 MIR184 Ivone Leong Phenotypes for gene: MIR184 were changed from EDICT syndrome 614303 to EDICT syndrome OMIM:614303, MONDO:0013678
Intellectual disability v3.603 ZFHX4 Ivone Leong Publications for gene: ZFHX4 were set to 26350204; 21802062
Intellectual disability v3.602 ZFHX4 Ivone Leong Phenotypes for gene: ZFHX4 were changed from to Developmental disorders; intellectual disability, dysmorphic features
Intellectual disability v3.601 ZFHX4 Ivone Leong Classified gene: ZFHX4 as Amber List (moderate evidence)
Intellectual disability v3.601 ZFHX4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. Based on the available evidence there is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Intellectual disability v3.601 ZFHX4 Ivone Leong Gene: zfhx4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.600 ZFHX4 Ivone Leong Mode of inheritance for gene: ZFHX4 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.599 ZFHX4 Ivone Leong Tag for-review tag was added to gene: ZFHX4.
Intellectual disability v3.599 UPF1 Ivone Leong Classified gene: UPF1 as Amber List (moderate evidence)
Intellectual disability v3.599 UPF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics).

PMID: 28539120 describes a patient with significant ID. The patient has SNVs in SQSTM1 and UPF1. The authors suggests that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

As the patient in the second case has another variant in another gene, there is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.599 UPF1 Ivone Leong Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.598 UPF1 Ivone Leong Publications for gene: UPF1 were set to 33057194
Intellectual disability v3.597 U2AF2 Ivone Leong Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v3.597 U2AF2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.597 U2AF2 Ivone Leong Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.596 TCF7L2 Ivone Leong Classified gene: TCF7L2 as Amber List (moderate evidence)
Intellectual disability v3.596 TCF7L2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.596 TCF7L2 Ivone Leong Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.595 SRRM2 Ivone Leong Classified gene: SRRM2 as Amber List (moderate evidence)
Intellectual disability v3.595 SRRM2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.595 SRRM2 Ivone Leong Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.594 SPEN Ivone Leong Classified gene: SPEN as Amber List (moderate evidence)
Intellectual disability v3.594 SPEN Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.594 SPEN Ivone Leong Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.593 SATB1 Ivone Leong Phenotypes for gene: SATB1 were changed from intellectual disability to intellectual disability; developmental disorders
Intellectual disability v3.592 SATB1 Ivone Leong Classified gene: SATB1 as Amber List (moderate evidence)
Intellectual disability v3.592 SATB1 Ivone Leong Added comment: Comment on list classification: Gene promoted from Red to Amber based on the provided evidence.
Intellectual disability v3.592 SATB1 Ivone Leong Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.591 SATB1 Ivone Leong Publications for gene: SATB1 were set to
Intellectual disability v3.590 MSL2 Ivone Leong Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v3.590 MSL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.590 MSL2 Ivone Leong Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.590 MSL2 Ivone Leong Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v3.590 MSL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.590 MSL2 Ivone Leong Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.589 RAB14 Ivone Leong Classified gene: RAB14 as Amber List (moderate evidence)
Intellectual disability v3.589 RAB14 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.589 RAB14 Ivone Leong Gene: rab14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.588 PSMC5 Ivone Leong Classified gene: PSMC5 as Amber List (moderate evidence)
Intellectual disability v3.588 PSMC5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.588 PSMC5 Ivone Leong Gene: psmc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.587 MMGT1 Ivone Leong Classified gene: MMGT1 as Amber List (moderate evidence)
Intellectual disability v3.587 MMGT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.587 MMGT1 Ivone Leong Gene: mmgt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.586 HNRNPD Ivone Leong Classified gene: HNRNPD as Amber List (moderate evidence)
Intellectual disability v3.586 HNRNPD Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.586 HNRNPD Ivone Leong Gene: hnrnpd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.585 FBXO31 Ivone Leong Classified gene: FBXO31 as Amber List (moderate evidence)
Intellectual disability v3.585 FBXO31 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.585 FBXO31 Ivone Leong Gene: fbxo31 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.584 FBXO31 Ivone Leong Tag watchlist tag was added to gene: FBXO31.
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Classified gene: PIK3C2A as Amber List (moderate evidence)
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as only 2/2 individuals assessed for ID (both from the same family) are reported with it (PMID:31034465). Although authors state that 'most affected individuals exhibited neurological involvement including developmental delay', this was not formally assessed or otherwise reported on in the remaining cases.
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Gene: pik3c2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.583 FBXO31 Ivone Leong Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant to ?Mental retardation, autosomal recessive 45, OMIM:615979; Intellectual disability, autosomal dominant
Intellectual disability v3.582 FOXP4 Ivone Leong Classified gene: FOXP4 as Amber List (moderate evidence)
Intellectual disability v3.582 FOXP4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Intellectual disability v3.582 FOXP4 Ivone Leong Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.581 DHX32 Ivone Leong Classified gene: DHX32 as Amber List (moderate evidence)
Intellectual disability v3.581 DHX32 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.581 DHX32 Ivone Leong Gene: dhx32 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.580 GIGYF1 Ivone Leong Classified gene: GIGYF1 as Amber List (moderate evidence)
Intellectual disability v3.580 GIGYF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.580 GIGYF1 Ivone Leong Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Classified gene: ATP6V0A1 as Amber List (moderate evidence)
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.578 DDX23 Ivone Leong Classified gene: DDX23 as Amber List (moderate evidence)
Intellectual disability v3.578 DDX23 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.578 DDX23 Ivone Leong Gene: ddx23 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.577 DDX23 Ivone Leong Tag watchlist tag was added to gene: DDX23.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Classified gene: ARHGAP35 as Amber List (moderate evidence)
Intellectual disability v3.577 ARHGAP35 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.576 ARHGAP35 Ivone Leong Tag watchlist tag was added to gene: ARHGAP35.
Ataxia and cerebellar anomalies - narrow panel v2.33 SVBP Arina Puzriakova Classified gene: SVBP as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.33 SVBP Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). SVBP is associated with a relevant phenotype in OMIM. 12 individuals from 5 independent families (PMIDs: 31363758 and 30607023) reported at present with biallelic variants.

Rating Amber as phenotypes include ataxia in only 2 families (remaining cases present spasticity rather than ataxia).
Ataxia and cerebellar anomalies - narrow panel v2.33 SVBP Arina Puzriakova Gene: svbp has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.32 SVBP Arina Puzriakova Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM:618569; Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MONDO:0032816
Severe microcephaly v2.49 SVBP Arina Puzriakova Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM:618569; Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MONDO:0032816
Severe microcephaly v2.48 SVBP Arina Puzriakova Tag for-review tag was added to gene: SVBP.
Severe microcephaly v2.48 SVBP Arina Puzriakova Classified gene: SVBP as Amber List (moderate evidence)
Severe microcephaly v2.48 SVBP Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).

12 individuals from 5 independent families (PMIDs: 31363758 and 30607023). Phenotypes include severe microcephaly in >3 families. SVBP is associated with a relevant phenotype in OMIM.
Severe microcephaly v2.48 SVBP Arina Puzriakova Gene: svbp has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.576 SVBP Arina Puzriakova Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM:618569; Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MONDO:0032816
Arthrogryposis v3.31 SCYL2 Arina Puzriakova Tag watchlist tag was added to gene: SCYL2.
Arthrogryposis v3.31 SCYL2 Arina Puzriakova Classified gene: SCYL2 as Amber List (moderate evidence)
Arthrogryposis v3.31 SCYL2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 2 unrelated families reported at present with different SCYL2 variants and a syndromic form of severe AMC comprising microcephaly, absent corpus callosum, optic atrophy, limb fractures, profound GDD, and early lethality. Rating Amber as additional cases required before inclusion on a diagnostic panel (added 'watchlist' tag).
Arthrogryposis v3.31 SCYL2 Arina Puzriakova Gene: scyl2 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.30 SCYL2 Arina Puzriakova Phenotypes for gene: SCYL2 were changed from Arthrogryposis multiplex congenita (AMC); Zain syndrome to Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, OMIM:618766; Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, MONDO:0032903
Congenital myaesthenic syndrome v2.7 TOR1AIP1 Arina Puzriakova Publications for gene: TOR1AIP1 were set to 24856141
Intellectual disability v3.575 AP2S1 Ivone Leong Classified gene: AP2S1 as Amber List (moderate evidence)
Intellectual disability v3.575 AP2S1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.575 AP2S1 Ivone Leong Gene: ap2s1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.574 AP2S1 Ivone Leong Tag watchlist tag was added to gene: AP2S1.
Congenital myaesthenic syndrome v2.6 TOR1AIP1 Arina Puzriakova Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, 617072 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900
Paediatric or syndromic cardiomyopathy v1.15 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.15 TOR1AIP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Paediatric or syndromic cardiomyopathy v1.15 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.14 TOR1AIP1 Arina Puzriakova gene: TOR1AIP1 was added
gene: TOR1AIP1 was added to Cardiomyopathies - including childhood onset. Sources: Literature
for-review tags were added to gene: TOR1AIP1.
Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOR1AIP1 were set to 24856141; 27342937; 32055997; 25425325
Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900
Review for gene: TOR1AIP1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 15 affected individuals from 10 families with biallelic variants in this gene. Of these, 7 individuals (5 families) reported in PMID:30723199 harbour the same founder variant presenting a very similar phenotype, and are therefore considered collectively here.

Muscular dystrophy is the prominent feature of the disease presentation observed in at least one case individual each family, but specifically proximal limb-girdle dystrophy was recorded in 4 unrelated kindreds. Additional common features also include joint contractures (4 fam), dilated cardiomyopathy (4 fam), developmental delay (4 fam), and cataracts (3 fam).

Age of onset for cardiomyopathy was variable ranging from childhood to adulthood.

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Note that one additional homozygous case (3-year-old boy) has been reported with what is thought to be a discrete phenotype characterised by progressive dystonia, cerebellar atrophy, and dilated cardiomyopathy (PMID: 25425325)
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.12 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.12 TOR1AIP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.12 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.11 TOR1AIP1 Arina Puzriakova gene: TOR1AIP1 was added
gene: TOR1AIP1 was added to Limb girdle muscular dystrophy. Sources: Literature
for-review tags were added to gene: TOR1AIP1.
Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOR1AIP1 were set to 24856141; 27342937; 30723199; 31299614; 32055997
Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900
Review for gene: TOR1AIP1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 15 affected individuals from 10 families with biallelic variants in this gene. Of these, 7 individuals (5 families) reported in PMID:30723199 harbour the same founder variant presenting a very similar phenotype, and are therefore considered collectively here.

Muscular dystrophy is the prominent feature of the disease presentation observed in at least one case individual each family, but specifically proximal limb-girdle dystrophy was recorded in 4 unrelated kindreds. Additional common features also include joint contractures (4 fam), dilated cardiomyopathy (4 fam), developmental delay (4 fam), and cataracts (3 fam).

-----
Note that one additional homozygous case has been reported with what is thought to be a discrete phenotype characterised by progressive dystonia, cerebellar atrophy, and dilated cardiomyopathy (PMID: 25425325)
Sources: Literature
Arthrogryposis v3.29 TOR1AIP1 Arina Puzriakova Phenotypes for gene: TOR1AIP1 were changed from joint contractures; ?Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, 617072 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900
Arthrogryposis v3.28 TOR1AIP1 Arina Puzriakova Publications for gene: TOR1AIP1 were set to 24856141
Arthrogryposis v3.27 TOR1AIP1 Arina Puzriakova Tag for-review tag was added to gene: TOR1AIP1.
Arthrogryposis v3.27 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Arthrogryposis v3.27 TOR1AIP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag). Joint contractures observed in at least 4/6 families reported to date (when considering 5 kindreds with same founder variant collectively).
Arthrogryposis v3.27 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.26 TOR1AIP1 Arina Puzriakova reviewed gene: TOR1AIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24856141, 27342937, 30723199, 31299614, 32055997; Phenotypes: Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.574 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.227 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.120 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v2.33 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.431 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v3.26 ADCY6 Arina Puzriakova Phenotypes for gene: ADCY6 were changed from Lethal congenital contracture syndrome 8 616287 to Lethal congenital contracture syndrome 8, OMIM:616287; Lethal congenital contracture syndrome 8, MONDO:0014570
Arthrogryposis v3.25 ADCY6 Arina Puzriakova Publications for gene: ADCY6 were set to 24319099
Arthrogryposis v3.24 ADCY6 Arina Puzriakova Tag for-review tag was added to gene: ADCY6.
Arthrogryposis v3.24 ADCY6 Arina Puzriakova Classified gene: ADCY6 as Amber List (moderate evidence)
Arthrogryposis v3.24 ADCY6 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag). At least 4 individuals from 3 unrelated families with distal AMC and distinct variants in the ADCY6 gene.
Arthrogryposis v3.24 ADCY6 Arina Puzriakova Gene: adcy6 has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.9 ABCC8 Ivone Leong Tag for-review tag was added to gene: ABCC8.
Pulmonary arterial hypertension v2.9 ABCC8 Ivone Leong Classified gene: ABCC8 as Amber List (moderate evidence)
Pulmonary arterial hypertension v2.9 ABCC8 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Pulmonary arterial hypertension v2.9 ABCC8 Ivone Leong Gene: abcc8 has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.8 ABCC8 Ivone Leong Publications for gene: ABCC8 were set to 31406341; 30354297
Pulmonary arterial hypertension v2.7 KDR Ivone Leong Tag watchlist tag was added to gene: KDR.
Pulmonary arterial hypertension v2.7 KDR Ivone Leong Classified gene: KDR as Amber List (moderate evidence)
Pulmonary arterial hypertension v2.7 KDR Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. Based on the available evidence this gene has been given an Amber rating.
Pulmonary arterial hypertension v2.7 KDR Ivone Leong Gene: kdr has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.6 KDR Ivone Leong Added comment: Comment on publications: PMID: 32880713 describes a mouse model where Kdr was conditionally knocked out. Kdr knockout led to mild pulmonary hypertension under normoxia that worsened under hypoxia. Kdr knockout mice had significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3+ endothelial cells obliterating the pulmonary artery vessel lumen.
Pulmonary arterial hypertension v2.6 KDR Ivone Leong Publications for gene: KDR were set to 31980491
Anophthalmia or microphthalmia v1.31 CAPN15 Eleanor Williams Classified gene: CAPN15 as Amber List (moderate evidence)
Anophthalmia or microphthalmia v1.31 CAPN15 Eleanor Williams Added comment: Comment on list classification: Promoting gene from red to amber, but with recommendation for green rating following next major review.
Anophthalmia or microphthalmia v1.31 CAPN15 Eleanor Williams Gene: capn15 has been classified as Amber List (Moderate Evidence).
Anophthalmia or microphthalmia v1.30 CAPN15 Eleanor Williams Tag for-review tag was added to gene: CAPN15.
Anophthalmia or microphthalmia v1.30 CAPN15 Eleanor Williams gene: CAPN15 was added
gene: CAPN15 was added to Anophthalmia or microphthalmia. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 32885237
Phenotypes for gene: CAPN15 were set to microphthalmia HP:0000568; coloboma HP:0000589
Review for gene: CAPN15 was set to GREEN
Added comment: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth.
Sources: Literature
Fetal anomalies v1.120 FKBP8 Eleanor Williams Classified gene: FKBP8 as Amber List (moderate evidence)
Fetal anomalies v1.120 FKBP8 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber. 5 cases reported with plausible disease causing variants but only the FKBP8 gene looked at.
Fetal anomalies v1.120 FKBP8 Eleanor Williams Gene: fkbp8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.119 FKBP8 Eleanor Williams gene: FKBP8 was added
gene: FKBP8 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FKBP8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FKBP8 were set to 32969478
Phenotypes for gene: FKBP8 were set to spina bifida HP:0002414
Review for gene: FKBP8 was set to AMBER
Added comment: Not associated with a phenotype in OMIM.

PMID: 32969478 - Tian et al 2020 - performed Sanger sequencing of FKBP8 on DNA samples from 472 spina bifida (SB) affected fetuses and 565 unaffected controls. 5 different rare heterozygous variants (MAF ≤ 0.001) were identified among the SB patients, while no deleterious rare variants were identified in the controls. 4 of the variants are missense, the other is a stop-gain. 2 cases were in white-Hispanic patients while the other 3 were non-white Hispanic. Functional studies showed that p.Glu140* affected FKBP8 localization to the mitochondria and impaired its interaction with BCL2 ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. Gene expression was studied in mouse Fkbp8-/- embryos and found to be abnormal. Previous mouse models have shown neural tube defects.

Sufficient cases to rate green, but only the FKBP8 gene looked at so perhaps some caution required while further evidence is gathered.
Sources: Literature
Skeletal dysplasia v2.34 TONSL Eleanor Williams Classified gene: TONSL as Amber List (moderate evidence)
Skeletal dysplasia v2.34 TONSL Eleanor Williams Added comment: Comment on list classification: updating from red to amber, but with a recommendation for green rating at the next GMS review.
Skeletal dysplasia v2.34 TONSL Eleanor Williams Gene: tonsl has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.33 TONSL Eleanor Williams Tag for-review tag was added to gene: TONSL.
Skeletal dysplasia v2.33 TONSL Eleanor Williams gene: TONSL was added
gene: TONSL was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: TONSL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TONSL were set to 32959051; 30773278; 30773277
Phenotypes for gene: TONSL were set to Spondyloepimetaphyseal dysplasia, sponastrime type OMIM:271510; spondyloepimetaphyseal dysplasia, sponastrime type MONDO:0010068
Review for gene: TONSL was set to GREEN
Added comment: Associated with Spondyloepimetaphyseal dysplasia, sponastrime type MIM#271510 (AR) in OMIM.

PMID: 30773277 - Burrage et al 2019 - identified, using WES or Sanger sequencing, compound heterozygous variants in TONSL in 9 individuals (8 families) with SPONASTRIME dysplasia. 4 other probands with SPONASTRIME dysplasia did not have biallelic variants in TONSL or in MMS22L, but two of them did have a single heterozygous variants in TONSL. The authors say they cannot exclude deep intronic, promotor variants or large intragenic rearrangements/deletions in these patients. An additional 4 individuals (3 families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities were also found to have compound heterozygous variants in TONSL.

PMID: 30773278 - Chang et al 2019 - Using WES they identified homozygous or compound heterozygous TONSL variants in 10 of 13 individuals (9 families) with SPONASTRIME dysplasia.

PMID: 32959051 - Micale et al 2020 - report a 9-year-old Italian girl with typical SPONASTRIME dysplasia who was found to have two novel missense variants in TONSL. Each parent was heterozygous for one of the variants. Both variants were found to be very rare in the gnomad database. Patient-derived fibroblasts show increased levels of spontaneous chromosomal breaks, reduced cell proliferation and enhanced apoptosis.
Sources: Literature
Arthrogryposis v3.23 NEK9 Arina Puzriakova Phenotypes for gene: NEK9 were changed from Arthrogryposis, Perthes disease, and upward gaze palsy 614262 to ?Arthrogryposis, Perthes disease, and upward gaze palsy, OMIM:614262; Arthrogryposis, Perthes disease, and upward gaze palsy, MONDO:0013660; Lethal congenital contracture syndrome 10, OMIM:617022; NEK9-related lethal skeletal dysplasia, MONDO:0014870
Arthrogryposis v3.22 NEK9 Arina Puzriakova Publications for gene: NEK9 were set to 26633546; 21271645
Arthrogryposis v3.21 NEK9 Arina Puzriakova Classified gene: NEK9 as Amber List (moderate evidence)
Arthrogryposis v3.21 NEK9 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber in line with the recent review by Rhiannon Mellis (GOSH). Additional cases/clinical evidence required before inclusion on a diagnostic panel.
Arthrogryposis v3.21 NEK9 Arina Puzriakova Gene: nek9 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.13 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Hypertrophic cardiomyopathy; Cardiomyopathy, dilated, 1S; Left ventricular noncompaction 5; Cardiomyopathy, familial hypertrophic, 1, to Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Left ventricular noncompaction 5, OMIM:613426
Paediatric disorders - additional genes v1.68 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Cardiomyopathy, dilated, 1S; Left ventricular noncompaction 5; Cardiomyopathy, hypertrophic, 1; Myopathy, myosin storage, autosomal recessive; Myopathy, myosin storage, autosomal dominant; Scapuloperoneal syndrome, myopathic type; Laing distal myopathy to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Scapuloperoneal syndrome, myopathic type, OMIM:181430; MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018; Left ventricular noncompaction 5, OMIM:613426
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.10 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, OMIM:160500 Laing early-onset distal myopathy, MONDO:0008050 Scapuloperoneal syndrome, myopathic type, OMIM:181430 MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600 Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426 Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358 Myopathy, myosin storage, autosomal dominant, MONDO:0012018 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Scapuloperoneal syndrome, myopathic type, OMIM:181430; MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018
Dilated and arrhythmogenic cardiomyopathy v1.8 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Cardiomyopathy, dilated, 1S (613426); Cardiomyopathy, dilated, 1S; Myopathy, myosin storage, autosomal recessive (255160); Scapuloperoneal syndrome, myopathic type (181430); Myopathy, myosin storage, autosomal dominant (608358); Cardiomyopathy, hypertrophic, 1 (192600); Left ventricular noncompaction 5 (613426); Laing distal myopathy (160500) to Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.9 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, 160500; cardiomyopathy; distal myopathy to Laing distal myopathy, OMIM:160500 Laing early-onset distal myopathy, MONDO:0008050 Scapuloperoneal syndrome, myopathic type, OMIM:181430 MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600 Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426 Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358 Myopathy, myosin storage, autosomal dominant, MONDO:0012018
Left Ventricular Noncompaction Cardiomyopathy v1.4 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Left ventricular noncompaction 5 ; Hypertrophic cardiomyopathy to Left ventricular noncompaction 5, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262
Distal myopathies v1.26 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Scapuloperoneal syndrome, myopathic type, OMIM:181430; MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409
Congenital myopathy v2.8 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing Distal Myopathy 160500 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018
Arthrogryposis v3.20 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing Distal Myopathy; Cardiomyopathy, familial hypertrophic, 1, 192600; Myopathy, myosin storage, autosomal recessive 255160; Myopathy, myosin storage, autosomal dominant 608358 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050
Dilated Cardiomyopathy and conduction defects v1.66 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Left ventricular noncompaction 5 (613426); Myopathy, myosin storage, autosomal dominant (608358); Laing distal myopathy (160500); Myopathy, myosin storage, autosomal recessive (255160); Cardiomyopathy, hypertrophic, 1 (192600); Cardiomyopathy, dilated, 1S (613426); Cardiomyopathy, dilated, 1S ; Scapuloperoneal syndrome, myopathic type (181430) to Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262
Hypertrophic cardiomyopathy v2.15 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Left ventricular noncompaction 5 (613426); Myopathy, myosin storage, autosomal dominant (608358); Laing distal myopathy (160500); Myopathy, myosin storage, autosomal recessive (255160); Cardiomyopathy, hypertrophic, 1 (192600); Cardiomyopathy, dilated, 1S (613426); Scapuloperoneal syndrome, myopathic type (181430); Cardiomyopathy, familial hypertrophic, 1, to Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647
Structural eye disease v1.22 CAPN15 Eleanor Williams changed review comment from: Publication relating to previous conference abstract now available:
PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families).; to: Publication relating to previous conference abstract now available:
PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth.
Structural eye disease v1.22 CAPN15 Eleanor Williams Phenotypes for gene: CAPN15 were changed from Anophthalmia, microphthalmia and coloboma to microphthalmia HP:0000568; coloboma HP:0000589
Structural eye disease v1.21 CAPN15 Eleanor Williams Publications for gene: CAPN15 were set to
Structural eye disease v1.20 CAPN15 Eleanor Williams Tag watchlist was removed from gene: CAPN15.
Tag for-review tag was added to gene: CAPN15.
Distal myopathies v1.25 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, 160500 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050
Structural eye disease v1.20 CAPN15 Eleanor Williams Classified gene: CAPN15 as Amber List (moderate evidence)
Structural eye disease v1.20 CAPN15 Eleanor Williams Added comment: Comment on list classification: Promoting gene from red to amber, but with recommendation for green rating following GMS review.
Structural eye disease v1.20 CAPN15 Eleanor Williams Gene: capn15 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.19 CAPN15 Eleanor Williams edited their review of gene: CAPN15: Added comment: Publication relating to previous conference abstract now available:
PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families).; Changed rating: GREEN; Changed publications: 32885237; Changed phenotypes: microphthalmia HP:0000568, coloboma HP:0000589
Arthrogryposis v3.19 MYH7 Arina Puzriakova Classified gene: MYH7 as Green List (high evidence)
Arthrogryposis v3.19 MYH7 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the next GMS panel update (added 'for-review' tag) as variants are associated with distal myopathy rather than arthrogryposis and therefore MYH7 should be demoted to RED on this panel.
Arthrogryposis v3.19 MYH7 Arina Puzriakova Gene: myh7 has been classified as Green List (High Evidence).
Arthrogryposis v3.18 MYH7 Arina Puzriakova Tag for-review tag was added to gene: MYH7.
Pigmentary skin disorders v1.7 XRCC2 Arina Puzriakova Publications for gene: XRCC2 were set to 22232082
Pigmentary skin disorders v1.6 XRCC2 Arina Puzriakova Phenotypes for gene: XRCC2 were changed from FANCONI ANEMIA, COMPLEMENTATION GROUP U; FANCU to ?Fanconi anemia, complementation group U, OMIM:617247; Fanconi anemia complementation group U, MONDO:0014987
Confirmed Fanconi anaemia or Bloom syndrome v1.11 XRCC2 Arina Puzriakova Phenotypes for gene: XRCC2 were changed from 617247 ?Fanconi anemia, complementation group U to ?Fanconi anemia, complementation group U, OMIM:617247; Fanconi anemia complementation group U, MONDO:0014987
Confirmed Fanconi anaemia or Bloom syndrome v1.10 XRCC2 Arina Puzriakova Publications for gene: XRCC2 were set to
Confirmed Fanconi anaemia or Bloom syndrome v1.9 XRCC2 Arina Puzriakova Classified gene: XRCC2 as Amber List (moderate evidence)
Confirmed Fanconi anaemia or Bloom syndrome v1.9 XRCC2 Arina Puzriakova Added comment: Comment on list classification: Single FA-U patient in literature at present but with supportive functional data. Additional published cases required to confirm pathogenicity and support inclusion of XRCC2 on a diagnostic FA panel.
Confirmed Fanconi anaemia or Bloom syndrome v1.9 XRCC2 Arina Puzriakova Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.19 SLC38A8 Eleanor Williams Phenotypes for gene: SLC38A8 were changed from Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis, 609218 to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216
Structural eye disease v1.18 SLC38A8 Eleanor Williams Publications for gene: SLC38A8 were set to 24045842
Structural eye disease v1.17 SLC38A8 Eleanor Williams reviewed gene: SLC38A8: Rating: ; Mode of pathogenicity: None; Publications: 32744312; Phenotypes: Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.8 SLC38A8 Eleanor Williams Phenotypes for gene: SLC38A8 were changed from Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis 609218 AR to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216
Albinism or congenital nystagmus v1.7 SLC38A8 Eleanor Williams Publications for gene: SLC38A8 were set to 24290379; 29345414; 24045842
Retinal disorders v2.23 SLC38A8 Eleanor Williams Phenotypes for gene: SLC38A8 were changed from Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis, 609218 to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216
Retinal disorders v2.22 SLC38A8 Eleanor Williams Publications for gene: SLC38A8 were set to 24290379; 24045842; 15466012; 24290379; 24045842
Retinal disorders v2.21 SLC38A8 Eleanor Williams reviewed gene: SLC38A8: Rating: ; Mode of pathogenicity: None; Publications: 32744312; Phenotypes: Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.6 SLC38A8 Eleanor Williams reviewed gene: SLC38A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 32744312; Phenotypes: Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.41 SPEF2 Ivone Leong Classified gene: SPEF2 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.41 SPEF2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. As respiratory phenotype is not in all affected individuals, this gene has been given an Amber rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.41 SPEF2 Ivone Leong Gene: spef2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.118 SCN1A Arina Puzriakova Phenotypes for gene: SCN1A were changed from SCN1A-RELATED SEIZURE DISORDERS to Dravet syndrome, OMIM:607208; Arthrogryposis multiplex congenita
Fetal anomalies v1.117 SCN1A Arina Puzriakova Publications for gene: SCN1A were set to
Fetal anomalies v1.116 SCN1A Arina Puzriakova Classified gene: SCN1A as Red List (low evidence)
Fetal anomalies v1.116 SCN1A Arina Puzriakova Added comment: Comment on list classification: Although it is anticipated that following birth early-onset seizures will likely represent the predominant characteristic of the phenotype, arthrogryposis multiplex congenita may be detected in utero as demonstrated with the cases in PMID:32928894. Therefore, this gene will be flagged for review at the next GMS panel update to assess whether this is sufficient for inclusion on this panel (added 'for-review' tag).
Fetal anomalies v1.116 SCN1A Arina Puzriakova Gene: scn1a has been classified as Red List (Low Evidence).
Fetal anomalies v1.115 SCN1A Arina Puzriakova Tag for-review tag was added to gene: SCN1A.
Fetal anomalies v1.115 SCN1A Arina Puzriakova reviewed gene: SCN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32928894, 29543227; Phenotypes: Dravet syndrome, OMIM:607208, Arthrogryposis multiplex congenita; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Respiratory ciliopathies including non-CF bronchiectasis v1.40 SPEF2 Ivone Leong Phenotypes for gene: SPEF2 were changed from Spermatogenic failure 43, MIM#618751; Primary ciliary dyskinesia-like phenotype to Spermatogenic failure 43, OMIM:618751, MONDO:0032898; Primary ciliary dyskinesia-like phenotype
Respiratory ciliopathies including non-CF bronchiectasis v1.39 DNAJB13 Ivone Leong reviewed gene: DNAJB13: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.39 DNAJB13 Ivone Leong Tag for-review tag was added to gene: DNAJB13.
Respiratory ciliopathies including non-CF bronchiectasis v1.39 DNAJB13 Ivone Leong Publications for gene: DNAJB13 were set to
Arthrogryposis v3.18 SCN1A Arina Puzriakova Classified gene: SCN1A as Amber List (moderate evidence)
Arthrogryposis v3.18 SCN1A Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases (4) reported in 2 papers (PMIDs: 32928894 and 29543227) with ACM and variants in this gene.

It is anticipated that early-onset seizures likely represent the predominant feature of the disease presentation (already Green on the Genetic epilepsy syndromes panel), however this gene will be flagged for review to assess whether inclusion on this panel is likely to be of clinical benefit.
Arthrogryposis v3.18 SCN1A Arina Puzriakova Gene: scn1a has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.38 DNAJB13 Ivone Leong Phenotypes for gene: DNAJB13 were changed from Ciliary dyskinesia, primary, 34, 617091 to Ciliary dyskinesia, primary, 34, OMIM:617091, MONDO:0014909
Respiratory ciliopathies including non-CF bronchiectasis v1.37 TTC12 Ivone Leong Classified gene: TTC12 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.37 TTC12 Ivone Leong Gene: ttc12 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.36 TTC12 Ivone Leong Classified gene: TTC12 as Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.36 TTC12 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Respiratory ciliopathies including non-CF bronchiectasis v1.36 TTC12 Ivone Leong Gene: ttc12 has been classified as Green List (High Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.35 TTC12 Ivone Leong Tag for-review tag was added to gene: TTC12.
Respiratory ciliopathies including non-CF bronchiectasis v1.35 TTC12 Ivone Leong Phenotypes for gene: TTC12 were changed from Ciliary dyskinesia to Ciliary dyskinesia, primary, 45, OMIM:618801; MONDO:0032924
Respiratory ciliopathies including non-CF bronchiectasis v1.34 FOXJ1 Ivone Leong Classified gene: FOXJ1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.34 FOXJ1 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Respiratory ciliopathies including non-CF bronchiectasis v1.34 FOXJ1 Ivone Leong Gene: foxj1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.33 FOXJ1 Ivone Leong Tag for-review tag was added to gene: FOXJ1.
Respiratory ciliopathies including non-CF bronchiectasis v1.33 FOXJ1 Ivone Leong Phenotypes for gene: FOXJ1 were changed from Motile ciliopathy; situs inversus, hydrocephalus to Ciliary dyskinesia, primary, 43, OMIM:618699, MONDO:0032874
Respiratory ciliopathies including non-CF bronchiectasis v1.32 NEK10 Ivone Leong Tag for-review tag was added to gene: NEK10.
Respiratory ciliopathies including non-CF bronchiectasis v1.32 NEK10 Ivone Leong Classified gene: NEK10 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.32 NEK10 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM. There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at next review.
Respiratory ciliopathies including non-CF bronchiectasis v1.32 NEK10 Ivone Leong Gene: nek10 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.31 NEK10 Ivone Leong Added comment: Comment on publications: PMID: 32414360 is an additional case
Respiratory ciliopathies including non-CF bronchiectasis v1.31 NEK10 Ivone Leong Publications for gene: NEK10 were set to 31959991
Respiratory ciliopathies including non-CF bronchiectasis v1.30 NEK10 Ivone Leong Phenotypes for gene: NEK10 were changed from Ciliary dyskinesia, primary, 44, MIM# 618781 to Ciliary dyskinesia, primary, 44, OMIM:618781, MONDO:0032914
Arthrogryposis v3.17 SCN1A Arina Puzriakova Phenotypes for gene: SCN1A were changed from Arthrogryposis multiplex congenita to Arthrogryposis multiplex congenita; Dravet syndrome, OMIM:607208
Arthrogryposis v3.16 SCN1A Arina Puzriakova Publications for gene: SCN1A were set to 32928894
Arthrogryposis v3.15 SCN1A Arina Puzriakova Tag for-review tag was added to gene: SCN1A.
Respiratory ciliopathies including non-CF bronchiectasis v1.29 RPGR Ivone Leong edited their review of gene: RPGR: Added comment: This gene is associated with an appropriate phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at the next review.; Changed rating: GREEN
Respiratory ciliopathies including non-CF bronchiectasis v1.29 RPGR Ivone Leong Tag for-review tag was added to gene: RPGR.
Respiratory ciliopathies including non-CF bronchiectasis v1.29 RPGR Ivone Leong Added comment: Comment on publications: PMID: 22888088 and 14627685 are extra cases
Respiratory ciliopathies including non-CF bronchiectasis v1.29 RPGR Ivone Leong Publications for gene: RPGR were set to 10094550; 12920075; 16055928
Respiratory ciliopathies including non-CF bronchiectasis v1.28 RPGR Ivone Leong Phenotypes for gene: RPGR were changed from Ciliopathies to Ciliopathies; Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness, OMIM:300455; primary ciliary dyskinesia-retinitis pigmentosa syndrome, MONDO:0010330
Respiratory ciliopathies including non-CF bronchiectasis v1.27 RPGR Ivone Leong Publications for gene: RPGR were set to
Respiratory ciliopathies including non-CF bronchiectasis v1.26 CFAP46 Ivone Leong reviewed gene: CFAP46: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.26 CFAP46 Ivone Leong Tag for-review tag was added to gene: CFAP46.
Respiratory ciliopathies including non-CF bronchiectasis v1.26 CFAP46 Ivone Leong Phenotypes for gene: CFAP46 were changed from to Heterotaxy
Respiratory ciliopathies including non-CF bronchiectasis v1.25 CFAP46 Ivone Leong Publications for gene: CFAP46 were set to
Sarcoma susceptibility v1.5 DICER1 Arina Puzriakova Phenotypes for gene: DICER1 were changed from Pleuropulmonary blastoma, 601200; Rhabdomyosarcoma, embryonal, 2, 180295 to Pleuropulmonary blastoma, OMIM:601200; Pleuropulmonary blastoma, MONDO:0011014; Rhabdomyosarcoma, embryonal, 2, OMIM:180295; Embryonal rhabdomyosarcoma (disease), MONDO:0009993
Adult solid tumours cancer susceptibility v2.7 DICER1 Arina Puzriakova Phenotypes for gene: DICER1 were changed from DICER1 syndrome, Familial Multinodular Goiter to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800; Pleuropulmonary blastoma, OMIM:601200; Pleuropulmonary blastoma, MONDO:0011014; Rhabdomyosarcoma, embryonal, 2, OMIM:180295; Embryonal rhabdomyosarcoma (disease), MONDO:0009993; DICER1 syndrome
Inherited non-medullary thyroid cancer v1.5 DICER1 Arina Puzriakova Phenotypes for gene: DICER1 were changed from Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors 138800; Pleuropulmonary blastoma 601200 to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800
Childhood solid tumours v2.16 DICER1 Arina Puzriakova Publications for gene: DICER1 were set to 21205968
Childhood solid tumours v2.15 DICER1 Arina Puzriakova Phenotypes for gene: DICER1 were changed from Familial Multinodular Goiter; DICER1 syndrome; 601200 to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800; Pleuropulmonary blastoma, OMIM:601200; Pleuropulmonary blastoma, MONDO:0011014; Rhabdomyosarcoma, embryonal, 2, OMIM:180295; Embryonal rhabdomyosarcoma (disease), MONDO:0009993; DICER1 syndrome; GLOW syndrome; Global developmental delay, lung cysts, overgrowth, and wilms tumor, MONDO:0032647
Hereditary neuropathy or pain disorder v1.18 UBA5 Arina Puzriakova gene: UBA5 was added
gene: UBA5 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: UBA5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBA5 were set to 32179706
Phenotypes for gene: UBA5 were set to Hypomyelinating neuropathy
Added comment: Note that UBA5 variants have been associated with a range of neurological phenotypes including epilepsy, ID and ataxia.

PMID: 32179706 (2020) - Five affected individuals from a consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Some in vitro functional data included. Due to early mortality, unclear whether additional features previously associated with UBA5 variants would have developed.
Sources: Literature
Intellectual disability v3.574 TFE3 Arina Puzriakova Tag Skewed X-inactivation tag was added to gene: TFE3.
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Tag Skewed X-inactivation tag was added to gene: TFE3.
Respiratory ciliopathies including non-CF bronchiectasis v1.24 CFAP54 Ivone Leong Tag for-review tag was added to gene: CFAP54.
Respiratory ciliopathies including non-CF bronchiectasis v1.24 CFAP54 Ivone Leong reviewed gene: CFAP54: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.24 CFAP54 Ivone Leong Publications for gene: CFAP54 were set to
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Early onset or syndromic epilepsy v2.226 TFE3 Arina Puzriakova Mode of inheritance for gene: TFE3 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)
Intellectual disability v3.574 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Intellectual disability v3.574 TFE3 Arina Puzriakova Mode of inheritance for gene: TFE3 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)
Respiratory ciliopathies including non-CF bronchiectasis v1.23 CFAP57 Ivone Leong Classified gene: CFAP57 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.23 CFAP57 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not associated with any phenotypes in OMIM or Gene2Phenotype and based on the available evidence this gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.23 CFAP57 Ivone Leong Gene: cfap57 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.22 CFAP57 Ivone Leong Added comment: Comment on publications: bioRxiv 773028 doi: https://doi.org/10.1101/773028 has now been published and is PMID: 32764743
Respiratory ciliopathies including non-CF bronchiectasis v1.22 CFAP57 Ivone Leong Publications for gene: CFAP57 were set to 32764743
Respiratory ciliopathies including non-CF bronchiectasis v1.21 CFAP57 Ivone Leong Publications for gene: CFAP57 were set to bioRxiv 773028 doi: https://doi.org/10.1101/773028
Respiratory ciliopathies including non-CF bronchiectasis v1.20 ITCH Ivone Leong Classified gene: ITCH as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.20 ITCH Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. Based on the available evidence this gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.20 ITCH Ivone Leong Gene: itch has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.19 ITCH Ivone Leong Phenotypes for gene: ITCH were changed from Autoimmune disease, multisystem, with facial dysmorphism 613385; primary ciliary dyskinesia to Autoimmune disease, multisystem, with facial dysmorphism OMIM:613385; syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245; primary ciliary dyskinesia
Respiratory ciliopathies including non-CF bronchiectasis v1.18 GOLGA3 Ivone Leong Classified gene: GOLGA3 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.18 GOLGA3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Based on the available evidence this gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.18 GOLGA3 Ivone Leong Gene: golga3 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.17 AKNA Ivone Leong Classified gene: AKNA as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.17 AKNA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Based on the available evidence this gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.17 AKNA Ivone Leong Gene: akna has been classified as Red List (Low Evidence).
Intellectual disability v3.573 ISCA-37418-Loss Zornitza Stark reviewed Region: ISCA-37418-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Smith-Magenis syndrome, MIM# 182290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.131 MET Eleanor Williams Classified gene: MET as Amber List (moderate evidence)
Monogenic hearing loss v2.131 MET Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber as two cases reported, with segregation data.
Monogenic hearing loss v2.131 MET Eleanor Williams Gene: met has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.130 MET Eleanor Williams gene: MET was added
gene: MET was added to Hearing loss. Sources: Expert list
Mode of inheritance for gene: MET was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MET were set to 25941349; 27717089
Phenotypes for gene: MET were set to Deafness, autosomal recessive 97 OMIM:616705; autosomal recessive nonsyndromic deafness 97 MONDO:0014739
Review for gene: MET was set to AMBER
Added comment: Gene suggested by Professor Sadaf Naz, PhD, School of Biological Sciences, University of the Punjab, Pakistan

Provisionally associated with ?Deafness, autosomal recessive 97 MIM#616705 in OMIM. 2 cases reported:

PMID: 25941349 - Mujtaba et al 2015 - report a large consanguineous Pakistani family with some members affected by hearing loss. They identified, through genome-wide homozygosity mapping and then whole exome sequencing, a homozygous missense variant located in MET (NM_000245.2), c.2521T>G (p.F841V) that segregates with hearing loss in 9 affected individuals.

PMID: 27717089 - Alabdullatif et al 2017 - from a review of clinical and molecular data for 227 individuals from a highly consanguineous population who underwent a combined (CGH+SNP) CMA test, they report 2 brothers with hearing loss and arthrogryposis in which a homozygous variant c.3557T>G (p.F1186C) in MET was identified through WES after a region of homozygosity was identified. The first cousin parents were both heterozygous for this variant. They suggest that the arthrogryposis could be a variable feature of the disease or be caused by a second recessive disease not detected in this study.
Sources: Expert list
Structural eye disease v1.17 CDH2 Arina Puzriakova Classified gene: CDH2 as Amber List (moderate evidence)
Structural eye disease v1.17 CDH2 Arina Puzriakova Added comment: Comment on list classification: Gene added following discussion with Helen Brittain (Genomics England Clinical Team) who indicated this panel may be applicable in view of the ocular abnormalities observed in some individuals with CDH2 variants. However, as the eye phenotypes were diverse, this warrants phenotypic consideration by the GMS team to assess the relevance to this panel (added 'for-review' tag)
Structural eye disease v1.17 CDH2 Arina Puzriakova Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.16 CDH2 Arina Puzriakova gene: CDH2 was added
gene: CDH2 was added to Structural eye disease. Sources: Literature
for-review tags were added to gene: CDH2.
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDH2 were set to 31585109; 31650526
Phenotypes for gene: CDH2 were set to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Review for gene: CDH2 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM, and is a 'probable' gene for 'Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects' in Gene2Phenotype.

2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various ocular abnormalities (11/13). Eye phenotype was variable and includes Peters anomaly, glaucoma, cataract, Duane anomaly, strabismus.

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature
Paediatric disorders - additional genes v1.67 CDH2 Arina Puzriakova Classified gene: CDH2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.67 CDH2 Arina Puzriakova Added comment: Comment on list classification: Gene added following discussion with Helen Brittain (Genomics England Clinical Team) who indicated this panel is relevant in view of the multiple congenital malformations associated with CDH2 variants.

Tagged 'for-review' as there is sufficient evidence to rate this gene Green at the next GMS panel update.
Paediatric disorders - additional genes v1.67 CDH2 Arina Puzriakova Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.66 CDH2 Arina Puzriakova gene: CDH2 was added
gene: CDH2 was added to Paediatric disorders - additional genes. Sources: Literature
for-review tags were added to gene: CDH2.
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDH2 were set to 31585109; 31650526
Phenotypes for gene: CDH2 were set to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Review for gene: CDH2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, and is a 'probable' gene for 'Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects' in Gene2Phenotype.

2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature
Malformations of cortical development v2.17 CDH2 Arina Puzriakova changed review comment from: 2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature; to: Associated with relevant phenotype in OMIM, and is a 'probable' gene for 'Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects' in Gene2Phenotype.

2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature
Intellectual disability v3.573 CDH2 Arina Puzriakova reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31650526; Phenotypes: Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Malformations of cortical development v2.17 CDH2 Arina Puzriakova Classified gene: CDH2 as Amber List (moderate evidence)
Malformations of cortical development v2.17 CDH2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Malformations of cortical development v2.17 CDH2 Arina Puzriakova Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.16 CDH2 Arina Puzriakova changed review comment from: 2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.
Sources: Literature; to: 2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature
Malformations of cortical development v2.16 CDH2 Arina Puzriakova gene: CDH2 was added
gene: CDH2 was added to Malformations of cortical development. Sources: Literature
for-review tags were added to gene: CDH2.
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDH2 were set to 31585109; 31650526
Phenotypes for gene: CDH2 were set to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Review for gene: CDH2 was set to GREEN
Added comment: 2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.
Sources: Literature
Intellectual disability v3.573 CDH2 Arina Puzriakova Phenotypes for gene: CDH2 were changed from Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929 to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Respiratory ciliopathies including non-CF bronchiectasis v1.16 NME5 Ivone Leong Classified gene: NME5 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.16 NME5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Therefore, there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.16 NME5 Ivone Leong Gene: nme5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.572 CDH2 Arina Puzriakova Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Respiratory ciliopathies including non-CF bronchiectasis v1.15 NME5 Ivone Leong Tag watchlist tag was added to gene: NME5.
Respiratory ciliopathies including non-CF bronchiectasis v1.15 CFAP74 Ivone Leong Tag watchlist tag was added to gene: CFAP74.
Respiratory ciliopathies including non-CF bronchiectasis v1.15 NME5 Ivone Leong Publications for gene: NME5 were set to 32185794
Respiratory ciliopathies including non-CF bronchiectasis v1.14 CFAP74 Ivone Leong Classified gene: CFAP74 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.14 CFAP74 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Based on the available evidence there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.14 CFAP74 Ivone Leong Gene: cfap74 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.13 OFD1 Ivone Leong reviewed gene: OFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.13 OFD1 Ivone Leong Mode of inheritance for gene: OFD1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Respiratory ciliopathies including non-CF bronchiectasis v1.12 OFD1 Ivone Leong Tag for-review tag was added to gene: OFD1.
Respiratory ciliopathies including non-CF bronchiectasis v1.12 OFD1 Ivone Leong Publications for gene: OFD1 were set to 31366608; 32276433; 31373179; 16783569
Respiratory ciliopathies including non-CF bronchiectasis v1.11 OFD1 Ivone Leong Publications for gene: OFD1 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 LCP2 Arina Puzriakova Tag watchlist tag was added to gene: LCP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 LCP2 Arina Puzriakova Classified gene: LCP2 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 LCP2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer (University of Florence). Rating Red pending publication of the Lev et al., 2021 article. Paper only describes a single individual and additional cases would be required before inclusion of LCP2 on an immunodeficiency panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 LCP2 Arina Puzriakova Gene: lcp2 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.10 OFD1 Ivone Leong Phenotypes for gene: OFD1 were changed from Ciliopathies; Primary ciliary dyskinesia to Ciliopathies; Primary ciliary dyskinesia; Simpson-Golabi-Behmel syndrome, type 2, OMIM:300209, MONDO:0010265
Primary immunodeficiency or monogenic inflammatory bowel disease v2.383 LCP2 Arina Puzriakova reviewed gene: LCP2: Rating: ; Mode of pathogenicity: None; Publications: 33231617; Phenotypes: Severe immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.9 OFD1 Ivone Leong Phenotypes for gene: OFD1 were changed from Ciliopathies to Ciliopathies; Primary ciliary dyskinesia
Primary immunodeficiency or monogenic inflammatory bowel disease v2.383 RNU7-1 Arina Puzriakova Tag watchlist tag was added to gene: RNU7-1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.383 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Type I interferonopathy, Aicardi-Goutières syndrome to Type I interferonopathy; Aicardi-Goutières syndrome
Primary immunodeficiency or monogenic inflammatory bowel disease v2.382 RNU7-1 Arina Puzriakova Classified gene: RNU7-1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.382 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Currently only one paper (PMID: 33230297) indicating pathogenicity of RNU7-1 variants, which also reports on a healthy individual with biallelic rare variants in this gene. Rating Amber awaiting further publications/clinical evidence to corroborate this gene-disease association (added 'watchlist' tag)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.382 RNU7-1 Arina Puzriakova Gene: rnu7-1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.381 RNU7-1 Arina Puzriakova reviewed gene: RNU7-1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33230297; Phenotypes: Type I interferonopathy, Aicardi–Goutières syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.381 LSM11 Arina Puzriakova Phenotypes for gene: LSM11 were changed from Type I interferonopathy, Aicardi-Goutières syndrome to Type I interferonopathy; Aicardi-Goutières syndrome
Primary immunodeficiency or monogenic inflammatory bowel disease v2.380 LSM11 Arina Puzriakova Classified gene: LSM11 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.380 LSM11 Arina Puzriakova Gene: lsm11 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 LSM11 Arina Puzriakova reviewed gene: LSM11: Rating: ; Mode of pathogenicity: None; Publications: 33230297; Phenotypes: Type I interferonopathy, Aicardi–Goutières syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.571 ISCA-37415-Gain Arina Puzriakova Phenotypes for Region: ISCA-37415-Gain were changed from to Intellectual disability; Developmental delay; Autism; Aortopathy
Intellectual disability v3.570 ISCA-37415-Gain Arina Puzriakova Publications for Region: ISCA-37415-Gain were set to 23637818; 24352232; 21614007
Inherited ovarian cancer (without breast cancer) v2.5 PALB2 Arina Puzriakova Tag for-review tag was added to gene: PALB2.
Inherited ovarian cancer (without breast cancer) v2.5 PALB2 Arina Puzriakova changed review comment from: Comment on list classification: Kept rating Red, as it remains unclear whether the risk is sufficiently high to warrant the inclusion of PALB2 in the ovarian cancer gene panel.; to: Comment on list classification: Kept rating Red, but this gene will be flagged for review (added 'for-review' tag) at the next GMS panel update to assess whether the risk is sufficiently high to warrant inclusion of PALB2 on the ovarian cancer gene panel in the context of two recent publications (PMIDs: 31841383 and 32546565) identified by the expert reviewer.
Intellectual disability v3.569 ISCA-37415-Gain Zornitza Stark reviewed Region: ISCA-37415-Gain: Rating: GREEN; Mode of pathogenicity: None; Publications: 30287593; Phenotypes: Intellectual disability, autism, aortopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.115 MN1 Rhiannon Mellis gene: MN1 was added
gene: MN1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203; 15870292
Phenotypes for gene: MN1 were set to CEBALID syndrome, 618774
Mode of pathogenicity for gene: MN1 was set to Other
Review for gene: MN1 was set to GREEN
Added comment: Copied from MN1 review on Cortical malformations panel:

Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P.

Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum - rhombencephalosynapsis).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature
Paediatric disorders - additional genes v1.65 PIGQ Sarah Leigh Classified gene: PIGQ as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.65 PIGQ Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Paediatric disorders - additional genes v1.65 PIGQ Sarah Leigh Gene: pigq has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.64 PIGQ Sarah Leigh commented on gene: PIGQ: Comments from Konstantinos Varvagiannis
Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548). Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362). Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality. PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis. More than 10 variants have been reported to date (missense / pLoF). Overall PIGQ can be considered for green rating in both ID and epilepsy gene panels.
Paediatric disorders - additional genes v1.64 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, OMIM:618548 as the name for this phenotype (12/11/2020).
Paediatric disorders - additional genes v1.64 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548 to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
Paediatric disorders - additional genes v1.63 PIGQ Sarah Leigh gene: PIGQ was added
gene: PIGQ was added to Paediatric disorders - additional genes. Sources: Literature
for-review tags were added to gene: PIGQ.
Mode of inheritance for gene: PIGQ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGQ were set to 32588908; 24463883; 25558065; 31148362
Phenotypes for gene: PIGQ were set to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
Review for gene: PIGQ was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for severe early onset epilepsy. At least 11 variants reported in seven unrelated cases of multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4)(Epileptic encephalopathy, early infantile, 77 618548)(OMIM:618548).
Sources: Literature
Intellectual disability v3.569 ATP2A2 Andrea Nemeth reviewed gene: ATP2A2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 25704118; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v1.62 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.62 STN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in three unrelated cases, together with a supportive zebrafish model and other functional studies.

There is enough evidence for this gene to be rated GREEN at the next major review.
Paediatric disorders - additional genes v1.62 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.21 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.21 STN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in three unrelated cases, together with a supportive zebrafish model and other functional studies.

There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset hereditary spastic paraplegia v2.21 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.32 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.32 STN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in three unrelated cases, together with a supportive zebrafish model and other functional studies.

There is enough evidence for this gene to be rated GREEN at the next major review.
Cytopenia - NOT Fanconi anaemia v1.32 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.61 STN1 Sarah Leigh gene: STN1 was added
gene: STN1 was added to Paediatric disorders - additional genes. Sources: Literature
for-review tags were added to gene: STN1.
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 27432940; 32627942
Phenotypes for gene: STN1 were set to Cerebroretinal microangiopathy with calcifications and cysts 2 OMIM:617341
Review for gene: STN1 was set to GREEN
Added comment: Comments from Zornitza Stark (Australian Genomics) Three individuals from unrelated families described with a multisystem disorder characterized by premature aging, pancytopaenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding, as well as intracranial calcifications and leukodystrophy, resulting in spasticity, ataxia, or dystonia. Gene belongs on multiple panels.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v1.31 STN1 Sarah Leigh gene: STN1 was added
gene: STN1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
for-review tags were added to gene: STN1.
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 27432940; 32627942
Phenotypes for gene: STN1 were set to Cerebroretinal microangiopathy with calcifications and cysts 2 OMIM:617341
Review for gene: STN1 was set to GREEN
Added comment: Comments from Zornitza Stark (Australian Genomics) Three individuals from unrelated families described with a multisystem disorder characterized by premature aging, pancytopaenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding, as well as intracranial calcifications and leukodystrophy, resulting in spasticity, ataxia, or dystonia. Gene belongs on multiple panels.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.20 STN1 Sarah Leigh gene: STN1 was added
gene: STN1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
for-review tags were added to gene: STN1.
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 27432940; 32627942
Phenotypes for gene: STN1 were set to Cerebroretinal microangiopathy with calcifications and cysts 2 OMIM:617341
Review for gene: STN1 was set to GREEN
Added comment: Comments from Zornitza Stark (Australian Genomics) Three individuals from unrelated families described with a multisystem disorder characterized by premature aging, pancytopaenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding, as well as intracranial calcifications and leukodystrophy, resulting in spasticity, ataxia, or dystonia. Gene belongs on multiple panels.
Sources: Literature
Hypophosphataemia or rickets v2.14 FAH Ivone Leong Classified gene: FAH as Amber List (moderate evidence)
Hypophosphataemia or rickets v2.14 FAH Ivone Leong Added comment: Comment on list classification: This gene is associated with an appropriate phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association.

FAH causes type I tyrosinemia and hypophosphataemic rickets is a feature of chronic disease, but patients present with liver phenotypes at the beginning before developing hypophosphataemic rickets. After consultation with the Genomics England Clinical Team, I have given this gene an Amber gene rating and tagged with "for-review" so that GMS experts can consider this gene in the scope of testing for the next iteration.

This gene is already Green on Undiagnosed metabolic disorders (v1.431) and Inborn errors of metabolism (v2.33) panels
Hypophosphataemia or rickets v2.14 FAH Ivone Leong Gene: fah has been classified as Amber List (Moderate Evidence).
Hypophosphataemia or rickets v2.13 FAH Ivone Leong Tag for-review tag was added to gene: FAH.
Hypophosphataemia or rickets v2.13 FAH Ivone Leong Phenotypes for gene: FAH were changed from Tyrosinemia, type I, 276700 to Tyrosinemia, type I, OMIM:276700, MONDO:0010161
Hypophosphataemia or rickets v2.12 ALPL Ivone Leong Tag for-review tag was added to gene: ALPL.
Hypophosphataemia or rickets v2.12 ALPL Ivone Leong Classified gene: ALPL as Amber List (moderate evidence)
Hypophosphataemia or rickets v2.12 ALPL Ivone Leong Added comment: Comment on list classification: This gene is associated with an appropriate phenotype in OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association. However, phosphate levels in the blood is normal for this phenotype. After consultation with the Genomics England Clinical Team, I have given this gene an Amber gene rating and tagged with "for-review" so that GMS experts can consider this gene in the scope of testing for the next iteration.
Hypophosphataemia or rickets v2.12 ALPL Ivone Leong Gene: alpl has been classified as Amber List (Moderate Evidence).
Hypophosphataemia or rickets v2.11 ALPL Ivone Leong Phenotypes for gene: ALPL were changed from Hypophosphatasia, infantile, 241500; Hypophosphatasia, childhood, 241500 to Hypophosphatasia, infantile, OMIM:241500, MONDO:0009427; Hypophosphatasia, childhood, OMIM:241500, MONDO:0009428
Pituitary hormone deficiency v2.5 RNPC3 Ivone Leong gene: RNPC3 was added
gene: RNPC3 was added to Pituitary hormone deficiency. Sources: Literature,Expert Review
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Phenotypes for gene: RNPC3 were set to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160
Review for gene: RNPC3 was set to RED
Added comment: This gene is an Amber gene on the Growth failure in early childhood panel (v1.16). The following reviews are present for this gene on that panel:

"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020

Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Zornitza Stark (Australian Genomics), 5 Oct 2020"

As the second case has low levels of prolactin and GH, this gene was added to this panel as a Red gene.
Sources: Literature, Expert Review
Bilateral congenital or childhood onset cataracts v2.18 RNPC3 Ivone Leong gene: RNPC3 was added
gene: RNPC3 was added to Cataracts. Sources: Expert Review,Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Phenotypes for gene: RNPC3 were set to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; congenital cataracts
Review for gene: RNPC3 was set to RED
Added comment: This gene is an Amber gene on the Growth failure in early childhood panel (v1.16). The following reviews are present for this gene on that panel:

"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020

Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Zornitza Stark (Australian Genomics), 5 Oct 2020"

As only 1 affected family has congenital cataracts, this gene is given a Red rating.
Sources: Expert Review, Literature
Intellectual disability v3.569 RNPC3 Ivone Leong gene: RNPC3 was added
gene: RNPC3 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Phenotypes for gene: RNPC3 were set to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; developmental delay/intellectual deficiency and delayed puberty
Review for gene: RNPC3 was set to RED
Added comment: This gene is an Amber gene on the Growth failure in early childhood panel (v1.16). The following reviews are present for this gene on that panel:

"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020

Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Zornitza Stark (Australian Genomics), 5 Oct 2020"

As only 1 affected family has developmental delay/intellectual deficiency, this gene is given a Red rating.
Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 RNU7-1 Boaz Palterer gene: RNU7-1 was added
gene: RNU7-1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Type I interferonopathy, Aicardi-Goutières syndrome
Penetrance for gene: RNU7-1 were set to unknown
Review for gene: RNU7-1 was set to AMBER
Added comment: 16 patients belonging to 11 independent pedigrees harbored biallelic variants, with a frequency of ≤0.005 alleles in the Genome Aggregation Database (gnomAD), in the RNU7-1 gene encoding small nuclear RNA (snRNA) U7
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 LSM11 Boaz Palterer gene: LSM11 was added
gene: LSM11 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LSM11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM11 were set to 33230297
Phenotypes for gene: LSM11 were set to Type I interferonopathy, Aicardi-Goutières syndrome
Penetrance for gene: LSM11 were set to unknown
Review for gene: LSM11 was set to AMBER
Added comment: Two siblings with AGS from consanguineous parents were found to have homozygous LSM11 mutation.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 LCP2 Boaz Palterer gene: LCP2 was added
gene: LCP2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LCP2 were set to 33231617
Phenotypes for gene: LCP2 were set to SCID; combined T and B cell immunodeficiency; severe neutrophil defects; impaired platelet aggregation
Penetrance for gene: LCP2 were set to unknown
Review for gene: LCP2 was set to AMBER
Added comment: One patient with severe combined immunodeficiency was found to have biallelic mutations in SLP76.
Sources: Literature
Monogenic hearing loss v2.129 PMP22 Eleanor Williams Classified gene: PMP22 as Amber List (moderate evidence)
Monogenic hearing loss v2.129 PMP22 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. Three independent cases reported in which patients have Charcot-Marie-Tooth disease plus hearing loss and variants in PMP22, but waiting for feedback from Genomics England clinical team as to whether this gene is appropriate to be green as HL is part of a syndrome of features.
Monogenic hearing loss v2.129 PMP22 Eleanor Williams Gene: pmp22 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.128 PMP22 Eleanor Williams Phenotypes for gene: PMP22 were changed from to Charcot-Marie-Tooth disease, type 1E OMIM:118300; Charcot-Marie-Tooth disease type 1E MONDO:0007311
Monogenic hearing loss v2.127 PMP22 Eleanor Williams Publications for gene: PMP22 were set to
Monogenic hearing loss v2.126 PMP22 Eleanor Williams Mode of inheritance for gene: PMP22 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.125 PMP22 Eleanor Williams changed review comment from: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ contained 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.; to: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ in 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.
Familial Meniere Disease v1.1 COCH Eleanor Williams commented on gene: COCH: Several cases of biallelic variants reported in families with hearing loss (see https://panelapp.genomicsengland.co.uk/panels/126/gene/COCH/) but none report Meniere disease combination of phenotype so leaving the mode of inheritance as monoallelic on the Familial Meniere Disease panel.
Monogenic hearing loss v2.125 COCH Eleanor Williams Added comment: Comment on mode of inheritance: Leaving mode of inheritance as Monoallelic only for now, but with recommendation that it should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next GMS review.
Monogenic hearing loss v2.125 COCH Eleanor Williams Mode of inheritance for gene: COCH was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.124 COCH Eleanor Williams edited their review of gene: COCH: Changed publications: 29449721, 31126177, 32562050, 32939038
Monogenic hearing loss v2.124 COCH Eleanor Williams edited their review of gene: COCH: Changed publications: 31126177
Monogenic hearing loss v2.124 COCH Eleanor Williams Publications for gene: COCH were set to PMID: 10400989; 11332404; 11709536; 12928864; 14512963; 16078052; 16261627; 16481359; 18312449; 19161137; 20097680; 22139968; 23684986; 7829101; 8817345; 9441737; 9806553; 9931344
Monogenic hearing loss v2.123 COCH Eleanor Williams Phenotypes for gene: COCH were changed from hearing loss; #601369:Deafness, autosomal dominant 9; Nonsyndromic Hearing Loss, Dominant to Deafness, autosomal recessive 110 OMIM:618094; Deafness, autosomal dominant 9 OMIM:601369; deafness, autosomal recessive 110 MONDO:0054860; autosomal dominant nonsyndromic deafness 9 MONDO:0011058
Monogenic hearing loss v2.122 COCH Eleanor Williams Tag for-review tag was added to gene: COCH.
Monogenic hearing loss v2.122 COCH Eleanor Williams reviewed gene: COCH: Rating: GREEN; Mode of pathogenicity: None; Publications: 29449721, 29449721, 31126177, 32562050; Phenotypes: Deafness, autosomal recessive 110 OMIM:618094, Deafness, autosomal dominant 9 OMIM:601369, deafness, autosomal recessive 110 MONDO:0054860, autosomal dominant nonsyndromic deafness 9 MONDO:0011058; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.122 THOC1 Eleanor Williams Phenotypes for gene: THOC1 were changed from Nonsyndromic hearing loss to Nonsyndromic hearing loss; nonsyndromic genetic deafness MONDO:0019497
Monogenic hearing loss v2.121 THOC1 Eleanor Williams Classified gene: THOC1 as Amber List (moderate evidence)
Monogenic hearing loss v2.121 THOC1 Eleanor Williams Added comment: Comment on list classification: Following review from Zornitza Stark changing the rating of THOC1 from grey to amber as there is one large family plus functional data to support the proposal that a variant in THOC1 is associated with hearing loss.
Monogenic hearing loss v2.121 THOC1 Eleanor Williams Gene: thoc1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.120 LMX1A Eleanor Williams Tag watchlist tag was added to gene: LMX1A.
Tag for-review tag was added to gene: LMX1A.
Monogenic hearing loss v2.120 LMX1A Eleanor Williams Classified gene: LMX1A as Amber List (moderate evidence)
Monogenic hearing loss v2.120 LMX1A Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber but with a recommendation for a green rating following GMS review.
Monogenic hearing loss v2.120 LMX1A Eleanor Williams Gene: lmx1a has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.119 LMX1A Eleanor Williams Added comment: Comment on mode of inheritance: Setting MOI to Monoallelic as only one case of biallelic reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Monogenic hearing loss v2.119 LMX1A Eleanor Williams Mode of inheritance for gene: LMX1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.118 LMX1A Eleanor Williams Phenotypes for gene: LMX1A were changed from to Deafness, autosomal dominant 7 OMIM:601412; autosomal dominant nonsyndromic deafness 7 MONDO:0011074
Monogenic hearing loss v2.117 LMX1A Eleanor Williams Publications for gene: LMX1A were set to
Monogenic hearing loss v2.116 LMX1A Eleanor Williams edited their review of gene: LMX1A: Changed rating: GREEN; Changed publications: 29754270, 29971487, 32840933, 19540218, 18985389; Changed phenotypes: Deafness, autosomal dominant 7 OMIM:601412, autosomal dominant nonsyndromic deafness 7 MONDO:0011074; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.116 LMX1A Eleanor Williams commented on gene: LMX1A
Inherited ovarian cancer (without breast cancer) v2.5 PALB2 marc tischkowitz commented on gene: PALB2: From the key paper (Yang 2020):
Table 3 - 16% risk to age 80 ( 95% CI 8-28%) if 2 first degree relatives affected at age 50, 11% risk to age 80 (95% CI 6-21) if mother and maternal grandmother diagnosed at age 50.

Therefore clinically actionable if there is a strong family history.

This paper and that of Song 2020 supersede previous published studies which are based on many fewer cases.
Monogenic hearing loss v2.116 NARS2 Eleanor Williams changed review comment from: Comment on list classification: Changing the rating from red to amber for NARS2. Only one family with non-syndromic deafness, but several with deafness in conjunction with other clinical features.; to: Comment on list classification: Changing the rating from red to amber for NARS2. Only one family with non-syndromic deafness, but several with deafness in conjunction with other clinical features. This gene should be reviewed at the next major GMS update to decide whether it would be appropriate for the panel as a green gene.
Monogenic hearing loss v2.116 NARS2 Eleanor Williams Tag for-review tag was added to gene: NARS2.
Monogenic hearing loss v2.116 NARS2 Eleanor Williams Classified gene: NARS2 as Amber List (moderate evidence)
Monogenic hearing loss v2.116 NARS2 Eleanor Williams Added comment: Comment on list classification: Changing the rating from red to amber for NARS2. Only one family with non-syndromic deafness, but several with deafness in conjunction with other clinical features.
Monogenic hearing loss v2.116 NARS2 Eleanor Williams Gene: nars2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.115 NARS2 Eleanor Williams commented on gene: NARS2: PMID: 25807530 - Simon et al 2015 - report 2 unrelated families with 3 different variants in NARS2. One family is segregating nonsyndromic hearing loss (DFNB94) and another with Leigh syndrome. In the family with Leigh syndrome two affected children failed the newborn hearing test.

PMID: 28077841 - Mizuguchi et al 2017 - report 4 individuals from 3 families with homozygous or compound het variants in NARS2 found by WES. All had hearing impairment (detected <2 years of age) among other clinical features including seizures and hypotonia.

PMID: 30327238 - Seaver et al 2018 - report two infant brothers who presented with focal status epilepticus that progressed to lethal epileptic encephalopathy. Compound het missense variants found by WES in NARS2. The younger brother failed the newborn hearing screen.

PMID: 25385316 - Vanlander et al 2015 - report 2 siblings born to consanguineous parents in which a homozygous missense mutation (c.822G>C) was found in NARS2). One sibling had mild intellectual disability and epilepsy in childhood, whereas the other had severe myopathy. Hearing loss NOT reported.
Monogenic hearing loss v2.115 NARS2 Eleanor Williams Phenotypes for gene: NARS2 were changed from to Deafness, autosomal recessive 94 OMIM:618434; Combined oxidative phosphorylation deficiency 24 OMIM:616239; deafness, autosomal recessive 94 MONDO:0032749; combined oxidative phosphorylation defect type 24 MONDO:0014547
Monogenic hearing loss v2.114 NARS2 Eleanor Williams Publications for gene: NARS2 were set to 25807530
Skeletal Muscle Channelopathies v1.24 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paroxysmal central nervous system disorders v1.6 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paroxysmal central nervous system disorders v1.5 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Skeletal muscle channelopathy v1.6 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Skeletal muscle channelopathy v1.6 CNBP_CCTG Arina Puzriakova Tag STR tag was added to STR: CNBP_CCTG.
Skeletal muscle channelopathy v1.6 CNBP_CCTG Arina Puzriakova Phenotypes for STR: CNBP_CCTG were changed from Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Skeletal muscle channelopathy v1.6 CNBP_CCTG Arina Puzriakova Phenotypes for STR: CNBP_CCTG were changed from Myotonic dystrophy 2, 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Distal myopathies v1.24 CNBP_CCTG Arina Puzriakova Phenotypes for STR: CNBP_CCTG were changed from Myotonic dystrophy 2 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Skeletal Muscle Channelopathies v1.23 CNBP_CCTG Arina Puzriakova Phenotypes for STR: CNBP_CCTG were changed from Myotonic dystrophy 2 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Skeletal muscle channelopathy v1.5 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonic dystrophy 2, 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Paroxysmal central nervous system disorders v1.5 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonia; MYOTONIC DYSTROPHY 2 (DM2) to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
COVID-19 research v1.70 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Steinert- myotonica dystrophia to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Distal myopathies v1.23 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonic dystrophy 2, 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Skeletal Muscle Channelopathies v1.22 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonia; MYOTONIC DYSTROPHY 2 (DM2) to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Steinert- myotonica dystrophia to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Classified gene: CNBP as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Added comment: Comment on list classification: Hypogammaglobulinemia has been reported in some cases which is relevant to this panel. However, patients are more likely to be recognised for skeletal muscle features of the disease presentation. Furthermore, the review is relevant to the CCTG repeat expansion rather than small variants (i.e. LoF, missense, etc) in this gene and therefore maintaining the Red rating on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Gene: cnbp has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.377 CNBP Arina Puzriakova Publications for gene: CNBP were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.376 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.568 DNMT3A Sarah Leigh Mode of pathogenicity for gene: DNMT3A was changed from None to Other
Intellectual disability v3.568 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from OVERGROWTH SYNDROME WITH INTELLECTUAL DISABILITY to Tatton-Brown-Rahman syndrome OMIM:615879; Heyn-Sproul-Jackson syndrome OMIM:618724; MONDO:0032882
Intellectual disability v3.567 DNMT3A Sarah Leigh Added comment: Comment on mode of pathogenicity: Tatton-Brown-Rahman syndrome 615879 is associated with loss of function variants and Heyn-Sproul-Jackson syndrome OMIM:618724 is associated with gain of function variants.
Intellectual disability v3.567 DNMT3A Sarah Leigh Mode of pathogenicity for gene: DNMT3A was changed from to None
Severe microcephaly v2.47 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from Heyn-Sproul-Jackson syndrome 618724 to Heyn-Sproul-Jackson syndrome OMIM:618724; MONDO:0032882
Severe microcephaly v2.46 DNMT3A Sarah Leigh edited their review of gene: DNMT3A: Added comment: Associated with relevant phenotype (Heyn-Sproul-Jackson syndrome 618724) in OMIM and as probable Gen2Phen gene for Microcephalic primordial dwarfism. At least two gain of function variants reported in three unrelated cases, together with supportive functional studies (pmid 30478443).; Changed rating: GREEN
Severe microcephaly v2.46 DNMT3A Sarah Leigh Tag for-review tag was added to gene: DNMT3A.
Severe microcephaly v2.46 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from intellectual disability; microcephaly; short stature to Heyn-Sproul-Jackson syndrome 618724
Severe microcephaly v2.45 DNMT3A Sarah Leigh Classified gene: DNMT3A as Amber List (moderate evidence)
Severe microcephaly v2.45 DNMT3A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Note gain of function variants associated with this phenotype.
Severe microcephaly v2.45 DNMT3A Sarah Leigh Gene: dnmt3a has been classified as Amber List (Moderate Evidence).
RASopathies v1.74 HRAS Arina Puzriakova Publications for gene: HRAS were set to 16170316; 16969868; 16443854; 21396583
Primary immunodeficiency or monogenic inflammatory bowel disease v2.375 UBA1 Arina Puzriakova Classified gene: UBA1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.375 UBA1 Arina Puzriakova Gene: uba1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.374 UBA1 Arina Puzriakova Classified gene: UBA1 as No list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.374 UBA1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Relevant phenotype but rating Red as this panel is not appropriate for somatic variant detection due to the coverage and therefore variants are unlikely to be picked up by our current pipeline (added 'somatic' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.374 UBA1 Arina Puzriakova Gene: uba1 has been removed from the panel.
Severe microcephaly v2.44 LMNB2 Sarah Leigh edited their review of gene: LMNB2: Added comment: Not associated with a relevant phenotype in OMIM or in Gen2Phen. PMID 33033404 reports five individuals with heterozygous variants in LMNB2. One of these cases was de novo for c.160A>C p.N54H (NM_032737.4) and the remaining cases had c.1192G>A, p.Glu398Lys (NM_032737.4), which was shown to be de novo in two cases, inherited from the unaffected mother (who was mosaic for the variant) and the inheritance in the remaining case was not established. All of these cases had moderate to severe developmental delay and microcephaly.; Changed rating: GREEN
Severe microcephaly v2.44 LMNB2 Sarah Leigh Tag for-review tag was added to gene: LMNB2.
Severe microcephaly v2.44 LMNB2 Sarah Leigh Classified gene: LMNB2 as Amber List (moderate evidence)
Severe microcephaly v2.44 LMNB2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.44 LMNB2 Sarah Leigh Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.566 LMNB2 Sarah Leigh Classified gene: LMNB2 as Amber List (moderate evidence)
Intellectual disability v3.566 LMNB2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.566 LMNB2 Sarah Leigh Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.565 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.225 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: RED; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.373 UBA1 Arina Puzriakova Phenotypes for gene: UBA1 were changed from Autoinflammatory disease, adult onset; VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) to VEXAS syndrome, somatic, OMIM:301054
Primary immunodeficiency or monogenic inflammatory bowel disease v2.372 UBA1 Arina Puzriakova Tag somatic tag was added to gene: UBA1.
Early onset or syndromic epilepsy v2.225 LMNB2 Sarah Leigh Publications for gene: LMNB2 were set to 16826530
Primary immunodeficiency or monogenic inflammatory bowel disease v2.372 SOCS1 Arina Puzriakova Phenotypes for gene: SOCS1 were changed from Common variable immunodeficiency to Common variable immunodeficiency; Early-onset autoimmunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.371 SOCS1 Arina Puzriakova Publications for gene: SOCS1 were set to 32499645; 10490099; 10490100
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Tag for-review tag was added to gene: SOCS1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Classified gene: SOCS1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) - at least 7 unrelated families with immune dysfunction associated with variants in this gene, as well as supportive functional data and animal model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Gene: socs1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 CNBP Boaz Palterer reviewed gene: CNBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 12601109; Phenotypes: myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, cardiac conduction defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 CNBP Boaz Palterer Deleted their review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 CNBP Boaz Palterer reviewed gene: CNBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 12601109/; Phenotypes: myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, cardiac conduction defects.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.565 DDC Arina Puzriakova Publications for gene: DDC were set to 20505134
Childhood onset dystonia, chorea or related movement disorder v1.64 DDC Arina Puzriakova Publications for gene: DDC were set to 27830117; 27604308; 24816252
Childhood onset dystonia, chorea or related movement disorder v1.63 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency, 608643; Dystonia to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Intellectual disability v3.564 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from AROMATIC L-AMINO-ACID DECARBOXYLASE DEFICIENCY to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Adult onset dystonia, chorea or related movement disorder v1.16 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency, 608643; Dystonia to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Early onset or syndromic epilepsy v2.224 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency 608643; floppy child; dystonia; hypotonia; developmental delay; oculogyric crisis to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Likely inborn error of metabolism v2.33 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency 608643 to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Fetal anomalies v1.115 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from AROMATIC L-AMINO-ACID DECARBOXYLASE DEFICIENCY to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Undiagnosed metabolic disorders v1.431 DDC Arina Puzriakova Publications for gene: DDC were set to 27604308; 24816252
Undiagnosed metabolic disorders v1.430 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency 608643 to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Adult onset neurodegenerative disorder v2.33 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Dystonia to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Neurotransmitter disorders v1.6 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency, 608643 to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Neurotransmitter disorders v1.5 DDC Arina Puzriakova Publications for gene: DDC were set to 27604308; 24816252; 27830117
Early onset dystonia v1.85 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Dystonia to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084; Floppy child; Dystonia; Hypotonia; Developmental delay; Oculogyric crisis
Early onset dystonia v1.84 DDC Arina Puzriakova Publications for gene: DDC were set to
Early onset dystonia v1.83 DDC Arina Puzriakova Mode of inheritance for gene: DDC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset dystonia v1.82 DDC Arina Puzriakova Classified gene: DDC as Green List (high evidence)
Early onset dystonia v1.82 DDC Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Green, in line with the review by Lothar Schlueter. Dystonia as a feature of the phenotype, most commonly arising in infancy. DDC is already Green on the GMS 'Childhood onset dystonia or chorea or related movement disorder' version 1.62 panel.
Early onset dystonia v1.82 DDC Arina Puzriakova Gene: ddc has been classified as Green List (High Evidence).
Intellectual disability v3.563 AGAP1 Arina Puzriakova Classified gene: AGAP1 as Amber List (moderate evidence)
Intellectual disability v3.563 AGAP1 Arina Puzriakova Added comment: Comment on list classification: New gene added as Amber. Clinical reports are generally limited and the contribution of secondary variants in other genes in 2 subjects cannot be ruled out. Additional cases necessary to corroborate this gene-disease association.
Intellectual disability v3.563 AGAP1 Arina Puzriakova Gene: agap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.562 AGAP1 Arina Puzriakova reviewed gene: AGAP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31700678, 30472483, 25666757; Phenotypes: Cerebral palsy, Developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.562 MPP5 Arina Puzriakova Classified gene: MPP5 as Amber List (moderate evidence)
Intellectual disability v3.562 MPP5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. ased on the evidence provided in PMID:33073849, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 3 unrelated individuals with de novo variants in the MPP5 gene associated with ID/GDD, language delay/regression and behavioural changes. Supportive animal model.
Intellectual disability v3.562 MPP5 Arina Puzriakova Gene: mpp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.561 MPP5 Arina Puzriakova Tag for-review tag was added to gene: MPP5.
Intellectual disability v3.561 JARID2 Arina Puzriakova Classified gene: JARID2 as Amber List (moderate evidence)
Intellectual disability v3.561 JARID2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag). Multiple unrelated individuals all with DD as the common feature, as well as ID in the majority of cases.
Intellectual disability v3.561 JARID2 Arina Puzriakova Gene: jarid2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.560 JARID2 Arina Puzriakova Phenotypes for gene: JARID2 were changed from Intellectual disability to Intellectual disability; Neurodevelopmental syndrome
Intellectual disability v3.559 JARID2 Arina Puzriakova Tag for-review tag was added to gene: JARID2.
Intellectual disability v3.559 JARID2 Arina Puzriakova reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33077894; Phenotypes: Neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.43 LMNB1 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; to: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).
Early onset or syndromic epilepsy v2.223 LMNB1 Sarah Leigh changed review comment from: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 2 were found in patients (3 from 2 families) who also had epileptic seizures (PMID 32910914; 33033404).; to: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 1 was found in 2 unrelated patients who also had epileptic seizures (PMID 32910914; 33033404).
Intellectual disability v3.559 LMNB1 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; to: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).
Severe microcephaly v2.43 LMNB1 Sarah Leigh edited their review of gene: LMNB1: Added comment: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; Changed rating: GREEN
Severe microcephaly v2.43 LMNB1 Sarah Leigh Tag for-review tag was added to gene: LMNB1.
Severe microcephaly v2.43 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Severe microcephaly v2.43 LMNB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.43 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.42 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 33033404
Severe microcephaly v2.41 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Congenital microcephaly; Global developmental delay; Intellectual disability; LMNB1-associated developmental disorder
Intellectual disability v3.559 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder
Early onset or syndromic epilepsy v2.223 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder
Early onset or syndromic epilepsy v2.222 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 32910914
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 2 were found in patients (3 from 2 families) who also had epileptic seizures (PMID 32910914; 33033404).
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.220 LMNB1 Sarah Leigh Tag watchlist tag was added to gene: LMNB1.
Intellectual disability v3.558 LMNB1 Sarah Leigh edited their review of gene: LMNB1: Added comment: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; Changed rating: GREEN; Changed phenotypes: LMNB1-associated developmental disorder
Intellectual disability v3.558 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Intellectual disability v3.558 LMNB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.558 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.557 LMNB1 Sarah Leigh Tag for-review tag was added to gene: LMNB1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.15 PJA1 Arina Puzriakova Classified gene: PJA1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.15 PJA1 Arina Puzriakova Gene: pja1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Classified gene: PJA1 as Red List (low evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on evidence provided in a single publication (PMID:32530565). Additional case supporting pathogenicity of other PJA1 variants required prior to inclusion on a diagnostic panel.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Gene: pja1 has been classified as Red List (Low Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.13 PJA1 Arina Puzriakova gene: PJA1 was added
gene: PJA1 was added to Craniosynostosis. Sources: Expert list
founder-effect tags were added to gene: PJA1.
Mode of inheritance for gene: PJA1 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: PJA1 were set to 32530565
Phenotypes for gene: PJA1 were set to Trigonocephaly; Intellectual disability
Added comment: Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals from 5 independent families, of which 5 patients were diagnosed with mild trigonocephaly. Some supportive data in a mouse model. Individuals shared a common haplotype, suggestive of founder effect.
Sources: Expert list
Intellectual disability v3.557 PJA1 Arina Puzriakova Classified gene: PJA1 as Amber List (moderate evidence)
Intellectual disability v3.557 PJA1 Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber - 7 individuals reported in PMID:32530565 all with ID, albeit due to a founder variant. Some cases with deletions encompassing this gene reported with mild DD, however contribution of other affected genes cannot be ruled out. Evidence of pathogenicity of other PJA1 variants is required prior to inclusion on a diagnostic panel.
Intellectual disability v3.557 PJA1 Arina Puzriakova Gene: pja1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.556 PJA1 Arina Puzriakova Tag founder-effect tag was added to gene: PJA1.
Intellectual disability v3.556 PJA1 Arina Puzriakova Publications for gene: PJA1 were set to 17941886; 12036302; 11533224
Intellectual disability v3.555 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 32910914
Intellectual disability v3.554 MAPK1 Catherine Snow Tag for-review tag was added to gene: MAPK1.
Intellectual disability v3.554 MAPK1 Catherine Snow Classified gene: MAPK1 as Amber List (moderate evidence)
Intellectual disability v3.554 MAPK1 Catherine Snow Gene: mapk1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.220 FAM50A Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284
Intellectual disability v3.553 MAPK1 Catherine Snow 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: 32721402; Phenotypes: Noonan syndrome 13, OMIM:619087, MONDO:0018997; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Classified gene: FAM50A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:32703943) reporting seizures in 3/6 individuals from 2 families with variants in this gene.
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Gene: fam50a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.553 FAM50A Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284
Intellectual disability v3.552 FAM50A Arina Puzriakova Classified gene: FAM50A as Amber List (moderate evidence)
Intellectual disability v3.552 FAM50A Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the evidence provided in PMID:32703943, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 6 individuals from 5 families, all exhibiting GDD/ID as the common presenting feature.
Intellectual disability v3.552 FAM50A Arina Puzriakova Gene: fam50a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.551 FAM50A Arina Puzriakova Tag for-review tag was added to gene: FAM50A.
Limb disorders v2.18 PRKACB Arina Puzriakova Classified gene: PRKACB as Amber List (moderate evidence)
Limb disorders v2.18 PRKACB Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - 4 unrelated cases, all presenting polydactyly of the hands and/or feet as well as other postaxial anomalies.
Limb disorders v2.18 PRKACB Arina Puzriakova Gene: prkacb has been classified as Amber List (Moderate Evidence).
Limb disorders v2.17 PRKACB Arina Puzriakova gene: PRKACB was added
gene: PRKACB was added to Limb disorders. Sources: Literature
for-review tags were added to gene: PRKACB.
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Review for gene: PRKACB was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACB variants, included postaxial polydactyly of hands (3/4 bilateral, 1/4 unilateral) and feet (3/4 bilateral), clinodactyly (2/4), brachydactyly (1/4) and congenital heart defects (CHD 4/4) namely a common atrium or AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumours. Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe).

WES was carried out in all. 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signalling likely underlies the developmental defects observed in affected individuals.
Sources: Literature
Intellectual disability v3.551 PRKACB Arina Puzriakova Classified gene: PRKACB as Amber List (moderate evidence)
Intellectual disability v3.551 PRKACB Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:33058759) reporting 2/4 unrelated individuals with ID among other features, although this presentation was mild in one of these cases.
Intellectual disability v3.551 PRKACB Arina Puzriakova Gene: prkacb has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.113 MPZL2 Eleanor Williams Tag for-review tag was added to gene: MPZL2.
Monogenic hearing loss v2.113 MPZL2 Eleanor Williams Phenotypes for gene: MPZL2 were changed from Deafness, autosomal recessive 111, MIM#618145 to Deafness, autosomal recessive 111 OMIM:618145; deafness, autosomal recessive 111 MONDO:0029142
Monogenic hearing loss v2.112 MPZL2 Eleanor Williams Publications for gene: MPZL2 were set to 29982980; 29961571
Monogenic hearing loss v2.111 MPZL2 Eleanor Williams Classified gene: MPZL2 as Amber List (moderate evidence)
Monogenic hearing loss v2.111 MPZL2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation of a green rating following GMS review. 15 cases reported, 3 different variants. Mouse model supports role of gene in hearing loss.
Monogenic hearing loss v2.111 MPZL2 Eleanor Williams Gene: mpzl2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.110 MPZL2 Eleanor Williams edited their review of gene: MPZL2: Changed rating: GREEN
Monogenic hearing loss v2.110 MPZL2 Eleanor Williams edited their review of gene: MPZL2: Changed publications: 29982980, 29961571, 32203226
Monogenic hearing loss v2.110 MPZL2 Eleanor Williams reviewed gene: MPZL2: Rating: ; Mode of pathogenicity: None; Publications: 29982980, 29961571; Phenotypes: Deafness, autosomal recessive 111 OMIM:618145, deafness, autosomal recessive 111 MONDO:0029142; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v2.33 NOP10 Moin Saleem gene: NOP10 was added
gene: NOP10 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: NOP10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOP10 were set to 32554502
Phenotypes for gene: NOP10 were set to steroid-resistant 6 nephrotic syndrome; cataracts (prior to steroid treatment); sensorineural deafness; enterocolitis
Penetrance for gene: NOP10 were set to unknown
Review for gene: NOP10 was set to RED
Added comment: 2 affected females in one pedigree
Sources: Literature
Proteinuric renal disease v2.33 DKC1 Moin Saleem gene: DKC1 was added
gene: DKC1 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: DKC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DKC1 were set to 32554502
Phenotypes for gene: DKC1 were set to steroid-resistant 6 nephrotic syndrome; cataracts (prior to steroid treatment); sensorineural deafness; enterocolitis
Penetrance for gene: DKC1 were set to unknown
Review for gene: DKC1 was set to RED
Added comment: six affected males in one pedigree
Sources: Literature
Monogenic hearing loss v2.110 PLS1 Eleanor Williams Tag for-review tag was added to gene: PLS1.
Monogenic hearing loss v2.110 PLS1 Eleanor Williams Phenotypes for gene: PLS1 were changed from Deafness to Deafness, autosomal dominant 76 OMIM:618787; deafness, autosomal dominant 76 MONDO:0032917
Monogenic hearing loss v2.109 PLS1 Eleanor Williams Classified gene: PLS1 as Amber List (moderate evidence)
Monogenic hearing loss v2.109 PLS1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation of green rating at the next GMS review.
Monogenic hearing loss v2.109 PLS1 Eleanor Williams Gene: pls1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.108 PLS1 Eleanor Williams edited their review of gene: PLS1: Changed rating: GREEN
Monogenic hearing loss v2.108 PLS1 Eleanor Williams edited their review of gene: PLS1: Changed publications: 31397523, 31432506, 30872814; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.108 PLS1 Eleanor Williams reviewed gene: PLS1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal dominant 76 OMIM:618787, deafness, autosomal dominant 76 MONDO:0032917; Mode of inheritance: None
Cholestasis v1.74 MPI Ivone Leong Tag for-review tag was added to gene: MPI.
Cholestasis v1.74 LIPA Ivone Leong Tag for-review tag was added to gene: LIPA.
Cholestasis v1.74 HADHA Ivone Leong Tag for-review tag was added to gene: HADHA.
Cholestasis v1.74 TRMU Ivone Leong Tag for-review tag was added to gene: TRMU.
Cholestasis v1.74 SMPD1 Ivone Leong Tag for-review tag was added to gene: SMPD1.
Cholestasis v1.74 POLG Ivone Leong Tag for-review tag was added to gene: POLG.
Cholestasis v1.74 MVK Ivone Leong Tag for-review tag was added to gene: MVK.
Cholestasis v1.74 GBE1 Ivone Leong Tag for-review tag was added to gene: GBE1.
Cholestasis v1.74 CFTR Ivone Leong Tag for-review tag was added to gene: CFTR.
Cholestasis v1.74 ADK Ivone Leong Tag for-review tag was added to gene: ADK.
Cholestasis v1.74 MPI Ivone Leong reviewed gene: MPI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 LIPA Ivone Leong reviewed gene: LIPA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 HADHA Ivone Leong reviewed gene: HADHA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 TRMU Ivone Leong reviewed gene: TRMU: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 SMPD1 Ivone Leong reviewed gene: SMPD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 POLG Ivone Leong reviewed gene: POLG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 MVK Ivone Leong reviewed gene: MVK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 GBE1 Ivone Leong reviewed gene: GBE1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 CFTR Ivone Leong reviewed gene: CFTR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 ADK Ivone Leong reviewed gene: ADK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.73 MPI Ivone Leong gene: MPI was added
gene: MPI was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: MPI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPI were set to 12414827; 10980531; 9585601; 28108845
Phenotypes for gene: MPI were set to Congenital disorder of glycosylation, type Ib, OMIM:602579
Cholestasis v1.73 LIPA Ivone Leong gene: LIPA was added
gene: LIPA was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: LIPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIPA were set to 8254026; 29702543; 8617513; 7759067; 8598644; 26137452; 29731497; 23485521
Phenotypes for gene: LIPA were set to lysosomal acid lipase deficiency; Wolman disease, OMIM:278000, MONDO:0019148; Cholesteryl ester storage disease, OMIM:278000, MONDO:0019149; Neonatal and Adult Cholestasis; cholestasis
Cholestasis v1.73 HADHA Ivone Leong gene: HADHA was added
gene: HADHA was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: HADHA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HADHA were set to 10518281; 9003853
Phenotypes for gene: HADHA were set to LCHAD deficiency, OMIM:609016, MONDO:0012173
Cholestasis v1.73 TRMU Ivone Leong gene: TRMU was added
gene: TRMU was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: TRMU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMU were set to 21153446; 21931168; 19732863; 23625533
Phenotypes for gene: TRMU were set to Liver failure, transient infantile, OMIM:613070
Cholestasis v1.73 SMPD1 Ivone Leong gene: SMPD1 was added
gene: SMPD1 was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: SMPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SMPD1 were set to Niemann-Pick disease, type A, OMIM:257200, MONDO:0009756
Cholestasis v1.73 POLG Ivone Leong gene: POLG was added
gene: POLG was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: POLG was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: POLG were set to Mitochondrial DNA depletion syndrome 4A (Alpers type), OMIM:203700, MONDO:0008758
Cholestasis v1.73 MVK Ivone Leong gene: MVK was added
gene: MVK was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: MVK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MVK were set to Mevalonic aciduria, OMIM:610377, MONDO:0012481
Cholestasis v1.73 GBE1 Ivone Leong gene: GBE1 was added
gene: GBE1 was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: GBE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBE1 were set to 8613547
Phenotypes for gene: GBE1 were set to Glycogen storage disease IV, OMIM:232500
Cholestasis v1.73 CFTR Ivone Leong gene: CFTR was added
gene: CFTR was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: CFTR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFTR were set to 21194565; 27806795; 22798282; 9934970
Phenotypes for gene: CFTR were set to Cholestasis; Neonatal and Adult Cholestasis; Cystic fibrosis, OMIM:219700, MONDO:0009061; {Pancreatitis, hereditary}, OMIM:167800
Cholestasis v1.73 ADK Ivone Leong gene: ADK was added
gene: ADK was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: ADK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADK were set to 21963049; 27500280; 26642971
Phenotypes for gene: ADK were set to Hypermethioninemia due to adenosine kinase deficiency, OMIM:614300, MONDO:0013676
Inherited non-medullary thyroid cancer v1.4 VTRNA2-1 Sarah Leigh Tag locus-type-rna-vault tag was added to gene: VTRNA2-1.
White matter disorders and cerebral calcification - narrow panel v1.26 STN1 Sarah Leigh edited their review of gene: STN1: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in three unrelated cases, together with a supportive zebrafish model and other functional studies.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.26 STN1 Sarah Leigh Tag for-review tag was added to gene: STN1.
Early onset or syndromic epilepsy v2.218 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, 618548 as the name for this phenotype (12/11/2020).
Early onset or syndromic epilepsy v2.218 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile, 77, 618548; Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome to Multiple congenital anomalies-hypotonia-seizures syndrome-4, OMIM:618548
White matter disorders and cerebral calcification - narrow panel v1.26 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.26 STN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - narrow panel v1.26 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.25 STN1 Sarah Leigh Phenotypes for gene: STN1 were changed from Cerebroretinal microangiopathy with calcifications and cysts 2, MIM# 617341 to Cerebroretinal microangiopathy with calcifications and cysts 2, OMIM:617341
Intellectual disability v3.550 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, OMIM:618548 as the name for this phenotype (12/11/2020).
Intellectual disability v3.550 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile 77, OMIM:618548 to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
DDG2P v2.12 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, 618548 as the name for this phenotype (12/11/2020).
DDG2P v2.12 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
Intellectual disability v3.549 NARS Sarah Leigh Tag new-gene-name tag was added to gene: NARS.
Intellectual disability v3.549 PIGQ Sarah Leigh edited their review of gene: PIGQ: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for severe early onset epilepsy. At least 11 variants reported in seven unrelated cases of multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4)(Epileptic encephalopathy, early infantile, 77 618548)(OMIM:618548).; Changed rating: GREEN; Changed phenotypes: OMIM:618548; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.549 PIGQ Sarah Leigh Classified gene: PIGQ as Amber List (moderate evidence)
Intellectual disability v3.549 PIGQ Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.549 PIGQ Sarah Leigh Gene: pigq has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.548 PIGQ Sarah Leigh Tag for-review tag was added to gene: PIGQ.
Possible mitochondrial disorder - nuclear genes v1.21 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Mitochondrial disorders v2.12 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Likely inborn error of metabolism v2.32 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to 27604308
Mitochondrial disorder with complex IV deficiency v1.6 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Fetal anomalies v1.114 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Paediatric or syndromic cardiomyopathy v1.12 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Likely inborn error of metabolism v2.31 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex IV deficiency; Cytochrome c oxidase deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Paediatric or syndromic cardiomyopathy v1.11 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Fetal anomalies v1.113 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051