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08 Sep 2025	Intellectual disability v9.72	PPOX	Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 37879139,40114189, 33159949, 35164799, 9811936, 8290408, 2004012, 6143163; Phenotypes: 620483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
08 Sep 2025	Intellectual disability v9.72	EXOSC8	Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
08 Sep 2025	Intellectual disability v9.71	EXOSC8	Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
08 Sep 2025	Hereditary neuropathy v1.500	PPOX	Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP). PMID: 38940544 Aarsand reports that variegate porphyria (VP) is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low. PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical. PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy. PMID:11286631 Kauppinen reports a patient who following birth presented with severe bullous skin disease followed by increased fragility and keloid-like scarring. His fingers were shortened. Mental status, EEG, and CT of the head were normal, but sensory polyneuropathy was shown in especially in the upper extremities. Fine motor coordination disturbances were accompanied by minor verbal and visuospatial deficiencies. DNA from the patient showed that he is compound heterozygous for PPOX: c.35T>C, p.(Ile12Thr) and c.767C>G, p.(Pro256Arg). PMID:10870850 Corrigall reports a 10-month-old child with fragile skin with blisters, scars, and milia most marked in sun-exposed areas. She had brachydactyly, photo-onycholysis, myopia, nystagmus, a sensory neuropathy and problems with concentration. She never had a typical acute attack. Genetic analysis showed that this patient was compound heterozygous for PPOX c.175C>T, p.(Arg59Trp) and c.1043A>G, p.(Tyr348Cys). PMID: 8290408 Hift reports child who within days of birth developed severe blistering of the face and hands. She had brachydactyly, severe myopia and a pendular nystagmus. Neurological development was delayed with normal intelligence. She had gross sensory neuropathy of the hands and feet but no acute attacks. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP). PMID: 38940544 Aarsand reports that variegate porphyria (VP) is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low. PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical. PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy, as reported by the previous reviewer. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
08 Sep 2025	Hereditary neuropathy v1.500	PPOX	Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 35584894, 37879139, 11286631, 10870850, 8290408; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
08 Sep 2025	Possible mitochondrial disorder - nuclear genes v4.8	PPOX	Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 33159949, 38940544, 10486317, 8290408, 37879139, 40114189; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
08 Sep 2025	Intellectual disability v9.70	EXOSC8	Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, MIM#616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
08 Sep 2025	Hereditary ataxia with onset in adulthood v8.8	EXOSC8	Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia type 1C to Pontocerebellar hypoplasia, type 1C, OMIM:616081
08 Sep 2025	Cerebellar hypoplasia v1.75	EXOSC8	Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia,type 1C, 616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
08 Sep 2025	Ataxia and cerebellar anomalies - narrow panel v8.18	EXOSC8	Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia,type 1C, 616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
08 Sep 2025	Fetal anomalies v6.47	EXOSC8	Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081; Pontocerebellar hypoplasia type 1C to Pontocerebellar hypoplasia, type 1C, OMIM:616081
08 Sep 2025	Fetal anomalies v6.46	EXOSC8	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EXOSC8. Tag Q3_25_NHS_review tag was added to gene: EXOSC8.
08 Sep 2025	Fetal anomalies v6.46	EXOC6B	Arina Puzriakova Phenotypes for gene: EXOC6B were changed from Spondyloepimetaphyseal dysplasia with joint laxity, type 3 to Spondyloepimetaphyseal dysplasia with joint laxity, type 3, OMIM:618395
08 Sep 2025	Fetal anomalies v6.45	EXOC6B	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EXOC6B. Tag Q3_25_NHS_review tag was added to gene: EXOC6B.
08 Sep 2025	Fetal anomalies v6.45	EFL1	Arina Puzriakova Phenotypes for gene: EFL1 were changed from Shwachman-Diamond syndrome 2 to Shwachman-Diamond syndrome 2, OMIM:617941
08 Sep 2025	Fetal anomalies v6.44	EFL1	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EFL1. Tag Q3_25_NHS_review tag was added to gene: EFL1.
08 Sep 2025	Intellectual disability v9.69	EEFSEC	Arina Puzriakova Phenotypes for gene: EEFSEC were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
08 Sep 2025	Fetal anomalies v6.44	EEFSEC	Arina Puzriakova Phenotypes for gene: EEFSEC were changed from Neurodevelopmental disorder with progressive spasticity and brain abnormalities to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
08 Sep 2025	Early onset or syndromic epilepsy v8.26	EEFSEC	Arina Puzriakova Phenotypes for gene: EEFSEC were changed from neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027 to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
08 Sep 2025	Ataxia and cerebellar anomalies - narrow panel v8.17	EEFSEC	Arina Puzriakova Phenotypes for gene: EEFSEC were changed from neurodevelopmental disorder, MONDO:0700092; hereditary cerebellar ataxia, MONDO:0100310 to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
08 Sep 2025	Fetal anomalies v6.43	EEFSEC	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EEFSEC. Tag Q3_25_NHS_review tag was added to gene: EEFSEC.
08 Sep 2025	Fetal anomalies v6.43	DST	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DST. Tag Q3_25_NHS_review tag was added to gene: DST.
08 Sep 2025	Fetal anomalies v6.43	DSE	Arina Puzriakova Phenotypes for gene: DSE were changed from Ehlers-Danlos syndrome, musculocontractural type 2 to Ehlers-Danlos syndrome, musculocontractural type 2, OMIM:615539
08 Sep 2025	Undiagnosed metabolic disorders v1.631	PPOX	Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen and plasma porphyrin fluorescence emission PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood. PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks. PMID: 8290408 Hift reports that the cutaneous VP presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma porphyrin fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence emission) as the penetrance of variegate porphyria is so low PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen and plasma porphyrin fluorescence emission PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood. PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks. PMID: 8290408 Hift reports that the cutaneous VP presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma porphyrin fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence emission) as the penetrance of VP is so low PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
08 Sep 2025	Fetal anomalies v6.42	DSE	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DSE. Tag Q3_25_NHS_review tag was added to gene: DSE.
08 Sep 2025	Fetal anomalies v6.42	DHX9	Arina Puzriakova Phenotypes for gene: DHX9 were changed from Intellectual developmental disorder, autosomal dominant 75 to Intellectual developmental disorder, autosomal dominant 75, OMIM:620988
08 Sep 2025	Fetal anomalies v6.41	DHX9	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DHX9. Tag Q3_25_NHS_review tag was added to gene: DHX9.
08 Sep 2025	Undiagnosed metabolic disorders v1.631	PPOX	Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 10486317, 8290408, 38940544, 37879139, 40114189, 33159949; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
08 Sep 2025	Fetal anomalies v6.41	DHRSX	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DHRSX. Tag Q3_25_NHS_review tag was added to gene: DHRSX.
08 Sep 2025	Fetal anomalies v6.41	COQ2	Arina Puzriakova Phenotypes for gene: COQ2 were changed from COENZYME Q10 DEFICIENCY; Coenzyme Q10 deficiency, primary, 1 to Coenzyme Q10 deficiency, primary, 1, OMIM:607426
08 Sep 2025	Fetal anomalies v6.40	COQ2	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: COQ2. Tag Q3_25_NHS_review tag was added to gene: COQ2.
08 Sep 2025	Skeletal dysplasia v8.8	COMP	Arina Puzriakova Phenotypes for gene: COMP were changed from Epiphyseal dysplasia, multiple, 1 132400; Pseudoachondroplasia 177170 to Epiphyseal dysplasia, multiple, 1, OMIM:132400; Pseudoachondroplasia, OMIM:177170
08 Sep 2025	Fetal anomalies v6.40	COMP	Arina Puzriakova Phenotypes for gene: COMP were changed from Pseudoachondroplasia; MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 1; Epiphyseal dysplasia, multiple, 1; ARE THE CAUSE OF PSEUDOACHONDROPLASIA to Epiphyseal dysplasia, multiple, 1, OMIM:132400; Pseudoachondroplasia, OMIM:177170
08 Sep 2025	Fetal anomalies v6.39	COMP	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: COMP. Tag Q3_25_NHS_review tag was added to gene: COMP.
08 Sep 2025	Fetal anomalies v6.39	COL25A1	Arina Puzriakova Phenotypes for gene: COL25A1 were changed from Arthrogryposis multiplex congenita, MONDO:0015168; Arthrogryposis multiplex congenita to Arthrogryposis multiplex congenita, MONDO:0015168
08 Sep 2025	Ehlers Danlos syndrome with a likely monogenic cause v4.2	FLNA	Neeti Ghali edited their review of gene: FLNA: Added comment: Currently on R125 panel as well as other panels but I would argue that there is a connective tissue phenotype for a number of patients with missense variants in FLNA. A patient recently had R101 for connective tissue features, but went on to have R125 because of valvular disease and a FLNA pathogenic variant was identified. This is reasonable given the function of the protein Filamin A. Therefore, it would be beneficial for it to also be on R101 panel; Changed publications to: 34863227, 30089473, 40883083, 23032111; Changed phenotypes to: connective tissue phenotype eg. hypermobility, skin hyperextensibility, perforated ear drum, retinal detachment, arterial fragility, aortic dilatation, arterial tortuosity, valvular disease, PVL, lung
08 Sep 2025	Fetal anomalies v6.38	COL25A1	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: COL25A1. Tag Q3_25_NHS_review tag was added to gene: COL25A1.
08 Sep 2025	Fetal anomalies v6.38	C1orf127	Arina Puzriakova Phenotypes for gene: C1orf127 were changed from Heterotaxy, visceral, 14, autosomal; Heterotaxy, visceral, 14, autosomal, OMIM:621080 to Heterotaxy, visceral, 14, autosomal, OMIM:621080
08 Sep 2025	Fetal anomalies v6.37	CELSR1	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: CELSR1. Tag Q3_25_NHS_review tag was added to gene: CELSR1.
08 Sep 2025	Fetal anomalies v6.37	CELSR1	Arina Puzriakova Phenotypes for gene: CELSR1 were changed from Lymphatic malformation 9, OMIM:619319; Lymphatic malformation-9 to Lymphatic malformation 9, OMIM:619319
08 Sep 2025	Variegate porphyria v1.1	PPOX	Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyria attack), plasma porphyrin fluorescence emission (cutaneous symptoms) PMID: 35584894 Schulenburg-Brand reports that patients with variegate porphyria (VP) may develop acute attacks often characterised by abdominal pain, nausea, vomiting and other neurological symptoms. They may also present with photosensitive skin lesions. Affected skin is excessively fragile, leading to blisters, milia, and scarring. PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks. PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (when in acute attacks urine porphobilinogen, followed by analysis of plasma fluorescence emission and when cutaneous symptoms alone, plasma porphyrin fluorescence emission s) as the penetrance of variegate porphyria is so low. Genetic testing of the PPOX gene should only be used for family testing so that the genetically predisposed individuals can be advised against precipitating factors such as alcohol and certain drugs. PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyria attack), plasma porphyrin fluorescence emission (cutaneous symptoms) PMID: 35584894 Schulenburg-Brand reports that patients with variegate porphyria (VP) may develop acute attacks often characterised by abdominal pain, nausea, vomiting and other neurological symptoms. They may also present with photosensitive skin lesions. Affected skin is excessively fragile, leading to blisters, milia, and scarring. PMID: 10486317 Whatley found that skin lesions were the only manifestation of VP in 59% of patients whereas 21% of patients had acute attacks and skin lesions. The remainder having only acute attacks. PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma porphyrin fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence emission) as the penetrance of variegate porphyria is so low. Genetic testing of the PPOX gene should only be used for family testing so that the genetically predisposed individuals can be advised against precipitating factors such as alcohol and certain drugs. PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
08 Sep 2025	Hereditary ataxia with onset in adulthood v8.7	CDK5	Arina Puzriakova Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, 616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
08 Sep 2025	Cerebellar hypoplasia v1.74	CDK5	Arina Puzriakova Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia 616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
08 Sep 2025	Ataxia and cerebellar anomalies - narrow panel v8.16	CDK5	Arina Puzriakova Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia 616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
08 Sep 2025	Fetal anomalies v6.36	CDK5	Arina Puzriakova Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
08 Sep 2025	Fetal anomalies v6.35	CDK5	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: CDK5. Tag Q3_25_NHS_review tag was added to gene: CDK5.
08 Sep 2025	Fetal anomalies v6.35	CTGF	Arina Puzriakova Phenotypes for gene: CTGF were changed from Kyphomelic dysplasia to kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
08 Sep 2025	Fetal anomalies v6.34	CTGF	Arina Puzriakova Tag new-gene-name tag was added to gene: CTGF. Tag Q3_25_promote_green tag was added to gene: CTGF. Tag Q3_25_NHS_review tag was added to gene: CTGF.
08 Sep 2025	Fetal anomalies v6.34	BHLHE22	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: BHLHE22. Tag Q3_25_NHS_review tag was added to gene: BHLHE22.
08 Sep 2025	Fetal anomalies v6.34	ARL6IP1	Arina Puzriakova Tag Q3_24_NHS_review tag was added to gene: ARL6IP1. Tag Q3_25_promote_green tag was added to gene: ARL6IP1.
08 Sep 2025	Vascular skin disorders v2.1	PPOX	Sharon Whatley reviewed gene: PPOX: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
08 Sep 2025	Cutaneous photosensitivity with a likely genetic cause v3.9	PPOX	Sharon Whatley changed review comment from: Relevant metabolic investigation: plasma porphyrin fluorescence emission PMID: 10486317 Whatley reports that vVariegate porphyria (VP) is usually classified as an acute porphyria but in 59% of cases skin lesions may be the only manifestation. PMID: 8290408 Hift reports that tThe cutaneous disease presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes. PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using a biochemical test for plasma porphyrin fluorescence emission as the penetrance is so low. PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (21 families) reported with homozygous VP (PMID: 40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: plasma porphyrin fluorescence emission PMID: 10486317 Whatley reports that variegate porphyria (VP) is usually classified as an acute porphyria but in 59% of cases skin lesions may be the only manifestation. PMID: 8290408 Hift reports that the cutaneous disease presents with photosensitivity which may result in blistering, erosions, a fragile skin with chronic scarring and pigmentary changes. PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using a biochemical test for plasma porphyrin fluorescence emission as the penetrance is so low. PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (21 families) reported with homozygous VP (PMID: 40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
08 Sep 2025	Cutaneous photosensitivity with a likely genetic cause v3.9	PPOX	Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 8290408, 38940544, 37879139, 40114189, 33159949; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
08 Sep 2025	Variegate porphyria v1.1	PPOX	Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 35584894, 10486317, 38940544, 37879139; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
08 Sep 2025	Non-acute porphyrias v1.26	PPOX	Sharon Whatley commented on gene: PPOX: Relevant metabolic investigation: plasma porphyrin fluorescence emission PMID: 10486317 Whatley reports that variegate porphyria (VP) is usually classified as an acute porphyria but in 59% of cases skin lesions may be the only manifestation. PMID: 38940544 Aarsand reports that VP is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed based on biochemical testing including analysis of plasma porphyrin fluorescence emission as the clinical penetrance is so low. PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (21 families) reported with homozygous VP (PMID: 40114189 Kaiser, 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. In some cases, patients may have hand deformities, nystagmus, growth delay and intellectual disability. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
08 Sep 2025	Non-acute porphyrias v1.26	PPOX	Sharon Whatley Deleted their comment
08 Sep 2025	Non-acute porphyrias v1.26	PPOX	Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 35584894, 10486317, 38940544, 37879139; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
07 Sep 2025	Paediatric or syndromic cardiomyopathy v7.86	PKD2	Achchuthan Shanmugasundram Classified gene: PKD2 as Amber List (moderate evidence)
07 Sep 2025	Paediatric or syndromic cardiomyopathy v7.86	PKD2	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are patients from five unrelated families reported with five different heterozygous PKD2 variants and with cardiomyopathy. Of these, four families were from APKD2 database at Mayo Clinic and one was from the UK 100,000 genomes cohort. There is also functional evidence available from zebrafish and mice model. Hence, this gene can be promoted to green rating in the next GMS update.
07 Sep 2025	Paediatric or syndromic cardiomyopathy v7.86	PKD2	Achchuthan Shanmugasundram Gene: pkd2 has been classified as Amber List (Moderate Evidence).
07 Sep 2025	Paediatric or syndromic cardiomyopathy v7.85	PKD2	Achchuthan Shanmugasundram changed review comment from: Autosomal dominant variants in PKD2 gene are associated with Polycystic kidney disease 2 (MIM #613095, OMIM phenotype accessed on 07 September 2025). Reports on human patients: PMID:23376035 (2014) examined ADPKD database at Mayo clinic with 2,620 ADPKD patients seen between 1984 and 2010, where 374 patients were genotyped and 67 of them were identified with PKD2 variants. Of these 67, six patients from four different families had a diagnosis of idiopathic dilated cardiomyopathy (IDCM). The identified variants were p.Arg361Ter, p.Arg807Ter, c.423_430del8 and c.1095-5A>G. PMID:29270497 (2017) reported 3,885 ADPKD patients seen in the period between 1984 and 2015 in the same database as PMID:23376035, of which seven patients from four families had the same PKD2 variants. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with hypertrophic cardiomyopathy was identified with a heterozygous stop-gain variant in PKD2 gene via analysis of data from singleton genome sequencing. Functional studies: PMID:23376035 (2014) studied Pkd2 mutant zebrafish, which showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants. PMID:27081851 (2016) reported that 9-month-old Pkd2+/- mice showed several anatomical features consistent with a dilated cardiac phenotype. However, Pkd2+/- 5-month-old mice did not present with a cardiac phenotype that paralleled either dilated cardiomyopathy or left ventricular hypertrophy, suggesting that PKD2 caused late-onset progressive cardiomyopathy. Sources: Literature; to: Autosomal dominant variants in PKD2 gene are associated with Polycystic kidney disease 2 (MIM #613095, OMIM phenotype accessed on 07 September 2025). Reports on human patients: PMID:23376035 (2014) examined ADPKD database at Mayo clinic with 2,620 ADPKD patients seen between 1984 and 2010, where 374 patients were genotyped and 67 of them were identified with PKD2 variants. Of these 67, six patients from four different families had a diagnosis of idiopathic dilated cardiomyopathy (IDCM). The identified variants were p.Arg361Ter, p.Arg807Ter, c.423_430del8 and c.1095-5A>G. PMID:29270497 (2017) reported 3,885 ADPKD patients seen in the period between 1984 and 2015 in the same database as PMID:23376035, of which seven patients from four families had the same PKD2 variants. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with hypertrophic cardiomyopathy was identified with a heterozygous stop-gain variant in PKD2 gene (p.Arg213Ter) via analysis of data from singleton genome sequencing. Functional studies: PMID:23376035 (2014) studied Pkd2 mutant zebrafish, which showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants. PMID:27081851 (2016) reported that 9-month-old Pkd2+/- mice showed several anatomical features consistent with a dilated cardiac phenotype. However, Pkd2+/- 5-month-old mice did not present with a cardiac phenotype that paralleled either dilated cardiomyopathy or left ventricular hypertrophy, suggesting that PKD2 caused late-onset progressive cardiomyopathy. Sources: Literature
07 Sep 2025	Paediatric or syndromic cardiomyopathy v7.85	PKD2	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PKD2.
07 Sep 2025	Paediatric or syndromic cardiomyopathy v7.85	PKD2	Achchuthan Shanmugasundram gene: PKD2 was added gene: PKD2 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: PKD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PKD2 were set to 23376035; 27081851; 29270497; 39472908 Phenotypes for gene: PKD2 were set to Polycystic kidney disease 2, OMIM:613095; polycystic kidney disease 2, MONDO:0013131; dilated cardiomyopathy, MONDO:0005021 Review for gene: PKD2 was set to GREEN Added comment: Autosomal dominant variants in PKD2 gene are associated with Polycystic kidney disease 2 (MIM #613095, OMIM phenotype accessed on 07 September 2025). Reports on human patients: PMID:23376035 (2014) examined ADPKD database at Mayo clinic with 2,620 ADPKD patients seen between 1984 and 2010, where 374 patients were genotyped and 67 of them were identified with PKD2 variants. Of these 67, six patients from four different families had a diagnosis of idiopathic dilated cardiomyopathy (IDCM). The identified variants were p.Arg361Ter, p.Arg807Ter, c.423_430del8 and c.1095-5A>G. PMID:29270497 (2017) reported 3,885 ADPKD patients seen in the period between 1984 and 2015 in the same database as PMID:23376035, of which seven patients from four families had the same PKD2 variants. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with hypertrophic cardiomyopathy was identified with a heterozygous stop-gain variant in PKD2 gene via analysis of data from singleton genome sequencing. Functional studies: PMID:23376035 (2014) studied Pkd2 mutant zebrafish, which showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants. PMID:27081851 (2016) reported that 9-month-old Pkd2+/- mice showed several anatomical features consistent with a dilated cardiac phenotype. However, Pkd2+/- 5-month-old mice did not present with a cardiac phenotype that paralleled either dilated cardiomyopathy or left ventricular hypertrophy, suggesting that PKD2 caused late-onset progressive cardiomyopathy. Sources: Literature
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.84	SELENON	Achchuthan Shanmugasundram Classified gene: SELENON as Red List (low evidence)
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.84	SELENON	Achchuthan Shanmugasundram Added comment: Comment on list classification: Biallelic SELENON variants cause an early-onset congenital muscular dystrophy characterised by spinal rigidity and respiratory failure, with no significant cardiomyopathy reported. Any observed cardiac abnormalities are secondary to respiratory failure in most of the reported cases. Hence, this gene should be rated red with the current evidence.
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.84	SELENON	Achchuthan Shanmugasundram Gene: selenon has been classified as Red List (Low Evidence).
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.83	SELENON	Achchuthan Shanmugasundram Publications for gene: SELENON were set to 35868898
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.82	SELENON	Achchuthan Shanmugasundram edited their review of gene: SELENON: Changed publications to: 35868898, 39472908
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.82	SELENON	Achchuthan Shanmugasundram Phenotypes for gene: SELENON were changed from to Congenital myopathy 3 with rigid spine, OMIM:602771; rigid spine muscular dystrophy 1, MONDO:0011271
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.81	SELENON	Achchuthan Shanmugasundram changed review comment from: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing. Sources: Literature; to: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing. This gene has been associated with Congenital myopathy 3 with rigid spine in OMIM (MIM #602771, OMIM accessed on 06 September 2025) and with SELENON-related myopathy in Gene2Phenotype (with 'definitive' rating). Sources: Literature
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.81	SELENON	Achchuthan Shanmugasundram edited their review of gene: SELENON: Changed phenotypes to: Congenital myopathy 3 with rigid spine, OMIM:602771, rigid spine muscular dystrophy 1, MONDO:0011271
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.81	SELENON	Achchuthan Shanmugasundram gene: SELENON was added gene: SELENON was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: SELENON was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SELENON were set to 35868898 Review for gene: SELENON was set to RED Added comment: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing. Sources: Literature
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.80	ADSSL1	Achchuthan Shanmugasundram Classified gene: ADSSL1 as Amber List (moderate evidence)
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.80	ADSSL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: Hypertrophic cardiomyopathy has been reported in a significant proportion of patients with biallelic ADSSL1 variants - 12 patients (25%) in PMID:32646962 and two additional unrelated families. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.80	ADSSL1	Achchuthan Shanmugasundram Gene: adssl1 has been classified as Amber List (Moderate Evidence).
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.79	ADSSL1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ADSSL1.
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.79	ADSSL1	Achchuthan Shanmugasundram commented on gene: ADSSL1: The 'new-gene-name' tag has been added as the official HGNC gene symbol of ADSSL1 is ADSS1.
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.79	ADSSL1	Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: ADSSL1.
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.79	ADSSL1	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 06 September 2025.
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.79	ADSSL1	Achchuthan Shanmugasundram Phenotypes for gene: ADSSL1 were changed from Myopathy, distal, 5, OMIM:617030; myopathy, distal, 5, MONDO:0014877; hypertrophic cardiomyopathy, MONDO:0005045 to Myopathy, distal, 5, OMIM:617030; myopathy, distal, 5, MONDO:0014877; hypertrophic cardiomyopathy, MONDO:0005045
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.78	ADSSL1	Achchuthan Shanmugasundram gene: ADSSL1 was added gene: ADSSL1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: ADSSL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADSSL1 were set to 32646962; 39472908; 40302423 Phenotypes for gene: ADSSL1 were set to Myopathy, distal, 5, OMIM:617030; myopathy, distal, 5, MONDO:0014877; hypertrophic cardiomyopathy, MONDO:0005045 Review for gene: ADSSL1 was set to GREEN Added comment: PMID:32646962 (2020) reported the identification of 63 patients from 59 families with biallelic variants of ADSSL1. Seven distinct variants were identified in total, of which c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other five were novel. Most of the reported patients presented with variable myopathy with distal and proximal limb muscle weakness (often childhood onset of exercise intolerance) and facial and bulbar involvement were common in them. Left ventricular hypertrophy (LVH) was noted in 12 (25.0%) of 48 patients on EKG or echocardiography. ADSSL1 variants in nine of these patients were identified by WES and 3 were identified by Sanger sequencing. Patient 12 developed progressive heart failure with LVH before the onset of apparent muscle weakness at age 20, and he died due to multiple organ failure at age 25. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Asp261Asn) in ADSSL1 gene via analysis of data from trio genome sequencing. PMID:40302423 (2025) reported the identification of compound heterozygous pathogenic variants (c.781G>A/c.919delA) in ADSSL1 gene in two siblings with ADSSL1-myopathy. LVH was observed in both siblings and pathologically confirmed in the case where autopsy was done. Sources: Literature
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.77	GLA	Achchuthan Shanmugasundram Classified gene: GLA as Amber List (moderate evidence)
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.77	GLA	Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of GLA variants with hypertrophic cardiomyopathy as part of the Fabry disease phenotype, this gene can be promoted to green rating in the next GMS update.
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.77	GLA	Achchuthan Shanmugasundram Gene: gla has been classified as Amber List (Moderate Evidence).
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.76	GLA	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: GLA.
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.76	GLA	Achchuthan Shanmugasundram Phenotypes for gene: GLA were changed from Fabry disease, 301500; HCM is a late complication in adults, also found in female carriers; Limb pain, angiokeratom; syndromic HCM; Fabry disease, cardiac variant, 301500; Fabry disease (Sphingolipidoses); Fabry Disease; Fabry disease; HCM to Fabry disease, OMIM:301500; Fabry disease, cardiac variant, OMIM:301500; Fabry disease, MONDO:0010526
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.75	GLA	Achchuthan Shanmugasundram Publications for gene: GLA were set to 27604308
06 Sep 2025	Paediatric or syndromic cardiomyopathy v7.74	GLA	Achchuthan Shanmugasundram reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 39472908, 39620496, 39995634; Phenotypes: Fabry disease, OMIM:301500, Fabry disease, cardiac variant, OMIM:301500, Fabry disease, MONDO:0010526; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
05 Sep 2025	Fetal anomalies v6.34	ARL2BP	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ARL2BP. Tag Q3_25_NHS_review tag was added to gene: ARL2BP.
05 Sep 2025	Fetal anomalies v6.34	ARL2BP	Arina Puzriakova Phenotypes for gene: ARL2BP were changed from Situs Inversus to Retinitis pigmentosa 82 with or without situs inversus, OMIM:615434; Situs Inversus
05 Sep 2025	Fetal anomalies v6.33	AGT	Arina Puzriakova Phenotypes for gene: AGT were changed from Renal tubular dysgenesis, OMIM:267430; Renal tubular dysgenesis to Renal tubular dysgenesis, OMIM:267430
05 Sep 2025	Fetal anomalies v6.32	AGT	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: AGT. Tag Q3_25_NHS_review tag was added to gene: AGT.
05 Sep 2025	Fetal anomalies v6.32	AGRN	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: AGRN. Tag Q3_25_NHS_review tag was added to gene: AGRN.
05 Sep 2025	Fetal anomalies v6.32	AGRN	Arina Puzriakova Phenotypes for gene: AGRN were changed from Fetal akinesia deformation sequence, MONDO:0008824; Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects to Fetal akinesia deformation sequence, MONDO:0008824; Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects, OMIM:615120
05 Sep 2025	Fetal anomalies v6.31	NODAL	Arina Puzriakova Phenotypes for gene: NODAL were changed from Heterotaxy, visceral, 5; HETEROTAXY SYNDROME to Heterotaxy, visceral, 5, OMIM:270100
05 Sep 2025	Fetal anomalies v6.30	NODAL	Arina Puzriakova Tag Q3_25_NHS_review tag was added to gene: NODAL. Tag Q3_25_demote_red tag was added to gene: NODAL.
05 Sep 2025	Fetal anomalies v6.30	MYH9	Arina Puzriakova Phenotypes for gene: MYH9 were changed from DEAFNESS AUTOSOMAL DOMINANT TYPE 17; MAY-HEGGLIN ANOMALY; SEBASTIAN SYNDROME; FECHTNER SYNDROME; EPSTEIN SYNDROME; Deafness, autosomal dominant 17; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss; MACROTHROMBOCYTOPENIA WITH PROGRESSIVE SENSORINEURAL DEAFNESS to Deafness, autosomal dominant 17; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
05 Sep 2025	Fetal anomalies v6.29	MYH9	Arina Puzriakova Tag Q3_25_NHS_review tag was added to gene: MYH9. Tag Q3_25_demote_red tag was added to gene: MYH9.
05 Sep 2025	Fetal anomalies v6.29	GNS	Arina Puzriakova Tag Q3_25_NHS_review tag was added to gene: GNS. Tag Q3_25_demote_amber tag was added to gene: GNS.
05 Sep 2025	Fetal anomalies v6.29	CDH11	Arina Puzriakova reviewed gene: CDH11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	FAAP100	Arina Puzriakova reviewed gene: FAAP100: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	BORCS5	Arina Puzriakova reviewed gene: BORCS5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MAGED2	Arina Puzriakova reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ZNRF3	Arina Puzriakova reviewed gene: ZNRF3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ZNHIT3	Arina Puzriakova reviewed gene: ZNHIT3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ZNF808	Arina Puzriakova reviewed gene: ZNF808: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ZMYND11	Arina Puzriakova reviewed gene: ZMYND11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ZEB1	Arina Puzriakova reviewed gene: ZEB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	WDR47	Arina Puzriakova reviewed gene: WDR47: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	UNC50	Arina Puzriakova reviewed gene: UNC50: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	UNC13D	Arina Puzriakova edited their review of gene: UNC13D: Added comment: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: GREEN
05 Sep 2025	Fetal anomalies v6.29	TPM1	Arina Puzriakova reviewed gene: TPM1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	C14orf80	Arina Puzriakova reviewed gene: C14orf80: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	TCP1	Arina Puzriakova reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	TCF20	Arina Puzriakova reviewed gene: TCF20: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	TAAR1	Arina Puzriakova reviewed gene: TAAR1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SUPT7L	Arina Puzriakova reviewed gene: SUPT7L: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	STXBP2	Arina Puzriakova reviewed gene: STXBP2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	STX5	Arina Puzriakova reviewed gene: STX5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	STX11	Arina Puzriakova reviewed gene: STX11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SRPK3	Arina Puzriakova reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SRP54	Arina Puzriakova reviewed gene: SRP54: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SPTA1	Arina Puzriakova edited their review of gene: SPTA1: Added comment: Upgraded from Red to Amber but there is sufficient evidence to make Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group. MOI has also been updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as per the review.; Changed rating: GREEN
05 Sep 2025	Fetal anomalies v6.29	SPOUT1	Arina Puzriakova reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SNAPC4	Arina Puzriakova reviewed gene: SNAPC4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SLC35A3	Arina Puzriakova reviewed gene: SLC35A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SLC30A5	Arina Puzriakova reviewed gene: SLC30A5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SLC19A1	Arina Puzriakova reviewed gene: SLC19A1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SLC12A9	Arina Puzriakova reviewed gene: SLC12A9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SIRT6	Arina Puzriakova reviewed gene: SIRT6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SENP7	Arina Puzriakova reviewed gene: SENP7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	SEL1L	Arina Puzriakova reviewed gene: SEL1L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	RPL26	Arina Puzriakova reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	RNU5B-1	Arina Puzriakova reviewed gene: RNU5B-1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	RNU5A-1	Arina Puzriakova reviewed gene: RNU5A-1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	RNF31	Arina Puzriakova reviewed gene: RNF31: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	RIPPLY2	Arina Puzriakova reviewed gene: RIPPLY2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	RBFOX2	Arina Puzriakova reviewed gene: RBFOX2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	RAB11B	Arina Puzriakova reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PYGL	Arina Puzriakova reviewed gene: PYGL: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PUS3	Arina Puzriakova reviewed gene: PUS3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PURA	Arina Puzriakova reviewed gene: PURA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PTEN	Arina Puzriakova reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PSKH1	Arina Puzriakova reviewed gene: PSKH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PROC	Arina Puzriakova reviewed gene: PROC: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PPFIBP1	Arina Puzriakova reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PPFIA3	Arina Puzriakova reviewed gene: PPFIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	POU3F3	Arina Puzriakova reviewed gene: POU3F3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PLVAP	Arina Puzriakova reviewed gene: PLVAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PLAA	Arina Puzriakova reviewed gene: PLAA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PIGW	Arina Puzriakova reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PIGQ	Arina Puzriakova reviewed gene: PIGQ: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PIGP	Arina Puzriakova reviewed gene: PIGP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PIGM	Arina Puzriakova reviewed gene: PIGM: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PIGG	Arina Puzriakova reviewed gene: PIGG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PIGC	Arina Puzriakova reviewed gene: PIGC: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PI4KA	Arina Puzriakova reviewed gene: PI4KA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PHF5A	Arina Puzriakova reviewed gene: PHF5A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PDE12	Arina Puzriakova reviewed gene: PDE12: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PDCD2	Arina Puzriakova reviewed gene: PDCD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PAK2	Arina Puzriakova reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	PAICS	Arina Puzriakova reviewed gene: PAICS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	OSBPL9	Arina Puzriakova reviewed gene: OSBPL9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ODC1	Arina Puzriakova reviewed gene: ODC1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NUP214	Arina Puzriakova reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NT5E	Arina Puzriakova reviewed gene: NT5E: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NR2F1	Arina Puzriakova reviewed gene: NR2F1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NODAL	Arina Puzriakova reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NMNAT1	Arina Puzriakova reviewed gene: NMNAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NKX2-6	Arina Puzriakova reviewed gene: NKX2-6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NFASC	Arina Puzriakova reviewed gene: NFASC: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NEXN	Arina Puzriakova edited their review of gene: NEXN: Added comment: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group. MOI has also been updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as per the review.; Changed rating: GREEN
05 Sep 2025	Fetal anomalies v6.29	NEUROD1	Arina Puzriakova reviewed gene: NEUROD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NEPRO	Arina Puzriakova reviewed gene: NEPRO: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NDUFB7	Arina Puzriakova edited their review of gene: NDUFB7: Added comment: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: AMBER
05 Sep 2025	Fetal anomalies v6.29	NAGS	Arina Puzriakova reviewed gene: NAGS: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	NAGLU	Arina Puzriakova reviewed gene: NAGLU: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MYL2	Arina Puzriakova reviewed gene: MYL2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MYH9	Arina Puzriakova reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MSL2	Arina Puzriakova reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MPL	Arina Puzriakova reviewed gene: MPL: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MIA3	Arina Puzriakova reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MET	Arina Puzriakova reviewed gene: MET: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MED11	Arina Puzriakova reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MAPK1	Arina Puzriakova reviewed gene: MAPK1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MAP3K3	Arina Puzriakova reviewed gene: MAP3K3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MAN2B2	Arina Puzriakova reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	MAL	Arina Puzriakova reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	LSS	Arina Puzriakova reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	LRRC8C	Arina Puzriakova reviewed gene: LRRC8C: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	LIPN	Arina Puzriakova reviewed gene: LIPN: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	LGI3	Arina Puzriakova reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	LDB1	Arina Puzriakova reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	LAGE3	Arina Puzriakova reviewed gene: LAGE3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	KMT2E	Arina Puzriakova reviewed gene: KMT2E: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	C12orf66	Arina Puzriakova reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	KDM6B	Arina Puzriakova reviewed gene: KDM6B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	KDM1A	Arina Puzriakova reviewed gene: KDM1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	KCNH2	Arina Puzriakova reviewed gene: KCNH2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	KCNB1	Arina Puzriakova reviewed gene: KCNB1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	KBTBD2	Arina Puzriakova reviewed gene: KBTBD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	KAT7	Arina Puzriakova reviewed gene: KAT7: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	JPH1	Arina Puzriakova reviewed gene: JPH1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ITGAV	Arina Puzriakova reviewed gene: ITGAV: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	IRF4	Arina Puzriakova reviewed gene: IRF4: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	IFT27	Arina Puzriakova reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	HNRNPU	Arina Puzriakova reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	HIRA	Arina Puzriakova reviewed gene: HIRA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	HECTD1	Arina Puzriakova reviewed gene: HECTD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	HDAC3	Arina Puzriakova reviewed gene: HDAC3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GUK1	Arina Puzriakova reviewed gene: GUK1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GTPBP1	Arina Puzriakova reviewed gene: GTPBP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GNS	Arina Puzriakova reviewed gene: GNS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GNPNAT1	Arina Puzriakova reviewed gene: GNPNAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GNAI2	Arina Puzriakova reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GEMIN4	Arina Puzriakova reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GDAP1	Arina Puzriakova reviewed gene: GDAP1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GATA5	Arina Puzriakova reviewed gene: GATA5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	GALT	Arina Puzriakova reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	G6PD	Arina Puzriakova reviewed gene: G6PD: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	FLVCR1	Arina Puzriakova reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	FLII	Arina Puzriakova reviewed gene: FLII: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	FGG	Arina Puzriakova reviewed gene: FGG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	FBXW11	Arina Puzriakova reviewed gene: FBXW11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	FBXO22	Arina Puzriakova reviewed gene: FBXO22: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	FAM177A1	Arina Puzriakova reviewed gene: FAM177A1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	EXOSC8	Arina Puzriakova reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	EXOC6B	Arina Puzriakova reviewed gene: EXOC6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ERG	Arina Puzriakova reviewed gene: ERG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	EFL1	Arina Puzriakova reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	EEFSEC	Arina Puzriakova reviewed gene: EEFSEC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DVL2	Arina Puzriakova reviewed gene: DVL2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DTNA	Arina Puzriakova reviewed gene: DTNA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DST	Arina Puzriakova reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DSE	Arina Puzriakova reviewed gene: DSE: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DSC2	Arina Puzriakova reviewed gene: DSC2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DOHH	Arina Puzriakova reviewed gene: DOHH: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DNAJC21	Arina Puzriakova reviewed gene: DNAJC21: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DHX9	Arina Puzriakova reviewed gene: DHX9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DHRSX	Arina Puzriakova reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DDX17	Arina Puzriakova reviewed gene: DDX17: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	DAND5	Arina Puzriakova reviewed gene: DAND5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	CYP24A1	Arina Puzriakova reviewed gene: CYP24A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	COQ2	Arina Puzriakova reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	COMP	Arina Puzriakova reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	COL25A1	Arina Puzriakova reviewed gene: COL25A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	C1orf127	Arina Puzriakova commented on gene: C1orf127: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.
05 Sep 2025	Fetal anomalies v6.29	CHAF1A	Arina Puzriakova reviewed gene: CHAF1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	CFI	Arina Puzriakova reviewed gene: CFI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	CELSR1	Arina Puzriakova edited their review of gene: CELSR1: Added comment: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: GREEN
05 Sep 2025	Fetal anomalies v6.29	CDK5	Arina Puzriakova reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	CCT8	Arina Puzriakova reviewed gene: CCT8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	CCT6A	Arina Puzriakova reviewed gene: CCT6A: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	CCT3	Arina Puzriakova reviewed gene: CCT3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	CTGF	Arina Puzriakova reviewed gene: CTGF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	BRD2	Arina Puzriakova reviewed gene: BRD2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	BORCS8	Arina Puzriakova reviewed gene: BORCS8: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	BICRA	Arina Puzriakova reviewed gene: BICRA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	BHLHE22	Arina Puzriakova reviewed gene: BHLHE22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	BAIAP2	Arina Puzriakova reviewed gene: BAIAP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ASCC3	Arina Puzriakova reviewed gene: ASCC3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ARPC5	Arina Puzriakova reviewed gene: ARPC5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ARL6IP1	Arina Puzriakova reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ARL2BP	Arina Puzriakova reviewed gene: ARL2BP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	AGT	Arina Puzriakova edited their review of gene: AGT: Added comment: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: GREEN
05 Sep 2025	Fetal anomalies v6.29	AGRN	Arina Puzriakova edited their review of gene: AGRN: Added comment: Upgraded from Red to Amber but there is sufficient evidence to make Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: GREEN
05 Sep 2025	Fetal anomalies v6.29	ACTN2	Arina Puzriakova reviewed gene: ACTN2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Sep 2025	Fetal anomalies v6.29	ACO2	Arina Puzriakova edited their review of gene: ACO2: Added comment: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group.; Changed rating: AMBER
05 Sep 2025	Fetal anomalies v6.28	CDH11	Natalie Chandler commented on gene: CDH11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	FAAP100	Sarah Graham commented on gene: FAAP100: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	BORCS5	Sarah Graham commented on gene: BORCS5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MAGED2	Sarah Graham commented on gene: MAGED2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ZNRF3	Sarah Graham commented on gene: ZNRF3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ZNHIT3	Sarah Graham commented on gene: ZNHIT3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ZNF808	Elizabeth Wall commented on gene: ZNF808: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ZMYND11	Natalie Bibb commented on gene: ZMYND11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ZEB1	Sarah Graham commented on gene: ZEB1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	WDR47	Sarah Graham commented on gene: WDR47: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	UNC50	Sarah Graham commented on gene: UNC50: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	UNC13D	Anna de Burca commented on gene: UNC13D: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	TPM1	Alice Gardham commented on gene: TPM1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	C14orf80	Sunayna Best commented on gene: C14orf80: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	TCP1	Natalie Bibb commented on gene: TCP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	TCF20	Stephanie Allen commented on gene: TCF20: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	TAAR1	Sarah Graham commented on gene: TAAR1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SUPT7L	Soo-Mi Park commented on gene: SUPT7L: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	STXBP2	Alice Gardham commented on gene: STXBP2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	STX5	Sahar Mansour commented on gene: STX5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	STX11	Vicki Harrison commented on gene: STX11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SRPK3	Sarah Graham commented on gene: SRPK3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SRP54	Stephanie Allen commented on gene: SRP54: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SPTA1	Sarah Graham commented on gene: SPTA1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SPOUT1	Sunayna Best commented on gene: SPOUT1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SNAPC4	Esther Kinning commented on gene: SNAPC4: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SLC35A3	Sunayna Best commented on gene: SLC35A3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SLC30A5	Natalie Chandler commented on gene: SLC30A5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SLC19A1	Soo-Mi Park commented on gene: SLC19A1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SLC12A9	Sarah Graham commented on gene: SLC12A9: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SIRT6	Natalie Canham commented on gene: SIRT6: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SENP7	Natalie Bibb commented on gene: SENP7: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	SEL1L	Anna de Burca commented on gene: SEL1L: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	RPL26	Elizabeth Wall commented on gene: RPL26: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	RNU5B-1	Natalie Chandler commented on gene: RNU5B-1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	RNU5A-1	Natalie Chandler commented on gene: RNU5A-1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	RNF31	Natalie Chandler commented on gene: RNF31: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	RIPPLY2	Sahar Mansour commented on gene: RIPPLY2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	RBFOX2	Anna de Burca commented on gene: RBFOX2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	RAB11B	Sahar Mansour commented on gene: RAB11B: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PYGL	Soo-Mi Park commented on gene: PYGL: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PUS3	Elizabeth Scotchman commented on gene: PUS3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PURA	Natalie Canham commented on gene: PURA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PTEN	Sunayna Best commented on gene: PTEN: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PSKH1	Sarah Graham commented on gene: PSKH1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PROC	Elizabeth Wall commented on gene: PROC: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PPFIBP1	Stephanie Allen commented on gene: PPFIBP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PPFIA3	Stephanie Allen commented on gene: PPFIA3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	POU3F3	Natalie Chandler commented on gene: POU3F3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PLVAP	Alice Gardham commented on gene: PLVAP: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PLAA	Stephanie Allen commented on gene: PLAA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PIGW	Sahar Mansour commented on gene: PIGW: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PIGQ	Esther Kinning commented on gene: PIGQ: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PIGP	Elizabeth Wall commented on gene: PIGP: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PIGM	Elizabeth Scotchman commented on gene: PIGM: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PIGG	Anna de Burca commented on gene: PIGG: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PIGC	Alice Gardham commented on gene: PIGC: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PI4KA	Anna de Burca commented on gene: PI4KA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PHF5A	Vicki Harrison commented on gene: PHF5A: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PDE12	Alice Gardham commented on gene: PDE12: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PDCD2	Soo-Mi Park commented on gene: PDCD2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PAK2	Sarah Graham commented on gene: PAK2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	PAICS	Sunayna Best commented on gene: PAICS: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	OSBPL9	Natalie Chandler commented on gene: OSBPL9: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ODC1	Anna de Burca commented on gene: ODC1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NUP214	Stephanie Allen commented on gene: NUP214: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NT5E	Natalie Chandler commented on gene: NT5E: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NR2F1	Soo-Mi Park commented on gene: NR2F1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NODAL	Natalie Chandler commented on gene: NODAL: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NMNAT1	Natalie Chandler commented on gene: NMNAT1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NKX2-6	Sunayna Best commented on gene: NKX2-6: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NFASC	Natalie Bibb commented on gene: NFASC: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NEXN	Sarah Graham commented on gene: NEXN: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NEUROD1	Soo-Mi Park commented on gene: NEUROD1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NEPRO	Natalie Canham commented on gene: NEPRO: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NDUFB7	Vicki Harrison commented on gene: NDUFB7: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NAGS	Elizabeth Wall commented on gene: NAGS: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	NAGLU	Sarah Graham commented on gene: NAGLU: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MYL2	Vicki Harrison commented on gene: MYL2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MYH9	Natalie Chandler commented on gene: MYH9: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MSL2	Natalie Chandler commented on gene: MSL2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MPL	Elizabeth Scotchman commented on gene: MPL: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MIA3	Sarah Graham commented on gene: MIA3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MET	Stephanie Allen commented on gene: MET: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MED11	Soo-Mi Park commented on gene: MED11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MAPK1	Sarah Graham commented on gene: MAPK1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MAP3K3	Alice Gardham commented on gene: MAP3K3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MAN2B2	Sarah Graham commented on gene: MAN2B2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	MAL	Sahar Mansour commented on gene: MAL: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	LSS	Natalie Chandler commented on gene: LSS: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	LRRC8C	Vicki Harrison commented on gene: LRRC8C: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	LIPN	Stephanie Allen commented on gene: LIPN: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	LGI3	Soo-Mi Park commented on gene: LGI3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	LDB1	Vicki Harrison commented on gene: LDB1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	LAGE3	Natalie Chandler commented on gene: LAGE3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	KMT2E	Natalie Bibb commented on gene: KMT2E: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	C12orf66	Sahar Mansour commented on gene: C12orf66: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	KDM6B	Sunayna Best commented on gene: KDM6B: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	KDM1A	Esther Kinning commented on gene: KDM1A: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	KCNH2	Sahar Mansour commented on gene: KCNH2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	KCNB1	Soo-Mi Park commented on gene: KCNB1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	KBTBD2	Esther Kinning commented on gene: KBTBD2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	KAT7	Natalie Chandler commented on gene: KAT7: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	JPH1	Sarah Graham commented on gene: JPH1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ITGAV	Natalie Canham commented on gene: ITGAV: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	IRF4	Natalie Chandler commented on gene: IRF4: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	IFT27	Sahar Mansour commented on gene: IFT27: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	HNRNPU	Sarah Graham commented on gene: HNRNPU: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	HIRA	Sarah Graham commented on gene: HIRA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	HECTD1	Sarah Graham commented on gene: HECTD1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	HDAC3	Sarah Graham commented on gene: HDAC3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GUK1	Esther Kinning commented on gene: GUK1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GTPBP1	Natalie Chandler commented on gene: GTPBP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GNS	Sarah Graham commented on gene: GNS: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GNPNAT1	Vicki Harrison commented on gene: GNPNAT1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GNAI2	Sarah Graham commented on gene: GNAI2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GEMIN4	Sahar Mansour commented on gene: GEMIN4: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GDAP1	Alice Gardham commented on gene: GDAP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GATA5	Natalie Chandler commented on gene: GATA5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	GALT	Sarah Graham commented on gene: GALT: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	G6PD	Sarah Graham commented on gene: G6PD: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	FLVCR1	Natalie Canham commented on gene: FLVCR1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	FLII	Sarah Graham commented on gene: FLII: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	FGG	Natalie Canham commented on gene: FGG: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	FBXW11	Elizabeth Scotchman commented on gene: FBXW11: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	FBXO22	Natalie Bibb commented on gene: FBXO22: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	FAM177A1	Vicki Harrison commented on gene: FAM177A1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	EXOSC8	Sarah Graham commented on gene: EXOSC8: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	EXOC6B	Natalie Bibb commented on gene: EXOC6B: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ERG	Sunayna Best commented on gene: ERG: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	EFL1	Esther Kinning commented on gene: EFL1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	EEFSEC	Natalie Chandler commented on gene: EEFSEC: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DVL2	Natalie Bibb commented on gene: DVL2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DTNA	Natalie Bibb commented on gene: DTNA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DST	Sarah Graham commented on gene: DST: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DSE	Natalie Chandler commented on gene: DSE: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DSC2	Alice Gardham commented on gene: DSC2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DOHH	Esther Kinning commented on gene: DOHH: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DNAJC21	Elizabeth Wall commented on gene: DNAJC21: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DHX9	Elizabeth Scotchman commented on gene: DHX9: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DHRSX	Elizabeth Scotchman commented on gene: DHRSX: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DDX17	Elizabeth Scotchman commented on gene: DDX17: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	DAND5	Elizabeth Wall commented on gene: DAND5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CYP24A1	Natalie Chandler commented on gene: CYP24A1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	COQ2	Anna de Burca commented on gene: COQ2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	COMP	Elizabeth Wall commented on gene: COMP: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	COL25A1	Sarah Graham commented on gene: COL25A1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	C1orf127	Elizabeth Scotchman commented on gene: C1orf127: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CHAF1A	Elizabeth Wall commented on gene: CHAF1A: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CFI	Esther Kinning commented on gene: CFI: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CELSR1	Sarah Graham commented on gene: CELSR1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CDK5	Sarah Graham commented on gene: CDK5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CCT8	Sarah Graham commented on gene: CCT8: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CCT6A	Sarah Graham commented on gene: CCT6A: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CCT3	Natalie Canham commented on gene: CCT3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	CTGF	Elizabeth Scotchman commented on gene: CTGF: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	BRD2	Natalie Canham commented on gene: BRD2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	BORCS8	Natalie Canham commented on gene: BORCS8: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	BICRA	Natalie Chandler commented on gene: BICRA: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	BHLHE22	Sarah Graham commented on gene: BHLHE22: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	BAIAP2	Anna de Burca commented on gene: BAIAP2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ASCC3	Anna de Burca commented on gene: ASCC3: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ARPC5	Stephanie Allen commented on gene: ARPC5: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ARL6IP1	Alice Gardham commented on gene: ARL6IP1: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ARL2BP	Vicki Harrison commented on gene: ARL2BP: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	AGT	Esther Kinning commented on gene: AGT: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	AGRN	Alice Gardham commented on gene: AGRN: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ACTN2	Natalie Chandler commented on gene: ACTN2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.28	ACO2	Natalie Chandler commented on gene: ACO2: This gene and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.27	DMPK_CTG	Arina Puzriakova Tag Q3_25_expert_review was removed from STR: DMPK_CTG.
05 Sep 2025	Fetal anomalies v6.27	DMPK_CTG	Arina Puzriakova Classified STR: DMPK_CTG as Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.27	DMPK_CTG	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support the association with Myotonic dystrophy. This STR is Green on multiple GMS panels meaning that it has been approved by the NHS STR working group and can be promoted to Green on this panel at the next GMS panel update.
05 Sep 2025	Fetal anomalies v6.27	DMPK_CTG	Arina Puzriakova Str: dmpk_ctg has been classified as Amber List (Moderate Evidence).
05 Sep 2025	Fetal anomalies v6.26	DMPK_CTG	Arina Puzriakova Tag Q3_25_promote_green tag was added to STR: DMPK_CTG. Tag Q3_25_expert_review tag was added to STR: DMPK_CTG. Tag Q3_25_NHS_review tag was added to STR: DMPK_CTG.
05 Sep 2025	Fetal anomalies v6.26	XYLT1_GCC	Arina Puzriakova Classified STR: XYLT1_GCC as Red List (low evidence)
05 Sep 2025	Fetal anomalies v6.26	XYLT1_GCC	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support an association with Desbuquois dysplasia, however, this STR is currently not green on any panels as it has not been approved by the NHS STR working group and is not NGS validated. Therefore the Red rating will be maintained for now.
05 Sep 2025	Fetal anomalies v6.26	XYLT1_GCC	Arina Puzriakova Str: xylt1_gcc has been classified as Red List (Low Evidence).
05 Sep 2025	Fetal anomalies v6.25	CNBP_CCTG	Arina Puzriakova Classified STR: CNBP_CCTG as Red List (low evidence)
05 Sep 2025	Fetal anomalies v6.25	CNBP_CCTG	Arina Puzriakova Added comment: Comment on list classification: This STR was downgraded from Amber to Red inline with the Red review by the R21 Clinical Oversight Group.
05 Sep 2025	Fetal anomalies v6.25	CNBP_CCTG	Arina Puzriakova Str: cnbp_cctg has been classified as Red List (Low Evidence).
05 Sep 2025	Fetal anomalies v6.24	DMPK_CTG	Arina Puzriakova commented on STR: DMPK_CTG: This STR and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.24	XYLT1_GCC	Arina Puzriakova commented on STR: XYLT1_GCC: This STR and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.24	CNBP_CCTG	Arina Puzriakova commented on STR: CNBP_CCTG: This STR and phenotype were reviewed during meetings in June & July 2025. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler & Elizabeth Scotchman (North Thames GLH), Natalie Bibb, Stephanie Allen & Sarah Graham (Central & South GLH) and Alice Gardham, Esther Kinning, Vicki Harrison, Anna DeBurca, Natalie Canham, Elizabeth Wall, Sunayna Best, Soo-Mi Park & Sahar Mansour (R21 Clinical Oversight Group).
05 Sep 2025	Fetal anomalies v6.24	XYLT1_GCC	Arina Puzriakova reviewed STR: XYLT1_GCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 22711505, 30554721; Phenotypes: Desbuquois dysplasia 2, OMIM:615777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	DMPK_CTG	Arina Puzriakova edited their review of STR: DMPK_CTG: Added comment: Green expert review added on behalf of Sunayna Best (Leeds Teaching Hospitals NHS Trust), as part of a review of this panel by the R21 Clinical Oversight Group: "Prenatal presentations of DM1 have been associated with nonspecific ultrasound findings such as clubbed foot, polyhydramnios, ventriculomegaly, and decreased fetal movement. Few published cases include prenatal neuroimaging findings, and ventriculomegaly has been described Shear et al, 2024: report expansion of the prenatal phenotype of DM1 with fetal SVT and frontal bossing with dilated subarachnoid spaces."; Changed rating: GREEN; Changed phenotypes to: Myotonic dystrophy 1; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	CNBP_CCTG	Arina Puzriakova changed review comment from: Red expert review added on behalf of Alice Gardham (North West Thames Genetics), as part of a review of this panel by the R21 Clinical Oversight Group: Myotonic dytrophy 2 - no fetal presentation.; to: Red expert review added on behalf of Alice Gardham (North West Thames Genetics), as part of a review of this panel by the R21 Clinical Oversight Group: "Myotonic dytrophy 2 - no fetal presentation."
05 Sep 2025	Fetal anomalies v6.24	CNBP_CCTG	Arina Puzriakova edited their review of STR: CNBP_CCTG: Added comment: Red expert review added on behalf of Alice Gardham (North West Thames Genetics), as part of a review of this panel by the R21 Clinical Oversight Group: Myotonic dytrophy 2 - no fetal presentation.; Changed rating: RED
05 Sep 2025	Fetal anomalies v6.24	CDH11	Natalie Chandler reviewed gene: CDH11: Rating: AMBER; Mode of pathogenicity: ; Publications: 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	FAAP100	Sarah Graham reviewed gene: FAAP100: Rating: GREEN; Mode of pathogenicity: ; Publications: 40232843, 40244696; Phenotypes: Fanconi anemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	BORCS5	Sarah Graham reviewed gene: BORCS5: Rating: GREEN; Mode of pathogenicity: ; Publications: 40385417; Phenotypes: Arthrogryposis multiplex congenita, brain malformations; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	MAGED2	Sarah Graham reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bartter syndrome, type 5, antenatal, transient; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
05 Sep 2025	Fetal anomalies v6.24	ZNRF3	Sarah Graham reviewed gene: ZNRF3: Rating: AMBER; Mode of pathogenicity: ; Publications: 39168120; Phenotypes: Complex neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	ZNHIT3	Sarah Graham reviewed gene: ZNHIT3: Rating: AMBER; Mode of pathogenicity: ; Publications: 39252897, 28335020; Phenotypes: PEHO syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ZNF808	Elizabeth Wall reviewed gene: ZNF808: Rating: RED; Mode of pathogenicity: ; Publications: 37973953, 37308312; Phenotypes: Pancreatic agenesis 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ZMYND11	Natalie Bibb reviewed gene: ZMYND11: Rating: AMBER; Mode of pathogenicity: ; Publications: 39521787; Phenotypes: Intellectual developmental disorder, autosomal dominant 30; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	ZEB1	Sarah Graham reviewed gene: ZEB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 37857482; Phenotypes: Anomalies of the corpus callosum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	WDR47	Sarah Graham reviewed gene: WDR47: Rating: GREEN; Mode of pathogenicity: ; Publications: 39609633; Phenotypes: Complex neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	UNC50	Sarah Graham reviewed gene: UNC50: Rating: AMBER; Mode of pathogenicity: ; Publications: 33820833, 40219868, 29016857; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	UNC13D	Anna de Burca reviewed gene: UNC13D: Rating: GREEN; Mode of pathogenicity: ; Publications: 33082562, 29262924, 21646258; Phenotypes: Hemophagocytic lymphohistiocytosis, familial, 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	TPM1	Alice Gardham reviewed gene: TPM1: Rating: AMBER; Mode of pathogenicity: ; Publications: 33553264; Phenotypes: Left ventricular noncompaction 9; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	C14orf80	Sunayna Best reviewed gene: C14orf80: Rating: AMBER; Mode of pathogenicity: ; Publications: 39979680; Phenotypes: severe growth impairment and endocrine complications; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	TCP1	Natalie Bibb reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39480921; Phenotypes: Intellectual developmental disorder with polymicrogyria and seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	TCF20	Stephanie Allen reviewed gene: TCF20: Rating: AMBER; Mode of pathogenicity: ; Publications: 30819258, 40066675; Phenotypes: Developmental delay with variable intellectual impairment and behavioral abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	TAAR1	Sarah Graham reviewed gene: TAAR1: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Cerebellar vermis hypoplasia, cystic kidneys, polydactyly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SUPT7L	Soo-Mi Park reviewed gene: SUPT7L: Rating: RED; Mode of pathogenicity: ; Publications: 38592547; Phenotypes: Fischer-Zirnsak progeroid syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	STXBP2	Alice Gardham reviewed gene: STXBP2: Rating: RED; Mode of pathogenicity: ; Publications: 38084697, 33593331; Phenotypes: Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	STX5	Sahar Mansour reviewed gene: STX5: Rating: GREEN; Mode of pathogenicity: ; Publications: 34711829; Phenotypes: Congenital disorder of glycosylation, type IIaa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	STX11	Vicki Harrison reviewed gene: STX11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Haemophagocytic lymphohistiocytosis, familial, 4, OMIM:603552; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SRPK3	Sarah Graham reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: 39073169; Phenotypes: X-linked intellectual developmental disorder-114; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
05 Sep 2025	Fetal anomalies v6.24	SRP54	Stephanie Allen reviewed gene: SRP54: Rating: AMBER; Mode of pathogenicity: ; Publications: 28972538, 29914977; Phenotypes: Neutropenia, severe congenital, 8, autosomal dominant; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	SPTA1	Sarah Graham reviewed gene: SPTA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31333484, 34132406, 30198572, 38031483; Phenotypes: Hereditary pyropoikilocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SPOUT1	Sunayna Best reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39962046; Phenotypes: Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SNAPC4	Esther Kinning reviewed gene: SNAPC4: Rating: AMBER; Mode of pathogenicity: ; Publications: 40186013; Phenotypes: Neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SLC35A3	Sunayna Best reviewed gene: SLC35A3: Rating: GREEN; Mode of pathogenicity: ; Publications: 28777481, 24031089, 28328131, 33416188; Phenotypes: Arthrogryposis, mental retardation, and seizures, OMIM:615553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SLC30A5	Natalie Chandler reviewed gene: SLC30A5: Rating: AMBER; Mode of pathogenicity: ; Publications: 39790720, 12095919, 33547425; Phenotypes: Cardiomyopathy, hydrops fetalis, or cystic hygroma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SLC19A1	Soo-Mi Park reviewed gene: SLC19A1: Rating: AMBER; Mode of pathogenicity: ; Publications: 32276275, 11266438, 36745868, 36517554; Phenotypes: Immunodeficiency 114, folate-responsive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SLC12A9	Sarah Graham reviewed gene: SLC12A9: Rating: GREEN; Mode of pathogenicity: ; Publications: 38334070; Phenotypes: SLC12A9-related syndromic neurodevelopmental disorder with lysosome defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SIRT6	Natalie Canham reviewed gene: SIRT6: Rating: AMBER; Mode of pathogenicity: ; Publications: 29555651, 30135584; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SENP7	Natalie Bibb reviewed gene: SENP7: Rating: GREEN; Mode of pathogenicity: ; Publications: 37460201, 39763084; Phenotypes: Fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	SEL1L	Anna de Burca reviewed gene: SEL1L: Rating: AMBER; Mode of pathogenicity: ; Publications: 37943610, 37943617; Phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	RPL26	Elizabeth Wall reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: ; Publications: 22431104, 39268718; Phenotypes: Diamond-Blackfan anaemia 11, OMIM:614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	RNU5B-1	Natalie Chandler reviewed gene: RNU5B-1: Rating: GREEN; Mode of pathogenicity: ; Publications: 40379786; Phenotypes: Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	RNU5A-1	Natalie Chandler reviewed gene: RNU5A-1: Rating: AMBER; Mode of pathogenicity: ; Publications: 40379786; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	RNF31	Natalie Chandler reviewed gene: RNF31: Rating: RED; Mode of pathogenicity: ; Publications: 30936877, 26008899; Phenotypes: Immunodeficiency 115 with autoinflammation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	RIPPLY2	Sahar Mansour reviewed gene: RIPPLY2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32212228, 33410135, 25343988, 26238661; Phenotypes: Spondylocostal dysostosis 6, OMIM:616566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	RBFOX2	Anna de Burca reviewed gene: RBFOX2: Rating: AMBER; Mode of pathogenicity: ; Publications: 35137168, 27485310, 27670201, 26785492, 25205790, 37165897; Phenotypes: Congenital heart disease, MONDO:0005453; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	RAB11B	Sahar Mansour reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: ; Publications: 39502218; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	PYGL	Soo-Mi Park reviewed gene: PYGL: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Glycogen storage disease VI; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
05 Sep 2025	Fetal anomalies v6.24	PUS3	Elizabeth Scotchman reviewed gene: PUS3: Rating: GREEN; Mode of pathogenicity: ; Publications: 27055666, 30697592, 31444731, 39891418, 30308082; Phenotypes: Neurodevelopmental disorder with microcephaly and gray sclerae; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PURA	Natalie Canham reviewed gene: PURA: Rating: RED; Mode of pathogenicity: ; Publications: 39521787; Phenotypes: Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	PTEN	Sunayna Best reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: ; Publications: 40261085; Phenotypes: Cowden syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	PSKH1	Sarah Graham reviewed gene: PSKH1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39132680; Phenotypes: hepatorenal syndrome, MONDO:0001382; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PROC	Elizabeth Wall reviewed gene: PROC: Rating: AMBER; Mode of pathogenicity: ; Publications: 39763161; Phenotypes: Thrombophilia 3 due to protein C deficiency, autosomal recessive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PPFIBP1	Stephanie Allen reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 35830857, 37229200; Phenotypes: Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PPFIA3	Stephanie Allen reviewed gene: PPFIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: 38508193, 38181735, 37034625, 38723631; Phenotypes: Paul-Chao neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	POU3F3	Natalie Chandler reviewed gene: POU3F3: Rating: AMBER; Mode of pathogenicity: ; Publications: 37593446, 31303265; Phenotypes: Snijders Blok-Fisher syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	PLVAP	Alice Gardham reviewed gene: PLVAP: Rating: AMBER; Mode of pathogenicity: ; Publications: 26207260, 29875123, 29661969, 31215290; Phenotypes: Diarrhoea 10, protein-losing enteropathy type, OMIM:618183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PLAA	Stephanie Allen reviewed gene: PLAA: Rating: GREEN; Mode of pathogenicity: ; Publications: 38650658, 28413018, 28007986, 31322726; Phenotypes: Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, OMIM:617527; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PIGW	Sahar Mansour reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: ; Publications: 40180615; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 11; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PIGQ	Esther Kinning reviewed gene: PIGQ: Rating: AMBER; Mode of pathogenicity: ; Publications: 24463883, 31148362, 25558065, 32588908; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 4; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PIGP	Elizabeth Wall reviewed gene: PIGP: Rating: GREEN; Mode of pathogenicity: ; Publications: 32042915, 28334793, 31139695; Phenotypes: Developmental and epileptic encephalopathy 55; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PIGM	Elizabeth Scotchman reviewed gene: PIGM: Rating: AMBER; Mode of pathogenicity: ; Publications: 25293775, 16767100; Phenotypes: Glycosylphosphatidylinositol deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PIGG	Anna de Burca reviewed gene: PIGG: Rating: GREEN; Mode of pathogenicity: ; Publications: 34113002, 26996948; Phenotypes: Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PIGC	Alice Gardham reviewed gene: PIGC: Rating: AMBER; Mode of pathogenicity: ; Publications: 32707268, 27694521; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PI4KA	Anna de Burca reviewed gene: PI4KA: Rating: GREEN; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PHF5A	Vicki Harrison reviewed gene: PHF5A: Rating: GREEN; Mode of pathogenicity: ; Publications: 37422718, 33811463; Phenotypes: PHF5A-related neurodevelopmental disorder with congenital malformations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	PDE12	Alice Gardham reviewed gene: PDE12: Rating: AMBER; Mode of pathogenicity: ; Publications: 39567835; Phenotypes: Mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PDCD2	Soo-Mi Park reviewed gene: PDCD2: Rating: AMBER; Mode of pathogenicity: ; Publications: 40208938; Phenotypes: hydrops fetalis and early pregnancy loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	PAK2	Sarah Graham reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: ; Publications: 40262506, 37808560, 39876536, 33693784, 38894571, 39994693; Phenotypes: Knobloch syndrome 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	PAICS	Sunayna Best reviewed gene: PAICS: Rating: GREEN; Mode of pathogenicity: ; Publications: 31178128, 38179855, 3965093, 30758658; Phenotypes: Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	OSBPL9	Natalie Chandler reviewed gene: OSBPL9: Rating: RED; Mode of pathogenicity: ; Publications: 40182349; Phenotypes: Fetal Cerebral Ventriculomegaly, Cerebellar Hypoplasia, and Arthrogryposis Multiplex; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ODC1	Anna de Burca reviewed gene: ODC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 40188065; Phenotypes: Bachmann-Bupp syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	NUP214	Stephanie Allen reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: ; Publications: 31178128, 39650934, 30758658; Phenotypes: Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NT5E	Natalie Chandler reviewed gene: NT5E: Rating: RED; Mode of pathogenicity: ; Publications: 26010187, 34999808, 26178434, 21288095, 32522903, 28825389, 27045881; Phenotypes: arterial calcification, joint calcification; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NR2F1	Soo-Mi Park reviewed gene: NR2F1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31318166, 32712214, 36221391, 32484994, 40066675; Phenotypes: Bosch-Boonstra-Schaaf optic atrophy syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
05 Sep 2025	Fetal anomalies v6.24	NODAL	Natalie Chandler reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: ; Publications: 19064609, 9354794; Phenotypes: Heterotaxy, visceral, 5; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	NMNAT1	Natalie Chandler reviewed gene: NMNAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NKX2-6	Sunayna Best reviewed gene: NKX2-6: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Conotruncal heart malformations, Persistent truncus arteriosus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NFASC	Natalie Bibb reviewed gene: NFASC: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Neurodevelopmental disorder with central and peripheral motor dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NEXN	Sarah Graham reviewed gene: NEXN: Rating: GREEN; Mode of pathogenicity: ; Publications: 33949776, 39183344, 35166435, 32058062; Phenotypes: Cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NEUROD1	Soo-Mi Park reviewed gene: NEUROD1: Rating: AMBER; Mode of pathogenicity: ; Publications: 26669242, 20573748, 10545951, 29521454, 26773576, 19609565; Phenotypes: Maturity-onset diabetes of the young 6; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
05 Sep 2025	Fetal anomalies v6.24	NEPRO	Natalie Canham reviewed gene: NEPRO: Rating: GREEN; Mode of pathogenicity: ; Publications: 31250547, 29620724, 26633546, 37294112; Phenotypes: Anauxetic dysplasia 3, OMIM:618853; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NDUFB7	Vicki Harrison reviewed gene: NDUFB7: Rating: AMBER; Mode of pathogenicity: ; Publications: 33502047, 40025060; Phenotypes: Mitochondrial complex I deficiency, nuclear type 39; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NAGS	Elizabeth Wall reviewed gene: NAGS: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: N-acetylglutamate synthase deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	NAGLU	Sarah Graham reviewed gene: NAGLU: Rating: AMBER; Mode of pathogenicity: ; Publications: 40066675; Phenotypes: Mucopolysaccharidosis type IIIB (Sanfilippo B); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	MYL2	Vicki Harrison reviewed gene: MYL2: Rating: AMBER; Mode of pathogenicity: ; Publications: 39831482; Phenotypes: Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, Cardiomyopathy, hypertrophic, 10; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	MYH9	Natalie Chandler reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: ; Publications: 16969870, 31384440; Phenotypes: Deafness, autosomal dominant 17, Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	MSL2	Natalie Chandler reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: ; Publications: 33057194, 38815585, 31332282; Phenotypes: Karayol-Borroto-Haghshenas neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	MPL	Elizabeth Scotchman reviewed gene: MPL: Rating: AMBER; Mode of pathogenicity: ; Publications: 39763161; Phenotypes: Amegakaryocytic thrombocytopenia, congenital, 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	MIA3	Sarah Graham reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: 32101163, 33778321, 40119123; Phenotypes: Odontochondrodysplasia-2 with hearing loss and diabetes; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	MET	Stephanie Allen reviewed gene: MET: Rating: RED; Mode of pathogenicity: ; Publications: 30777867, 38429387; Phenotypes: ?Arthrogryposis, distal, type 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	MED11	Soo-Mi Park reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: ; Publications: 39578696, 36001086; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
05 Sep 2025	Fetal anomalies v6.24	MAPK1	Sarah Graham reviewed gene: MAPK1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 40257485, 32721402; Phenotypes: Noonan syndrome 13; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	MAP3K3	Alice Gardham reviewed gene: MAP3K3: Rating: RED; Mode of pathogenicity: ; Publications: 25728774; Phenotypes: Cerebral cavernous malformations 5; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	MAN2B2	Sarah Graham reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: ; Publications: 38622837, 35637269, 31775018; Phenotypes: Congenital disorder of glycosylation type 1EE with or without immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	MAL	Sahar Mansour reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: Other; Publications: 35217805; Phenotypes: ?Leukodystrophy, hypomyelinating, 28; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	LSS	Natalie Chandler reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: ; Publications: 39359128; Phenotypes: Alopecia-intellectual disability syndrome 4, Cataract 44; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	LRRC8C	Vicki Harrison reviewed gene: LRRC8C: Rating: AMBER; Mode of pathogenicity: ; Publications: 39623139; Phenotypes: TIMES syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	LIPN	Stephanie Allen reviewed gene: LIPN: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Ichthyosis, congenital, autosomal recessive 8; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	LGI3	Soo-Mi Park reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: ; Publications: 35948005; Phenotypes: Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
05 Sep 2025	Fetal anomalies v6.24	LDB1	Vicki Harrison reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39680505; Phenotypes: Congenital hydrocephalus, MONDO:0016349; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	LAGE3	Natalie Chandler reviewed gene: LAGE3: Rating: GREEN; Mode of pathogenicity: ; Publications: 28805828, 31069511, 36682911; Phenotypes: Galloway-Mowat syndrome 2, X-linked; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
05 Sep 2025	Fetal anomalies v6.24	KMT2E	Natalie Bibb reviewed gene: KMT2E: Rating: AMBER; Mode of pathogenicity: ; Publications: 40186013; Phenotypes: O'Donnell-Luria-Rodan syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	C12orf66	Sahar Mansour reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: ; Publications: 39824192; Phenotypes: Intellectual developmental disorder, autosomal recessive 83; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	KDM6B	Sunayna Best reviewed gene: KDM6B: Rating: AMBER; Mode of pathogenicity: ; Publications: 31124270, 37196654; Phenotypes: Stolerman neurodevelopmental syndrome, OMIM:618505; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	KDM1A	Esther Kinning reviewed gene: KDM1A: Rating: AMBER; Mode of pathogenicity: ; Publications: 26656649, 24838796, 27094131; Phenotypes: Cleft palate, psychomotor retardation, and distinctive facial features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	KCNH2	Sahar Mansour reviewed gene: KCNH2: Rating: AMBER; Mode of pathogenicity: ; Publications: 36973673, 39698424, 38094730; Phenotypes: Short QT syndrome 1, OMIM:609620, Long QT syndrome 2, OMIM:613688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	KCNB1	Soo-Mi Park reviewed gene: KCNB1: Rating: AMBER; Mode of pathogenicity: ; Publications: 36257979, 31513310, 39237446; Phenotypes: Developmental and epileptic encephalopathy 26; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
05 Sep 2025	Fetal anomalies v6.24	KBTBD2	Esther Kinning reviewed gene: KBTBD2: Rating: AMBER; Mode of pathogenicity: ; Publications: 39313616; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	KAT7	Natalie Chandler reviewed gene: KAT7: Rating: RED; Mode of pathogenicity: ; Publications: 40186013; Phenotypes: Abnormal male external genitalia morphology, Tetralogy of Fallot; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	JPH1	Sarah Graham reviewed gene: JPH1: Rating: AMBER; Mode of pathogenicity: ; Publications: 39209426; Phenotypes: Congenital myopathy-25; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ITGAV	Natalie Canham reviewed gene: ITGAV: Rating: GREEN; Mode of pathogenicity: ; Publications: 39526957; Phenotypes: Syndromic disease, MONDO:0002254; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	IRF4	Natalie Chandler reviewed gene: IRF4: Rating: RED; Mode of pathogenicity: ; Publications: 29537367, 36917008, 29408330, 36662884; Phenotypes: Immunodeficiency 131; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	IFT27	Sahar Mansour reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: ; Publications: 25443296, 2970430, 24488770, 30761183, 37239474, 26763875; Phenotypes: Bardet-Biedl syndrome 19; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	HNRNPU	Sarah Graham reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: ; Publications: 39976380, 39965881, 39237446, 35138025; Phenotypes: Developmental and epileptic encephalopathy 54; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	HIRA	Sarah Graham reviewed gene: HIRA: Rating: AMBER; Mode of pathogenicity: ; Publications: 38511226, 33417013; Phenotypes: Complex neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	HECTD1	Sarah Graham reviewed gene: HECTD1: Rating: AMBER; Mode of pathogenicity: ; Publications: 37165897, 38451291, 39879987; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	HDAC3	Sarah Graham reviewed gene: HDAC3: Rating: GREEN; Mode of pathogenicity: ; Publications: 39047730; Phenotypes: HDAC3-related neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	GUK1	Esther Kinning reviewed gene: GUK1: Rating: RED; Mode of pathogenicity: ; Publications: 39230499; Phenotypes: Mitochondrial DNA depletion syndrome 21; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	GTPBP1	Natalie Chandler reviewed gene: GTPBP1: Rating: AMBER; Mode of pathogenicity: ; Publications: 38118446; Phenotypes: Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	GNS	Sarah Graham reviewed gene: GNS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Mucopolysaccharidosis type IIID, OMIM:252940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	GNPNAT1	Vicki Harrison reviewed gene: GNPNAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: 39945447; Phenotypes: Rhizomelic dysplasia, Ain-Naz type; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	GNAI2	Sarah Graham reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: ; Publications: 39298586; Phenotypes: Syndromic developmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	GEMIN4	Sahar Mansour reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	GDAP1	Alice Gardham reviewed gene: GDAP1: Rating: RED; Mode of pathogenicity: ; Publications: 39945447; Phenotypes: Charcot-Marie-Tooth disease, type 4A; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	GATA5	Natalie Chandler reviewed gene: GATA5: Rating: AMBER; Mode of pathogenicity: ; Publications: 40076735; Phenotypes: Congenital heart defects, multiple types, 5; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	GALT	Sarah Graham reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Galactosemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	G6PD	Sarah Graham reviewed gene: G6PD: Rating: AMBER; Mode of pathogenicity: ; Publications: 39041728; Phenotypes: Glucose-6-phosphate dehydrogenase deficiency; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
05 Sep 2025	Fetal anomalies v6.24	FLVCR1	Natalie Canham reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39306721; Phenotypes: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	FLII	Sarah Graham reviewed gene: FLII: Rating: AMBER; Mode of pathogenicity: ; Publications: 37561591, 32870709; Phenotypes: Cardiomyopathy, dilated, 2J; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	FGG	Natalie Canham reviewed gene: FGG: Rating: RED; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Hypofibrinogenemia, congenital, Afibrinogenemia, congenital; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	FBXW11	Elizabeth Scotchman reviewed gene: FBXW11: Rating: AMBER; Mode of pathogenicity: ; Publications: 40188065, 31402090; Phenotypes: Neurodevelopmental, jaw, eye, and digital syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	FBXO22	Natalie Bibb reviewed gene: FBXO22: Rating: AMBER; Mode of pathogenicity: ; Publications: 40215970; Phenotypes: Tayoun-Maawali syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	FAM177A1	Vicki Harrison reviewed gene: FAM177A1: Rating: AMBER; Mode of pathogenicity: ; Publications: 38767059, 25558065; Phenotypes: Neurodevelopmental disorder with white matter abnormalities and gait disturbance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	EXOSC8	Sarah Graham reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: ; Publications: 34210538, 38017281, 24989451; Phenotypes: Pontocerebellar hypoplasia type 1C; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	EXOC6B	Natalie Bibb reviewed gene: EXOC6B: Rating: GREEN; Mode of pathogenicity: ; Publications: 30284759, 26669664, 36150098; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ERG	Sunayna Best reviewed gene: ERG: Rating: AMBER; Mode of pathogenicity: ; Publications: 36928819; Phenotypes: Lymphatic malformation 14; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	EFL1	Esther Kinning reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31151987, 29970384, 34115847, 28331068; Phenotypes: Shwachman-Diamond syndrome 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	EEFSEC	Natalie Chandler reviewed gene: EEFSEC: Rating: GREEN; Mode of pathogenicity: ; Publications: 39753114; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	DVL2	Natalie Bibb reviewed gene: DVL2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 35047859, 30521570, 33599851; Phenotypes: Robinow syndrome, MONDO:0019978; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	DTNA	Natalie Bibb reviewed gene: DTNA: Rating: RED; Mode of pathogenicity: ; Publications: 36799992; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	DST	Sarah Graham reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: ; Publications: 37431644; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	DSE	Natalie Chandler reviewed gene: DSE: Rating: GREEN; Mode of pathogenicity: ; Publications: 31655143, 32130795, 25703627, 23704329; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	DSC2	Alice Gardham reviewed gene: DSC2: Rating: RED; Mode of pathogenicity: ; Publications: 40188065; Phenotypes: Arrhythmogenic right ventricular dysplasia, familial, 11; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	DOHH	Esther Kinning reviewed gene: DOHH: Rating: AMBER; Mode of pathogenicity: ; Publications: 35858628; Phenotypes: Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, OMIM:620066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	DNAJC21	Elizabeth Wall reviewed gene: DNAJC21: Rating: AMBER; Mode of pathogenicity: ; Publications: 27346687, 28062395, 29700810; Phenotypes: Bone marrow failure syndrome 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	DHX9	Elizabeth Scotchman reviewed gene: DHX9: Rating: GREEN; Mode of pathogenicity: ; Publications: 37467750, 37369308; Phenotypes: Intellectual developmental disorder, autosomal dominant 75; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	DHRSX	Elizabeth Scotchman reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: ; Publications: 38821050; Phenotypes: Congenital disorder of glycosylation, type 1DD, OMIM:301133; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	DDX17	Elizabeth Scotchman reviewed gene: DDX17: Rating: RED; Mode of pathogenicity: ; Publications: 39405200; Phenotypes: Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	DAND5	Elizabeth Wall reviewed gene: DAND5: Rating: AMBER; Mode of pathogenicity: ; Publications: 34215651, 36316122; Phenotypes: Heterotaxy, visceral, 13, autosomal; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	CYP24A1	Natalie Chandler reviewed gene: CYP24A1: Rating: RED; Mode of pathogenicity: ; Publications: 22337913, 28324001, 27105398, 34307984; Phenotypes: hypercalcaemia, nephrocalcinosis, cystic kidney disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	COQ2	Anna de Burca reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: ; Publications: 39763161; Phenotypes: Coenzyme Q10 deficiency, primary, 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	COMP	Elizabeth Wall reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 40188065, 39521787; Phenotypes: Epiphyseal dysplasia, multiple, 1, Pseudoachondroplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	COL25A1	Sarah Graham reviewed gene: COL25A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 40158061; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	C1orf127	Elizabeth Scotchman reviewed gene: C1orf127: Rating: GREEN; Mode of pathogenicity: ; Publications: 39753129; Phenotypes: Heterotaxy, visceral, 14, autosomal; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	CHAF1A	Elizabeth Wall reviewed gene: CHAF1A: Rating: AMBER; Mode of pathogenicity: ; Publications: 39333427; Phenotypes: Oculo-auriculo-vertebral spectrum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	CFI	Esther Kinning reviewed gene: CFI: Rating: AMBER; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Complement factor I deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	CELSR1	Sarah Graham reviewed gene: CELSR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 38272662; Phenotypes: Lymphatic malformation-9; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	CDK5	Sarah Graham reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: ; Publications: 25560765, 40186457; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	CCT8	Sarah Graham reviewed gene: CCT8: Rating: AMBER; Mode of pathogenicity: ; Publications: 39480921; Phenotypes: CCT8-related neurodevelopmental disorder with brain abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	CCT6A	Sarah Graham reviewed gene: CCT6A: Rating: RED; Mode of pathogenicity: ; Publications: 39480921; Phenotypes: CCT6A-related neurodevelopmental disorder with or without brain abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
05 Sep 2025	Fetal anomalies v6.24	CCT3	Natalie Canham reviewed gene: CCT3: Rating: AMBER; Mode of pathogenicity: ; Publications: 39480921; Phenotypes: Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	CTGF	Elizabeth Scotchman reviewed gene: CTGF: Rating: GREEN; Mode of pathogenicity: ; Publications: 39506047, 39414788, 12736220; Phenotypes: Kyphomelic dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	BRD2	Natalie Canham reviewed gene: BRD2: Rating: RED; Mode of pathogenicity: ; Publications: 40186013; Phenotypes: Agenesis of corpus callosum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	BORCS8	Natalie Canham reviewed gene: BORCS8: Rating: RED; Mode of pathogenicity: ; Publications: 38128568; Phenotypes: Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	BICRA	Natalie Chandler reviewed gene: BICRA: Rating: AMBER; Mode of pathogenicity: ; Publications: 33232675; Phenotypes: Coffin-Siris syndrome 12; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	BHLHE22	Sarah Graham reviewed gene: BHLHE22: Rating: GREEN; Mode of pathogenicity: ; Publications: 39502664; Phenotypes: Complex neurodevelopmental disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	BAIAP2	Anna de Burca reviewed gene: BAIAP2: Rating: AMBER; Mode of pathogenicity: ; Publications: 38149472; Phenotypes: Lissencephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	ASCC3	Anna de Burca reviewed gene: ASCC3: Rating: AMBER; Mode of pathogenicity: ; Publications: 21937992, 35047834; Phenotypes: Intellectual developmental disorder, autosomal recessive 81, OMIM:620700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ARPC5	Stephanie Allen reviewed gene: ARPC5: Rating: RED; Mode of pathogenicity: ; Publications: 37382373, 37349293; Phenotypes: Immunodeficiency 113 with autoimmunity and autoinflammation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ARL6IP1	Alice Gardham reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39954331; Phenotypes: Spastic paraplegia 61, autosomal recessive, OMIM:615685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ARL2BP	Vicki Harrison reviewed gene: ARL2BP: Rating: GREEN; Mode of pathogenicity: ; Publications: 36507858, 40384762, 38649918, 23849777, 27790702; Phenotypes: Situs Inversus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	AGT	Esther Kinning reviewed gene: AGT: Rating: GREEN; Mode of pathogenicity: ; Publications: 39641285; Phenotypes: Renal tubular dysgenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	AGRN	Alice Gardham reviewed gene: AGRN: Rating: GREEN; Mode of pathogenicity: ; Publications: 39807604; Phenotypes: Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.24	ACTN2	Natalie Chandler reviewed gene: ACTN2: Rating: RED; Mode of pathogenicity: ; Publications: 39521787; Phenotypes: Congenital myopathy 8, Cardiomyopathy, hypertrophic, 23, with or without LVNC, Cardiomyopathy, dilated, 1AA, with or without LVNC; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Sep 2025	Fetal anomalies v6.24	ACO2	Natalie Chandler reviewed gene: ACO2: Rating: AMBER; Mode of pathogenicity: ; Publications: 39891418; Phenotypes: Infantile cerebellar-retinal degeneration; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Sep 2025	Fetal anomalies v6.23	CNBP_CCTG	Arina Puzriakova Classified STR: CNBP_CCTG as Red List (low evidence)
05 Sep 2025	Fetal anomalies v6.23	CNBP_CCTG	Arina Puzriakova Str: cnbp_cctg has been classified as Red List (Low Evidence).
05 Sep 2025	Fetal anomalies v6.22	XYLT1_GCC	Arina Puzriakova Entity copied from Skeletal dysplasia v8.7
05 Sep 2025	Fetal anomalies v6.22	XYLT1_GCC	Arina Puzriakova STR: XYLT1_GCC was added STR: XYLT1_GCC was added to Fetal anomalies. Sources: Literature STR, NGS Not Validated tags were added to STR: XYLT1_GCC. Mode of inheritance for STR: XYLT1_GCC was set to BIALLELIC, autosomal or pseudoautosomal Publications for STR: XYLT1_GCC were set to 22711505; 30554721 Phenotypes for STR: XYLT1_GCC were set to Desbuquois dysplasia 2, OMIM:615777; Desbuquois dysplasia 2, MONDO:0014343
05 Sep 2025	Fetal anomalies v6.21	CDH11	Arina Puzriakova gene: CDH11 was added gene: CDH11 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: CDH11 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CDH11 were set to 33811546; 29271567 Phenotypes for gene: CDH11 were set to Elsahy-Waters syndrome
05 Sep 2025	Fetal anomalies v6.21	FAAP100	Arina Puzriakova gene: FAAP100 was added gene: FAAP100 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: FAAP100 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAAP100 were set to 40244696; 40232843 Phenotypes for gene: FAAP100 were set to Fanconi anemia
05 Sep 2025	Fetal anomalies v6.21	BORCS5	Arina Puzriakova gene: BORCS5 was added gene: BORCS5 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BORCS5 were set to 40385417 Phenotypes for gene: BORCS5 were set to Arthrogryposis multiplex congenita, brain malformations
05 Sep 2025	Fetal anomalies v6.21	MAGED2	Arina Puzriakova gene: MAGED2 was added gene: MAGED2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: MAGED2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: MAGED2 were set to Bartter syndrome, type 5, antenatal, transient
05 Sep 2025	Fetal anomalies v6.21	ZNRF3	Arina Puzriakova gene: ZNRF3 was added gene: ZNRF3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZNRF3 were set to 39168120 Phenotypes for gene: ZNRF3 were set to Complex neurodevelopmental disorder
05 Sep 2025	Fetal anomalies v6.21	ZNHIT3	Arina Puzriakova Source Expert Review Amber was added to ZNHIT3. Added phenotypes PEHO syndrome for gene: ZNHIT3 Publications for gene: ZNHIT3 were updated from 28335020; 31048081 to 39252897; 28335020; 31048081 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	ZNF808	Arina Puzriakova gene: ZNF808 was added gene: ZNF808 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: ZNF808 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF808 were set to 37308312; 37973953 Phenotypes for gene: ZNF808 were set to Pancreatic agenesis 3
05 Sep 2025	Fetal anomalies v6.21	ZMYND11	Arina Puzriakova Mode of inheritance for gene ZMYND11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Intellectual developmental disorder, autosomal dominant 30 for gene: ZMYND11 Publications for gene: ZMYND11 were updated from to 39521787
05 Sep 2025	Fetal anomalies v6.21	ZEB1	Arina Puzriakova gene: ZEB1 was added gene: ZEB1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: ZEB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZEB1 were set to 37857482 Phenotypes for gene: ZEB1 were set to Anomalies of the corpus callosum
05 Sep 2025	Fetal anomalies v6.21	WDR47	Arina Puzriakova gene: WDR47 was added gene: WDR47 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: WDR47 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WDR47 were set to 39609633 Phenotypes for gene: WDR47 were set to Complex neurodevelopmental disorder
05 Sep 2025	Fetal anomalies v6.21	UNC50	Arina Puzriakova gene: UNC50 was added gene: UNC50 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: UNC50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNC50 were set to 29016857; 40219868; 33820833 Phenotypes for gene: UNC50 were set to Arthrogryposis multiplex congenita
05 Sep 2025	Fetal anomalies v6.21	UNC13D	Arina Puzriakova Added phenotypes Hemophagocytic lymphohistiocytosis, familial, 3 for gene: UNC13D Publications for gene: UNC13D were updated from 33082562; 33249554 to 21646258; 33249554; 29262924; 33082562
05 Sep 2025	Fetal anomalies v6.21	TPM1	Arina Puzriakova gene: TPM1 was added gene: TPM1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: TPM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TPM1 were set to 33553264 Phenotypes for gene: TPM1 were set to Left ventricular noncompaction 9
05 Sep 2025	Fetal anomalies v6.21	C14orf80	Arina Puzriakova gene: C14orf80 was added gene: C14orf80 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: C14orf80 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C14orf80 were set to 39979680 Phenotypes for gene: C14orf80 were set to severe growth impairment and endocrine complications
05 Sep 2025	Fetal anomalies v6.21	TCP1	Arina Puzriakova gene: TCP1 was added gene: TCP1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: TCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TCP1 were set to 39480921 Phenotypes for gene: TCP1 were set to Intellectual developmental disorder with polymicrogyria and seizures
05 Sep 2025	Fetal anomalies v6.21	TCF20	Arina Puzriakova Mode of inheritance for gene TCF20 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Developmental delay with variable intellectual impairment and behavioral abnormalities for gene: TCF20 Publications for gene: TCF20 were updated from to 30819258; 40066675
05 Sep 2025	Fetal anomalies v6.21	TAAR1	Arina Puzriakova gene: TAAR1 was added gene: TAAR1 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: TAAR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TAAR1 were set to 39891418 Phenotypes for gene: TAAR1 were set to Cerebellar vermis hypoplasia, cystic kidneys, polydactyly
05 Sep 2025	Fetal anomalies v6.21	SUPT7L	Arina Puzriakova gene: SUPT7L was added gene: SUPT7L was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: SUPT7L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SUPT7L were set to 38592547 Phenotypes for gene: SUPT7L were set to Fischer-Zirnsak progeroid syndrome
05 Sep 2025	Fetal anomalies v6.21	STXBP2	Arina Puzriakova gene: STXBP2 was added gene: STXBP2 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: STXBP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STXBP2 were set to 33593331; 38084697 Phenotypes for gene: STXBP2 were set to Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease
05 Sep 2025	Fetal anomalies v6.21	STX5	Arina Puzriakova Added phenotypes Congenital disorder of glycosylation, type IIaa for gene: STX5
05 Sep 2025	Fetal anomalies v6.21	STX11	Arina Puzriakova gene: STX11 was added gene: STX11 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: STX11 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: STX11 were set to Haemophagocytic lymphohistiocytosis, familial, 4, OMIM:603552
05 Sep 2025	Fetal anomalies v6.21	SRPK3	Arina Puzriakova gene: SRPK3 was added gene: SRPK3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SRPK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SRPK3 were set to 39073169 Phenotypes for gene: SRPK3 were set to X-linked intellectual developmental disorder-114
05 Sep 2025	Fetal anomalies v6.21	SRP54	Arina Puzriakova Mode of inheritance for gene SRP54 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Neutropenia, severe congenital, 8, autosomal dominant for gene: SRP54 Publications for gene: SRP54 were updated from to 28972538; 29914977
05 Sep 2025	Fetal anomalies v6.21	SPTA1	Arina Puzriakova Source Expert Review Amber was added to SPTA1. Mode of inheritance for gene SPTA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal Added phenotypes Hereditary pyropoikilocytosis for gene: SPTA1 Publications for gene: SPTA1 were updated from 31333484; 33082562; 34132406 to 34132406; 30198572; 38031483; 33082562; 31333484 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	SPOUT1	Arina Puzriakova gene: SPOUT1 was added gene: SPOUT1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPOUT1 were set to 39962046 Phenotypes for gene: SPOUT1 were set to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities
05 Sep 2025	Fetal anomalies v6.21	SNAPC4	Arina Puzriakova gene: SNAPC4 was added gene: SNAPC4 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNAPC4 were set to 40186013 Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction
05 Sep 2025	Fetal anomalies v6.21	SLC35A3	Arina Puzriakova gene: SLC35A3 was added gene: SLC35A3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35A3 were set to 28328131; 28777481; 24031089; 33416188 Phenotypes for gene: SLC35A3 were set to Arthrogryposis, mental retardation, and seizures, OMIM:615553
05 Sep 2025	Fetal anomalies v6.21	SLC30A5	Arina Puzriakova gene: SLC30A5 was added gene: SLC30A5 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SLC30A5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC30A5 were set to 33547425; 12095919; 39790720 Phenotypes for gene: SLC30A5 were set to Cardiomyopathy, hydrops fetalis, or cystic hygroma
05 Sep 2025	Fetal anomalies v6.21	SLC19A1	Arina Puzriakova gene: SLC19A1 was added gene: SLC19A1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SLC19A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC19A1 were set to 32276275; 36745868; 11266438; 36517554 Phenotypes for gene: SLC19A1 were set to Immunodeficiency 114, folate-responsive
05 Sep 2025	Fetal anomalies v6.21	SLC12A9	Arina Puzriakova gene: SLC12A9 was added gene: SLC12A9 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SLC12A9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC12A9 were set to 38334070 Phenotypes for gene: SLC12A9 were set to SLC12A9-related syndromic neurodevelopmental disorder with lysosome defects
05 Sep 2025	Fetal anomalies v6.21	SIRT6	Arina Puzriakova Added phenotypes Neurodevelopmental disorder, MONDO:0700092 for gene: SIRT6 Publications for gene: SIRT6 were updated from 29555651; 30135584 to 30135584; 29555651
05 Sep 2025	Fetal anomalies v6.21	SENP7	Arina Puzriakova gene: SENP7 was added gene: SENP7 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SENP7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SENP7 were set to 37460201; 39763084 Phenotypes for gene: SENP7 were set to Fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia
05 Sep 2025	Fetal anomalies v6.21	SEL1L	Arina Puzriakova gene: SEL1L was added gene: SEL1L was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEL1L were set to 37943617; 37943610 Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia
05 Sep 2025	Fetal anomalies v6.21	RPL26	Arina Puzriakova gene: RPL26 was added gene: RPL26 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: RPL26 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPL26 were set to 22431104; 39268718 Phenotypes for gene: RPL26 were set to Diamond-Blackfan anaemia 11, OMIM:614900
05 Sep 2025	Fetal anomalies v6.21	RNU5B-1	Arina Puzriakova gene: RNU5B-1 was added gene: RNU5B-1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RNU5B-1 were set to 40379786 Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302
05 Sep 2025	Fetal anomalies v6.21	RNU5A-1	Arina Puzriakova gene: RNU5A-1 was added gene: RNU5A-1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RNU5A-1 were set to 40379786 Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder, MONDO:0700092
05 Sep 2025	Fetal anomalies v6.21	RNF31	Arina Puzriakova gene: RNF31 was added gene: RNF31 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: RNF31 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF31 were set to 26008899; 30936877 Phenotypes for gene: RNF31 were set to Immunodeficiency 115 with autoinflammation
05 Sep 2025	Fetal anomalies v6.21	RIPPLY2	Arina Puzriakova gene: RIPPLY2 was added gene: RIPPLY2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: RIPPLY2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RIPPLY2 were set to 26238661; 25343988; 32212228; 33410135 Phenotypes for gene: RIPPLY2 were set to Spondylocostal dysostosis 6, OMIM:616566
05 Sep 2025	Fetal anomalies v6.21	RBFOX2	Arina Puzriakova gene: RBFOX2 was added gene: RBFOX2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RBFOX2 were set to 27670201; 25205790; 37165897; 26785492; 27485310; 35137168 Phenotypes for gene: RBFOX2 were set to Congenital heart disease, MONDO:0005453
05 Sep 2025	Fetal anomalies v6.21	RAB11B	Arina Puzriakova Added phenotypes Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter for gene: RAB11B Publications for gene: RAB11B were updated from 29106825 to 39502218; 29106825
05 Sep 2025	Fetal anomalies v6.21	PYGL	Arina Puzriakova Added phenotypes Glycogen storage disease VI for gene: PYGL Publications for gene: PYGL were updated from to 39891418
05 Sep 2025	Fetal anomalies v6.21	PUS3	Arina Puzriakova gene: PUS3 was added gene: PUS3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PUS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PUS3 were set to 31444731; 39891418; 30308082; 30697592; 27055666 Phenotypes for gene: PUS3 were set to Neurodevelopmental disorder with microcephaly and gray sclerae
05 Sep 2025	Fetal anomalies v6.21	PURA	Arina Puzriakova Mode of inheritance for gene PURA was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties for gene: PURA Publications for gene: PURA were updated from to 39521787
05 Sep 2025	Fetal anomalies v6.21	PTEN	Arina Puzriakova Source Expert Review Amber was added to PTEN. Mode of inheritance for gene PTEN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Cowden syndrome 1 for gene: PTEN Publications for gene: PTEN were updated from to 40261085 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	PSKH1	Arina Puzriakova gene: PSKH1 was added gene: PSKH1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PSKH1 were set to 39132680 Phenotypes for gene: PSKH1 were set to hepatorenal syndrome, MONDO:0001382
05 Sep 2025	Fetal anomalies v6.21	PROC	Arina Puzriakova gene: PROC was added gene: PROC was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PROC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PROC were set to 39763161 Phenotypes for gene: PROC were set to Thrombophilia 3 due to protein C deficiency, autosomal recessive
05 Sep 2025	Fetal anomalies v6.21	PPFIBP1	Arina Puzriakova gene: PPFIBP1 was added gene: PPFIBP1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPFIBP1 were set to 35830857; 37229200 Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities
05 Sep 2025	Fetal anomalies v6.21	PPFIA3	Arina Puzriakova gene: PPFIA3 was added gene: PPFIA3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PPFIA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PPFIA3 were set to 37034625; 38508193; 38723631; 38181735 Phenotypes for gene: PPFIA3 were set to Paul-Chao neurodevelopmental syndrome
05 Sep 2025	Fetal anomalies v6.21	POU3F3	Arina Puzriakova gene: POU3F3 was added gene: POU3F3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: POU3F3 were set to 37593446; 31303265 Phenotypes for gene: POU3F3 were set to Snijders Blok-Fisher syndrome
05 Sep 2025	Fetal anomalies v6.21	PLVAP	Arina Puzriakova gene: PLVAP was added gene: PLVAP was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLVAP were set to 31215290; 29875123; 29661969; 26207260 Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
05 Sep 2025	Fetal anomalies v6.21	PLAA	Arina Puzriakova Added phenotypes Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, OMIM:617527 for gene: PLAA Publications for gene: PLAA were updated from 28007986; 28413018; 31322726 to 31322726; 38650658; 28413018; 28007986
05 Sep 2025	Fetal anomalies v6.21	PIGW	Arina Puzriakova gene: PIGW was added gene: PIGW was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PIGW was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGW were set to 40180615 Phenotypes for gene: PIGW were set to Glycosylphosphatidylinositol biosynthesis defect 11
05 Sep 2025	Fetal anomalies v6.21	PIGQ	Arina Puzriakova gene: PIGQ was added gene: PIGQ was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PIGQ was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGQ were set to 24463883; 25558065; 31148362; 32588908 Phenotypes for gene: PIGQ were set to Multiple congenital anomalies-hypotonia-seizures syndrome 4
05 Sep 2025	Fetal anomalies v6.21	PIGP	Arina Puzriakova gene: PIGP was added gene: PIGP was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PIGP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGP were set to 28334793; 32042915; 31139695 Phenotypes for gene: PIGP were set to Developmental and epileptic encephalopathy 55
05 Sep 2025	Fetal anomalies v6.21	PIGM	Arina Puzriakova gene: PIGM was added gene: PIGM was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PIGM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGM were set to 25293775; 16767100 Phenotypes for gene: PIGM were set to Glycosylphosphatidylinositol deficiency
05 Sep 2025	Fetal anomalies v6.21	PIGG	Arina Puzriakova Added phenotypes Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy for gene: PIGG
05 Sep 2025	Fetal anomalies v6.21	PIGC	Arina Puzriakova gene: PIGC was added gene: PIGC was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PIGC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGC were set to 32707268; 27694521 Phenotypes for gene: PIGC were set to Glycosylphosphatidylinositol biosynthesis defect 16
05 Sep 2025	Fetal anomalies v6.21	PI4KA	Arina Puzriakova Added phenotypes Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis for gene: PI4KA Publications for gene: PI4KA were updated from 34415310 to 34415310; 39891418
05 Sep 2025	Fetal anomalies v6.21	PHF5A	Arina Puzriakova gene: PHF5A was added gene: PHF5A was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PHF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PHF5A were set to 33811463; 37422718 Phenotypes for gene: PHF5A were set to PHF5A-related neurodevelopmental disorder with congenital malformations
05 Sep 2025	Fetal anomalies v6.21	PDE12	Arina Puzriakova Added phenotypes Mitochondrial disease, MONDO:0044970 for gene: PDE12
05 Sep 2025	Fetal anomalies v6.21	PDCD2	Arina Puzriakova gene: PDCD2 was added gene: PDCD2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PDCD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDCD2 were set to 40208938 Phenotypes for gene: PDCD2 were set to hydrops fetalis and early pregnancy loss
05 Sep 2025	Fetal anomalies v6.21	PAK2	Arina Puzriakova gene: PAK2 was added gene: PAK2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAK2 were set to 39994693; 40262506; 33693784; 38894571; 37808560; 39876536 Phenotypes for gene: PAK2 were set to Knobloch syndrome 2
05 Sep 2025	Fetal anomalies v6.21	PAICS	Arina Puzriakova Added phenotypes Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426 for gene: PAICS Publications for gene: PAICS were updated from 31600779 to 31178128; 31600779; 3965093; 38179855; 30758658
05 Sep 2025	Fetal anomalies v6.21	OSBPL9	Arina Puzriakova gene: OSBPL9 was added gene: OSBPL9 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: OSBPL9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OSBPL9 were set to 40182349 Phenotypes for gene: OSBPL9 were set to Fetal Cerebral Ventriculomegaly, Cerebellar Hypoplasia, and Arthrogryposis Multiplex
05 Sep 2025	Fetal anomalies v6.21	ODC1	Arina Puzriakova gene: ODC1 was added gene: ODC1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: ODC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ODC1 were set to 40188065 Phenotypes for gene: ODC1 were set to Bachmann-Bupp syndrome
05 Sep 2025	Fetal anomalies v6.21	NUP214	Arina Puzriakova Added phenotypes Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426 for gene: NUP214 Publications for gene: NUP214 were updated from 31178128; 38179855; 30758658; 3965093 to 31178128; 3965093; 38179855; 39650934; 30758658
05 Sep 2025	Fetal anomalies v6.21	NT5E	Arina Puzriakova gene: NT5E was added gene: NT5E was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: NT5E was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NT5E were set to 21288095; 32522903; 28825389; 26178434; 34999808; 27045881; 26010187 Phenotypes for gene: NT5E were set to arterial calcification; joint calcification
05 Sep 2025	Fetal anomalies v6.21	NR2F1	Arina Puzriakova Source Expert Review Amber was added to NR2F1. Mode of inheritance for gene NR2F1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Bosch-Boonstra-Schaaf optic atrophy syndrome for gene: NR2F1 Publications for gene: NR2F1 were updated from to 40066675; 32712214; 31318166; 36221391; 32484994 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	NODAL	Arina Puzriakova Mode of inheritance for gene NODAL was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Heterotaxy, visceral, 5 for gene: NODAL Publications for gene: NODAL were updated from to 9354794; 19064609
05 Sep 2025	Fetal anomalies v6.21	NMNAT1	Arina Puzriakova Source Expert Review Amber was added to NMNAT1. Added phenotypes Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis for gene: NMNAT1 Publications for gene: NMNAT1 were updated from to 39891418 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	NKX2-6	Arina Puzriakova Added phenotypes Conotruncal heart malformations; Persistent truncus arteriosus for gene: NKX2-6 Publications for gene: NKX2-6 were updated from 32198970; 15649947; 24421281; 25319568; 25380965 to 25319568; 15649947; 32198970; 39891418; 25380965; 24421281
05 Sep 2025	Fetal anomalies v6.21	NFASC	Arina Puzriakova gene: NFASC was added gene: NFASC was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: NFASC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NFASC were set to 39891418 Phenotypes for gene: NFASC were set to Neurodevelopmental disorder with central and peripheral motor dysfunction
05 Sep 2025	Fetal anomalies v6.21	NEXN	Arina Puzriakova Mode of inheritance for gene NEXN was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal Added phenotypes Cardiomyopathy for gene: NEXN Publications for gene: NEXN were updated from 33947203; 32058062; 35166435; 33027564; 33949776 to 39183344; 33947203; 33949776; 33027564; 35166435; 32058062
05 Sep 2025	Fetal anomalies v6.21	NEUROD1	Arina Puzriakova gene: NEUROD1 was added gene: NEUROD1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: NEUROD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEUROD1 were set to 26773576; 10545951; 29521454; 26669242; 19609565; 20573748 Phenotypes for gene: NEUROD1 were set to Maturity-onset diabetes of the young 6
05 Sep 2025	Fetal anomalies v6.21	NEPRO	Arina Puzriakova gene: NEPRO was added gene: NEPRO was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEPRO were set to 29620724; 31250547; 37294112; 26633546 Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, OMIM:618853
05 Sep 2025	Fetal anomalies v6.21	NDUFB7	Arina Puzriakova Added phenotypes Mitochondrial complex I deficiency, nuclear type 39 for gene: NDUFB7 Publications for gene: NDUFB7 were updated from 33502047; 27626371; 40025060 to 27626371; 40025060; 33502047
05 Sep 2025	Fetal anomalies v6.21	NAGS	Arina Puzriakova Added phenotypes N-acetylglutamate synthase deficiency for gene: NAGS Publications for gene: NAGS were updated from to 39891418
05 Sep 2025	Fetal anomalies v6.21	NAGLU	Arina Puzriakova Added phenotypes Mucopolysaccharidosis type IIIB (Sanfilippo B) for gene: NAGLU Publications for gene: NAGLU were updated from to 40066675
05 Sep 2025	Fetal anomalies v6.21	MYL2	Arina Puzriakova gene: MYL2 was added gene: MYL2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: MYL2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: MYL2 were set to 39831482 Phenotypes for gene: MYL2 were set to Cardiomyopathy, hypertrophic, 10; Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy
05 Sep 2025	Fetal anomalies v6.21	MYH9	Arina Puzriakova Added phenotypes Deafness, autosomal dominant 17; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss for gene: MYH9 Publications for gene: MYH9 were updated from to 16969870; 31384440
05 Sep 2025	Fetal anomalies v6.21	MSL2	Arina Puzriakova gene: MSL2 was added gene: MSL2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MSL2 were set to 38815585; 33057194; 31332282 Phenotypes for gene: MSL2 were set to Karayol-Borroto-Haghshenas neurodevelopmental syndrome
05 Sep 2025	Fetal anomalies v6.21	MPL	Arina Puzriakova gene: MPL was added gene: MPL was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: MPL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MPL were set to 39763161 Phenotypes for gene: MPL were set to Amegakaryocytic thrombocytopenia, congenital, 1
05 Sep 2025	Fetal anomalies v6.21	MIA3	Arina Puzriakova gene: MIA3 was added gene: MIA3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MIA3 were set to 32101163; 40119123; 33778321 Phenotypes for gene: MIA3 were set to Odontochondrodysplasia-2 with hearing loss and diabetes
05 Sep 2025	Fetal anomalies v6.21	MET	Arina Puzriakova gene: MET was added gene: MET was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: MET was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MET were set to 30777867; 38429387 Phenotypes for gene: MET were set to ?Arthrogryposis, distal, type 1
05 Sep 2025	Fetal anomalies v6.21	MED11	Arina Puzriakova gene: MED11 was added gene: MED11 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED11 were set to 36001086; 39578696 Phenotypes for gene: MED11 were set to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities
05 Sep 2025	Fetal anomalies v6.21	MAPK1	Arina Puzriakova Mode of pathogenicity for gene MAPK1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Added phenotypes Noonan syndrome 13 for gene: MAPK1 Publications for gene: MAPK1 were updated from 32721402 to 32721402; 40257485
05 Sep 2025	Fetal anomalies v6.21	MAP3K3	Arina Puzriakova gene: MAP3K3 was added gene: MAP3K3 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: MAP3K3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAP3K3 were set to 25728774 Phenotypes for gene: MAP3K3 were set to Cerebral cavernous malformations 5
05 Sep 2025	Fetal anomalies v6.21	MAN2B2	Arina Puzriakova gene: MAN2B2 was added gene: MAN2B2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: MAN2B2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAN2B2 were set to 35637269; 31775018; 38622837 Phenotypes for gene: MAN2B2 were set to Congenital disorder of glycosylation type 1EE with or without immunodeficiency
05 Sep 2025	Fetal anomalies v6.21	MAL	Arina Puzriakova gene: MAL was added gene: MAL was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAL were set to 35217805 Phenotypes for gene: MAL were set to ?Leukodystrophy, hypomyelinating, 28 Mode of pathogenicity for gene: MAL was set to Other
05 Sep 2025	Fetal anomalies v6.21	LSS	Arina Puzriakova gene: LSS was added gene: LSS was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LSS were set to 39359128 Phenotypes for gene: LSS were set to Cataract 44; Alopecia-intellectual disability syndrome 4
05 Sep 2025	Fetal anomalies v6.21	LRRC8C	Arina Puzriakova gene: LRRC8C was added gene: LRRC8C was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LRRC8C were set to 39623139 Phenotypes for gene: LRRC8C were set to TIMES syndrome
05 Sep 2025	Fetal anomalies v6.21	LIPN	Arina Puzriakova Added phenotypes Ichthyosis, congenital, autosomal recessive 8 for gene: LIPN Publications for gene: LIPN were updated from 21439540 to 21439540; 39891418
05 Sep 2025	Fetal anomalies v6.21	LGI3	Arina Puzriakova gene: LGI3 was added gene: LGI3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LGI3 were set to 35948005 Phenotypes for gene: LGI3 were set to Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007
05 Sep 2025	Fetal anomalies v6.21	LDB1	Arina Puzriakova gene: LDB1 was added gene: LDB1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LDB1 were set to 39680505 Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349
05 Sep 2025	Fetal anomalies v6.21	LAGE3	Arina Puzriakova Added phenotypes Galloway-Mowat syndrome 2, X-linked for gene: LAGE3 Publications for gene: LAGE3 were updated from 31069511; 28805828 to 31069511; 28805828; 36682911
05 Sep 2025	Fetal anomalies v6.21	KMT2E	Arina Puzriakova Source Expert Review Amber was added to KMT2E. Mode of inheritance for gene KMT2E was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes O'Donnell-Luria-Rodan syndrome for gene: KMT2E Publications for gene: KMT2E were updated from to 40186013 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	C12orf66	Arina Puzriakova gene: C12orf66 was added gene: C12orf66 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C12orf66 were set to 39824192 Phenotypes for gene: C12orf66 were set to Intellectual developmental disorder, autosomal recessive 83
05 Sep 2025	Fetal anomalies v6.21	KDM6B	Arina Puzriakova gene: KDM6B was added gene: KDM6B was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: KDM6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KDM6B were set to 31124270; 37196654 Phenotypes for gene: KDM6B were set to Stolerman neurodevelopmental syndrome, OMIM:618505
05 Sep 2025	Fetal anomalies v6.21	KDM1A	Arina Puzriakova Added phenotypes Cleft palate, psychomotor retardation, and distinctive facial features for gene: KDM1A Publications for gene: KDM1A were updated from 27094131; 24838796; 26656649 to 27094131; 24838796; 26656649
05 Sep 2025	Fetal anomalies v6.21	KCNH2	Arina Puzriakova gene: KCNH2 was added gene: KCNH2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: KCNH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNH2 were set to 36973673; 38094730; 39698424 Phenotypes for gene: KCNH2 were set to Short QT syndrome 1, OMIM:609620; Long QT syndrome 2, OMIM:613688
05 Sep 2025	Fetal anomalies v6.21	KCNB1	Arina Puzriakova Source Expert Review Amber was added to KCNB1. Mode of inheritance for gene KCNB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Developmental and epileptic encephalopathy 26 for gene: KCNB1 Publications for gene: KCNB1 were updated from to 36257979; 39237446; 31513310 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	KBTBD2	Arina Puzriakova gene: KBTBD2 was added gene: KBTBD2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KBTBD2 were set to 39313616 Phenotypes for gene: KBTBD2 were set to Neurodevelopmental disorder, MONDO:0700092
05 Sep 2025	Fetal anomalies v6.21	KAT7	Arina Puzriakova gene: KAT7 was added gene: KAT7 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: KAT7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KAT7 were set to 40186013 Phenotypes for gene: KAT7 were set to Abnormal male external genitalia morphology; Tetralogy of Fallot
05 Sep 2025	Fetal anomalies v6.21	JPH1	Arina Puzriakova gene: JPH1 was added gene: JPH1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: JPH1 were set to 39209426 Phenotypes for gene: JPH1 were set to Congenital myopathy-25
05 Sep 2025	Fetal anomalies v6.21	ITGAV	Arina Puzriakova Added phenotypes Syndromic disease, MONDO:0002254 for gene: ITGAV
05 Sep 2025	Fetal anomalies v6.21	IRF4	Arina Puzriakova gene: IRF4 was added gene: IRF4 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: IRF4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: IRF4 were set to 36917008; 36662884; 29537367; 29408330 Phenotypes for gene: IRF4 were set to Immunodeficiency 131
05 Sep 2025	Fetal anomalies v6.21	IFT27	Arina Puzriakova Added phenotypes Bardet-Biedl syndrome 19 for gene: IFT27 Publications for gene: IFT27 were updated from 25443296; 24488770; 26763875; 30761183 to 25443296; 37239474; 24488770; 30761183; 26763875; 2970430
05 Sep 2025	Fetal anomalies v6.21	HNRNPU	Arina Puzriakova Source Expert Review Amber was added to HNRNPU. Mode of inheritance for gene HNRNPU was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Developmental and epileptic encephalopathy 54 for gene: HNRNPU Publications for gene: HNRNPU were updated from to 39237446; 39965881; 35138025; 39976380 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	HIRA	Arina Puzriakova gene: HIRA was added gene: HIRA was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HIRA were set to 33417013; 38511226 Phenotypes for gene: HIRA were set to Complex neurodevelopmental disorder
05 Sep 2025	Fetal anomalies v6.21	HECTD1	Arina Puzriakova gene: HECTD1 was added gene: HECTD1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: HECTD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: HECTD1 were set to 39879987; 38451291; 37165897 Phenotypes for gene: HECTD1 were set to Neurodevelopmental disorder, MONDO:0700092
05 Sep 2025	Fetal anomalies v6.21	HDAC3	Arina Puzriakova gene: HDAC3 was added gene: HDAC3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: HDAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HDAC3 were set to 39047730 Phenotypes for gene: HDAC3 were set to HDAC3-related neurodevelopmental disorder
05 Sep 2025	Fetal anomalies v6.21	GUK1	Arina Puzriakova gene: GUK1 was added gene: GUK1 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GUK1 were set to 39230499 Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome 21
05 Sep 2025	Fetal anomalies v6.21	GTPBP1	Arina Puzriakova Added phenotypes Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888 for gene: GTPBP1
05 Sep 2025	Fetal anomalies v6.21	GNS	Arina Puzriakova Added phenotypes Mucopolysaccharidosis type IIID, OMIM:252940 for gene: GNS
05 Sep 2025	Fetal anomalies v6.21	GNPNAT1	Arina Puzriakova gene: GNPNAT1 was added gene: GNPNAT1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNPNAT1 were set to 39945447 Phenotypes for gene: GNPNAT1 were set to Rhizomelic dysplasia, Ain-Naz type
05 Sep 2025	Fetal anomalies v6.21	GNAI2	Arina Puzriakova gene: GNAI2 was added gene: GNAI2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: GNAI2 were set to 39298586 Phenotypes for gene: GNAI2 were set to Syndromic developmental disorder
05 Sep 2025	Fetal anomalies v6.21	GEMIN4	Arina Puzriakova gene: GEMIN4 was added gene: GEMIN4 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: GEMIN4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GEMIN4 were set to 39891418 Phenotypes for gene: GEMIN4 were set to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities
05 Sep 2025	Fetal anomalies v6.21	GDAP1	Arina Puzriakova gene: GDAP1 was added gene: GDAP1 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: GDAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GDAP1 were set to 39945447 Phenotypes for gene: GDAP1 were set to Charcot-Marie-Tooth disease, type 4A
05 Sep 2025	Fetal anomalies v6.21	GATA5	Arina Puzriakova Mode of inheritance for gene GATA5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Added phenotypes Congenital heart defects, multiple types, 5 for gene: GATA5 Publications for gene: GATA5 were updated from 33082562 to 40076735; 33082562
05 Sep 2025	Fetal anomalies v6.21	GALT	Arina Puzriakova Source Expert Review Amber was added to GALT. Added phenotypes Galactosemia for gene: GALT Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	G6PD	Arina Puzriakova Source Expert Review Amber was added to G6PD. Added phenotypes Glucose-6-phosphate dehydrogenase deficiency for gene: G6PD Publications for gene: G6PD were updated from 33082562 to 39041728; 33082562 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	FLVCR1	Arina Puzriakova Added phenotypes Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060 for gene: FLVCR1
05 Sep 2025	Fetal anomalies v6.21	FLII	Arina Puzriakova gene: FLII was added gene: FLII was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: FLII was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FLII were set to 37561591; 32870709 Phenotypes for gene: FLII were set to Cardiomyopathy, dilated, 2J
05 Sep 2025	Fetal anomalies v6.21	FGG	Arina Puzriakova gene: FGG was added gene: FGG was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: FGG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FGG were set to 39891418 Phenotypes for gene: FGG were set to Afibrinogenemia, congenital; Hypofibrinogenemia, congenital
05 Sep 2025	Fetal anomalies v6.21	FBXW11	Arina Puzriakova Added phenotypes Neurodevelopmental, jaw, eye, and digital syndrome for gene: FBXW11 Publications for gene: FBXW11 were updated from 31402090 to 31402090; 40188065
05 Sep 2025	Fetal anomalies v6.21	FBXO22	Arina Puzriakova gene: FBXO22 was added gene: FBXO22 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: FBXO22 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FBXO22 were set to 40215970 Phenotypes for gene: FBXO22 were set to Tayoun-Maawali syndrome
05 Sep 2025	Fetal anomalies v6.21	FAM177A1	Arina Puzriakova gene: FAM177A1 was added gene: FAM177A1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: FAM177A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM177A1 were set to 38767059; 25558065 Phenotypes for gene: FAM177A1 were set to Neurodevelopmental disorder with white matter abnormalities and gait disturbance
05 Sep 2025	Fetal anomalies v6.21	EXOSC8	Arina Puzriakova Added phenotypes Pontocerebellar hypoplasia type 1C for gene: EXOSC8 Publications for gene: EXOSC8 were updated from 24989451; 34210538 to 38017281; 34210538; 24989451
05 Sep 2025	Fetal anomalies v6.21	EXOC6B	Arina Puzriakova gene: EXOC6B was added gene: EXOC6B was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: EXOC6B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOC6B were set to 30284759; 36150098; 26669664 Phenotypes for gene: EXOC6B were set to Spondyloepimetaphyseal dysplasia with joint laxity, type 3
05 Sep 2025	Fetal anomalies v6.21	ERG	Arina Puzriakova gene: ERG was added gene: ERG was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: ERG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ERG were set to 36928819 Phenotypes for gene: ERG were set to Lymphatic malformation 14
05 Sep 2025	Fetal anomalies v6.21	EFL1	Arina Puzriakova gene: EFL1 was added gene: EFL1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: EFL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EFL1 were set to 28331068; 31151987; 34115847; 29970384 Phenotypes for gene: EFL1 were set to Shwachman-Diamond syndrome 2
05 Sep 2025	Fetal anomalies v6.21	EEFSEC	Arina Puzriakova gene: EEFSEC was added gene: EEFSEC was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EEFSEC were set to 39753114 Phenotypes for gene: EEFSEC were set to Neurodevelopmental disorder with progressive spasticity and brain abnormalities
05 Sep 2025	Fetal anomalies v6.21	DVL2	Arina Puzriakova Mode of pathogenicity for gene DVL2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Added phenotypes Robinow syndrome, MONDO:0019978 for gene: DVL2 Publications for gene: DVL2 were updated from 35047859; 33599851; 30521570 to 33599851; 30521570; 35047859
05 Sep 2025	Fetal anomalies v6.21	DTNA	Arina Puzriakova gene: DTNA was added gene: DTNA was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: DTNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DTNA were set to 36799992 Phenotypes for gene: DTNA were set to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2
05 Sep 2025	Fetal anomalies v6.21	DST	Arina Puzriakova gene: DST was added gene: DST was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DST were set to 37431644 Phenotypes for gene: DST were set to Arthrogryposis multiplex congenita
05 Sep 2025	Fetal anomalies v6.21	DSE	Arina Puzriakova gene: DSE was added gene: DSE was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: DSE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DSE were set to 31655143; 25703627; 23704329; 32130795 Phenotypes for gene: DSE were set to Ehlers-Danlos syndrome, musculocontractural type 2
05 Sep 2025	Fetal anomalies v6.21	DSC2	Arina Puzriakova gene: DSC2 was added gene: DSC2 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: DSC2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: DSC2 were set to 40188065 Phenotypes for gene: DSC2 were set to Arrhythmogenic right ventricular dysplasia, familial, 11
05 Sep 2025	Fetal anomalies v6.21	DOHH	Arina Puzriakova Added phenotypes Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, OMIM:620066 for gene: DOHH
05 Sep 2025	Fetal anomalies v6.21	DNAJC21	Arina Puzriakova gene: DNAJC21 was added gene: DNAJC21 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: DNAJC21 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAJC21 were set to 29700810; 28062395; 27346687 Phenotypes for gene: DNAJC21 were set to Bone marrow failure syndrome 3
05 Sep 2025	Fetal anomalies v6.21	DHX9	Arina Puzriakova gene: DHX9 was added gene: DHX9 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DHX9 were set to 37369308; 37467750 Phenotypes for gene: DHX9 were set to Intellectual developmental disorder, autosomal dominant 75
05 Sep 2025	Fetal anomalies v6.21	DHRSX	Arina Puzriakova gene: DHRSX was added gene: DHRSX was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: DHRSX was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHRSX were set to 38821050 Phenotypes for gene: DHRSX were set to Congenital disorder of glycosylation, type 1DD, OMIM:301133
05 Sep 2025	Fetal anomalies v6.21	DDX17	Arina Puzriakova gene: DDX17 was added gene: DDX17 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: DDX17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DDX17 were set to 39405200 Phenotypes for gene: DDX17 were set to Neurodevelopmental disorder, MONDO:0700092
05 Sep 2025	Fetal anomalies v6.21	DAND5	Arina Puzriakova gene: DAND5 was added gene: DAND5 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: DAND5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DAND5 were set to 36316122; 34215651 Phenotypes for gene: DAND5 were set to Heterotaxy, visceral, 13, autosomal
05 Sep 2025	Fetal anomalies v6.21	CYP24A1	Arina Puzriakova gene: CYP24A1 was added gene: CYP24A1 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: CYP24A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYP24A1 were set to 28324001; 34307984; 22337913; 27105398 Phenotypes for gene: CYP24A1 were set to cystic kidney disease; hypercalcaemia; nephrocalcinosis
05 Sep 2025	Fetal anomalies v6.21	COQ2	Arina Puzriakova Source Expert Review Amber was added to COQ2. Added phenotypes Coenzyme Q10 deficiency, primary, 1 for gene: COQ2 Publications for gene: COQ2 were updated from to 39763161 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	COMP	Arina Puzriakova Source Expert Review Amber was added to COMP. Mode of inheritance for gene COMP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Mode of pathogenicity for gene COMP was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Added phenotypes Pseudoachondroplasia; Epiphyseal dysplasia, multiple, 1 for gene: COMP Publications for gene: COMP were updated from to 39521787; 40188065 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	COL25A1	Arina Puzriakova Source Expert Review Amber was added to COL25A1. Added phenotypes Arthrogryposis multiplex congenita for gene: COL25A1 Publications for gene: COL25A1 were updated from 26437029; 35077597 to 26437029; 40158061; 35077597 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	C1orf127	Arina Puzriakova Added phenotypes Heterotaxy, visceral, 14, autosomal for gene: C1orf127
05 Sep 2025	Fetal anomalies v6.21	CHAF1A	Arina Puzriakova gene: CHAF1A was added gene: CHAF1A was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: CHAF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CHAF1A were set to 39333427 Phenotypes for gene: CHAF1A were set to Oculo-auriculo-vertebral spectrum
05 Sep 2025	Fetal anomalies v6.21	CFI	Arina Puzriakova gene: CFI was added gene: CFI was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: CFI was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CFI were set to 39891418 Phenotypes for gene: CFI were set to Complement factor I deficiency
05 Sep 2025	Fetal anomalies v6.21	CELSR1	Arina Puzriakova Added phenotypes Lymphatic malformation-9 for gene: CELSR1 Publications for gene: CELSR1 were updated from 26855770; 31215153; 31403174 to 38272662; 31403174; 26855770; 31215153
05 Sep 2025	Fetal anomalies v6.21	CDK5	Arina Puzriakova gene: CDK5 was added gene: CDK5 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK5 were set to 25560765; 40186457 Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia
05 Sep 2025	Fetal anomalies v6.21	CCT8	Arina Puzriakova gene: CCT8 was added gene: CCT8 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: CCT8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CCT8 were set to 39480921 Phenotypes for gene: CCT8 were set to CCT8-related neurodevelopmental disorder with brain abnormalities
05 Sep 2025	Fetal anomalies v6.21	CCT6A	Arina Puzriakova gene: CCT6A was added gene: CCT6A was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: CCT6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CCT6A were set to 39480921 Phenotypes for gene: CCT6A were set to CCT6A-related neurodevelopmental disorder with or without brain abnormalities
05 Sep 2025	Fetal anomalies v6.21	CCT3	Arina Puzriakova gene: CCT3 was added gene: CCT3 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: CCT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CCT3 were set to 39480921 Phenotypes for gene: CCT3 were set to Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination
05 Sep 2025	Fetal anomalies v6.21	CTGF	Arina Puzriakova gene: CTGF was added gene: CTGF was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTGF were set to 39506047; 12736220; 39414788 Phenotypes for gene: CTGF were set to Kyphomelic dysplasia
05 Sep 2025	Fetal anomalies v6.21	BRD2	Arina Puzriakova gene: BRD2 was added gene: BRD2 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: BRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BRD2 were set to 40186013 Phenotypes for gene: BRD2 were set to Agenesis of corpus callosum
05 Sep 2025	Fetal anomalies v6.21	BORCS8	Arina Puzriakova gene: BORCS8 was added gene: BORCS8 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BORCS8 were set to 38128568 Phenotypes for gene: BORCS8 were set to Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities
05 Sep 2025	Fetal anomalies v6.21	BICRA	Arina Puzriakova gene: BICRA was added gene: BICRA was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BICRA were set to 33232675 Phenotypes for gene: BICRA were set to Coffin-Siris syndrome 12
05 Sep 2025	Fetal anomalies v6.21	BHLHE22	Arina Puzriakova gene: BHLHE22 was added gene: BHLHE22 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: BHLHE22 were set to 39502664 Phenotypes for gene: BHLHE22 were set to Complex neurodevelopmental disorder
05 Sep 2025	Fetal anomalies v6.21	BAIAP2	Arina Puzriakova gene: BAIAP2 was added gene: BAIAP2 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BAIAP2 were set to 38149472 Phenotypes for gene: BAIAP2 were set to Lissencephaly
05 Sep 2025	Fetal anomalies v6.21	ASCC3	Arina Puzriakova Added phenotypes Intellectual developmental disorder, autosomal recessive 81, OMIM:620700 for gene: ASCC3
05 Sep 2025	Fetal anomalies v6.21	ARPC5	Arina Puzriakova gene: ARPC5 was added gene: ARPC5 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARPC5 were set to 37349293; 37382373 Phenotypes for gene: ARPC5 were set to Immunodeficiency 113 with autoimmunity and autoinflammation
05 Sep 2025	Fetal anomalies v6.21	ARL6IP1	Arina Puzriakova gene: ARL6IP1 was added gene: ARL6IP1 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: ARL6IP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARL6IP1 were set to 39954331 Phenotypes for gene: ARL6IP1 were set to Spastic paraplegia 61, autosomal recessive, OMIM:615685
05 Sep 2025	Fetal anomalies v6.21	ARL2BP	Arina Puzriakova gene: ARL2BP was added gene: ARL2BP was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: ARL2BP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARL2BP were set to 27790702; 36507858; 23849777; 38649918; 40384762 Phenotypes for gene: ARL2BP were set to Situs Inversus
05 Sep 2025	Fetal anomalies v6.21	AGT	Arina Puzriakova Added phenotypes Renal tubular dysgenesis for gene: AGT Publications for gene: AGT were updated from 16116425; 28976722; 33163725; 34234805 to 34234805; 28976722; 16116425; 39641285; 33163725
05 Sep 2025	Fetal anomalies v6.21	AGRN	Arina Puzriakova Source Expert Review Amber was added to AGRN. Added phenotypes Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects for gene: AGRN Publications for gene: AGRN were updated from 31730230; 39807604 to 31730230; 39807604 Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
05 Sep 2025	Fetal anomalies v6.21	ACTN2	Arina Puzriakova gene: ACTN2 was added gene: ACTN2 was added to Fetal anomalies. Sources: Expert Review Red Mode of inheritance for gene: ACTN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ACTN2 were set to 39521787 Phenotypes for gene: ACTN2 were set to Cardiomyopathy, hypertrophic, 23, with or without LVNC; Cardiomyopathy, dilated, 1AA, with or without LVNC; Congenital myopathy 8
05 Sep 2025	Fetal anomalies v6.21	ACO2	Arina Puzriakova Added phenotypes Infantile cerebellar-retinal degeneration for gene: ACO2 Publications for gene: ACO2 were updated from 34056600 to 34056600; 39891418
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.74	TANGO2	Achchuthan Shanmugasundram Publications for gene: TANGO2 were set to 26805781; 30245509; 31339582; 32527145; 35568137; 40156300
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.73	TANGO2	Achchuthan Shanmugasundram edited their review of gene: TANGO2: Changed publications to: 26805781, 30245509, 31339582, 32527145, 35568137, 39472908, 40156300
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.73	TANGO2	Achchuthan Shanmugasundram changed review comment from: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion). PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion). PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy. PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing. PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy. Sources: Literature; to: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion). PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion). PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy. PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing. PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult patient with unspecified cardiomyopathy was identified with an intragenic homozygous deletion in TANGO2 gene via analysis of data from trio genome sequencing. PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy. Sources: Literature
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.73	TANGO2	Achchuthan Shanmugasundram changed review comment from: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion). PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion). PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy. PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing. PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy. Sources: Literature; to: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion). PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion). PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy. PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing. PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy. Sources: Literature
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.73	TANGO2	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: TANGO2.
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.73	TANGO2	Achchuthan Shanmugasundram Classified gene: TANGO2 as Amber List (moderate evidence)
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.73	TANGO2	Achchuthan Shanmugasundram Added comment: Comment on list classification: Although cardiomyopathy was reported only in a very small proportion of patients with biallelic TANGO2 variants from earlier studies, 19 patients (70%) from the multi-centre study from PMID:35568137 and both unrelated patients from PMID:4015630 were reported with cardiomyopathy. As there are over 20 patients reported with cardiomyopathy, this gene can be promoted to green rating on this panel in the next GMS update.
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.73	TANGO2	Achchuthan Shanmugasundram Gene: tango2 has been classified as Amber List (Moderate Evidence).
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.72	TANGO2	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM (MIM #616878, accessed on 05 September 2025) and Gene2Phenotype (TANGO2-related infancy-onset recurrent metabolic crises with encephalocardiomyopathy with 'definitive' rating on the DD panel).
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.72	TANGO2	Achchuthan Shanmugasundram Phenotypes for gene: TANGO2 were changed from Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820 to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820
05 Sep 2025	Cardiac arrhythmias - additional genes v3.7	TANGO2	Achchuthan Shanmugasundram Publications for gene: TANGO2 were set to 26805781; 26805782; 30245509; 31339582; 32929747
05 Sep 2025	Cardiac arrhythmias - additional genes v3.6	TANGO2	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are over 20 unrelated patients reported with biallelic TANGO2 variants and with cardiac arrhythmia as one of the clinical presentations of the TANGO2-related disorder. Expert review is being sought on the promotion of this gene to green rating on this panel. This is due to this gene being not previously approved for promotion to green rating on this panel by the NHS Genomic Medicine Service.; to: Comment on list classification: There are over 30 unrelated patients reported with biallelic TANGO2 variants and with cardiac arrhythmia as one of the clinical presentations of the TANGO2-related disorder. Expert review is being sought on the promotion of this gene to green rating on this panel. This is due to this gene being not previously approved for promotion to green rating on this panel by the NHS Genomic Medicine Service.
05 Sep 2025	Cardiac arrhythmias - additional genes v3.6	TANGO2	Achchuthan Shanmugasundram edited their review of gene: TANGO2: Changed publications to: 26805781, 26805782, 30245509, 31339582, 32929747, 35568137, 40156300
05 Sep 2025	Cardiac arrhythmias - additional genes v3.6	TANGO2	Achchuthan Shanmugasundram changed review comment from: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Life-threatening cardiac tachyarrhythmia presented as torsade de pointes or ventricular tachycardia in 4 of 12 patients. PMID:26805782 (2016) reported the identification of three different biallelic truncating variants in TANGO2 genes in three unrelated patients with infantile-onset metabolic disorder characterised by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Arrhythmia was reported in five of 14 patients. PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). All, but one patient showed cardiac arrhythmias. PMID:32929747 (2021) conducted a retrospective analysis of patients with a diagnosis of TANGO2 disease, where seven single nucleotide variants (five were novel), 2 small deletions and exons 3-9 deletion were identified in 20 patients from 14 families. 12 of these patients had cardiac abnormalities - long QT in ten, Brugada pattern in two, and cardiac arrhythmia in six.; to: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Life-threatening cardiac tachyarrhythmia presented as torsade de pointes or ventricular tachycardia in 4 of 12 patients. PMID:26805782 (2016) reported the identification of three different biallelic truncating variants in TANGO2 genes in three unrelated patients with infantile-onset metabolic disorder characterised by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Arrhythmia was reported in five of 14 patients. PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). All, but one patient showed cardiac arrhythmias. PMID:32929747 (2021) conducted a retrospective analysis of patients with a diagnosis of TANGO2 disease, where seven single nucleotide variants (five were novel), 2 small deletions and exons 3-9 deletion were identified in 20 patients from 14 families. 12 of these patients had cardiac abnormalities - long QT in ten, Brugada pattern in two, and cardiac arrhythmia in six. PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
05 Sep 2025	Paediatric or syndromic cardiomyopathy v7.71	TANGO2	Achchuthan Shanmugasundram gene: TANGO2 was added gene: TANGO2 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TANGO2 were set to 26805781; 30245509; 31339582; 32527145; 35568137; 40156300 Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820 Review for gene: TANGO2 was set to GREEN Added comment: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion). PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion). PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy. PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing. PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy. Sources: Literature
05 Sep 2025	Cardiac arrhythmias - additional genes v3.6	TANGO2	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: TANGO2. Tag Q3_25_expert_review tag was added to gene: TANGO2.
05 Sep 2025	Cardiac arrhythmias - additional genes v3.6	TANGO2	Achchuthan Shanmugasundram Classified gene: TANGO2 as Amber List (moderate evidence)
05 Sep 2025	Cardiac arrhythmias - additional genes v3.6	TANGO2	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are over 20 unrelated patients reported with biallelic TANGO2 variants and with cardiac arrhythmia as one of the clinical presentations of the TANGO2-related disorder. Expert review is being sought on the promotion of this gene to green rating on this panel. This is due to this gene being not previously approved for promotion to green rating on this panel by the NHS Genomic Medicine Service.
05 Sep 2025	Cardiac arrhythmias - additional genes v3.6	TANGO2	Achchuthan Shanmugasundram Gene: tango2 has been classified as Amber List (Moderate Evidence).
05 Sep 2025	Cardiac arrhythmias - additional genes v3.5	TANGO2	Achchuthan Shanmugasundram Publications for gene: TANGO2 were set to 26805782; 30245509
05 Sep 2025	Cardiac arrhythmias - additional genes v3.4	TANGO2	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM (MIM #616878, accessed on 05 September 2025) and Gene2Phenotype (TANGO2-related infancy-onset recurrent metabolic crises with encephalocardiomyopathy with 'definitive' rating on the DD panel).
05 Sep 2025	Cardiac arrhythmias - additional genes v3.4	TANGO2	Achchuthan Shanmugasundram Phenotypes for gene: TANGO2 were changed from Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 616878 to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820
05 Sep 2025	Cardiac arrhythmias - additional genes v3.3	TANGO2	Achchuthan Shanmugasundram reviewed gene: TANGO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26805781, 26805782, 30245509, 31339582, 32929747; Phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
03 Sep 2025	Acute rhabdomyolysis v2.3	POC5	Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and sometimes accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel. This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and sometimes accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel.
03 Sep 2025	Acute rhabdomyolysis v2.3	POC5	Arina Puzriakova Entity copied from Rhabdomyolysis and metabolic muscle disorders v5.9
03 Sep 2025	Acute rhabdomyolysis v2.3	POC5	Arina Puzriakova gene: POC5 was added gene: POC5 was added to Acute rhabdomyolysis. Sources: Literature,Expert Review Amber dd_review, Q3_25_promote_green tags were added to gene: POC5. Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POC5 were set to 29272404; 40590205 Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology; muscle cramps
03 Sep 2025	Rhabdomyolysis and metabolic muscle disorders v5.9	POC5	Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel. This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and sometimes accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel. This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.
03 Sep 2025	Rhabdomyolysis and metabolic muscle disorders v5.9	POC5	Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (often triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel. This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel. This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.
03 Sep 2025	Rhabdomyolysis and metabolic muscle disorders v5.9	POC5	Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (often triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel. This disorder is also relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (often triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel. This disorder is relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.
03 Sep 2025	Rhabdomyolysis and metabolic muscle disorders v5.9	POC5	Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
03 Sep 2025	Rhabdomyolysis and metabolic muscle disorders v5.9	POC5	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Although rhabdomyolysis was only considered in one patient (P5 in PMID: 40590205), debilitating muscle pain/cramps (often triggered by exercise and accompanied by elevated serum CK) represent a notable feature of the disorder which is best captured by this panel. This disorder is also relevant to the R381 Other rare neuromuscular disorders super panel, which will be applied through inclusion on this panel.
03 Sep 2025	Rhabdomyolysis and metabolic muscle disorders v5.9	POC5	Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
03 Sep 2025	Ophthalmological ciliopathies v5.3	POC5	Arina Puzriakova changed review comment from: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature; to: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature
03 Sep 2025	Severe insulin resistance and lipodystrophy syndromes v4.62	POC5	Arina Puzriakova changed review comment from: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature; to: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature
03 Sep 2025	Monogenic diabetes v3.3	POC5	Arina Puzriakova changed review comment from: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature; to: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature
03 Sep 2025	Retinal disorders v8.23	POC5	Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
03 Sep 2025	Rhabdomyolysis and metabolic muscle disorders v5.8	POC5	Arina Puzriakova gene: POC5 was added gene: POC5 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature dd_review, Q3_25_promote_green tags were added to gene: POC5. Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POC5 were set to 29272404; 40590205 Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology; muscle cramps Review for gene: POC5 was set to GREEN Added comment: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and neuromuscular abnormalities (10/12) primarily comprising intermittent, involuntary painful muscle cramps (8/12). Muscle cramps arose in childhood and were often disabling and difficult to treat. Elevated serum CK levels were noted in 4 individuals. Ten different variants identified with two variants found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature
02 Sep 2025	DDG2P v6.5	TNFRSF13B	Arina Puzriakova Classified gene: TNFRSF13B as Green List (high evidence)
02 Sep 2025	DDG2P v6.5	TNFRSF13B	Arina Puzriakova Added comment: Comment on list classification: The content of this panel reflects genes and classifications assigned by Gene2Phenotype on their DDG2P panel. 'TNFRSF13B-related immunodeficiency, common variable' is currently classified as 'strong' (https://www.ebi.ac.uk/gene2phenotype/gene/TNFRSF13B) which maps to the PanelApp rating of Green - therefore this rating will be maintained on this panel.
02 Sep 2025	DDG2P v6.5	TNFRSF13B	Arina Puzriakova Gene: tnfrsf13b has been classified as Green List (High Evidence).
02 Sep 2025	DDG2P v6.4	PDE1B	Arina Puzriakova Classified gene: PDE1B as No list
02 Sep 2025	DDG2P v6.4	PDE1B	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support this gene disease association, however, the content of this panel reflects genes and classifications assigned by Gene2Phenotype (G2P) on their DDG2P panel. PDE1B is currently not associated with any disease models in G2P and therefore the grey rating will be maintained on this panel at this time. PDE1B has already been curated on other GMS panels with a green recommendation (Childhood onset dystonia, chorea or related movement disorder and Ataxia and cerebellar anomalies) to capture the evidence and ensure inclusion of this gene in the NHS GMS.
02 Sep 2025	DDG2P v6.4	PDE1B	Arina Puzriakova Gene: pde1b has been removed from the panel.
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.70	ATAD3A	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ATAD3A.
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.70	ATAD3A	Achchuthan Shanmugasundram Classified gene: ATAD3A as Amber List (moderate evidence)
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.70	ATAD3A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in ATAD3A gene with syndromic cardiomyopathy. Although the majority of the cases are reported with CNVs involving deletions or duplications of ATAD3 gene cluster (ATAD3A, ATAD3B & ATAD3C genes), there are also patients reported with small variants in monoallelic or biallelic states (as homozygous or as compound heterozygous with the CNV). Hence, this gene can be promoted to green rating in the next GMS update.
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.70	ATAD3A	Achchuthan Shanmugasundram Gene: atad3a has been classified as Amber List (Moderate Evidence).
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.69	ATAD3A	Achchuthan Shanmugasundram Tag cnv tag was added to gene: ATAD3A.
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.69	ATAD3A	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 02 September 2025.
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.69	ATAD3A	Achchuthan Shanmugasundram Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, OMIM:617183; Harel-Yoon syndrome, MONDO:0014958; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, MONDO:0032931 to Harel-Yoon syndrome, OMIM:617183; Harel-Yoon syndrome, MONDO:0014958; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, MONDO:0032931
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.68	ATAD3A	Achchuthan Shanmugasundram gene: ATAD3A was added gene: ATAD3A was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ATAD3A were set to 27640307; 28549128; 31727539; 32004445; 33575671; 37095554 Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, OMIM:617183; Harel-Yoon syndrome, MONDO:0014958; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, MONDO:0032931 Review for gene: ATAD3A was set to GREEN Added comment: PMID:27640307 (2016) reported the identification of the same recurrent de novo ATAD3A variant (c.1582C>T/ p.Arg528Trp) in five unrelated individuals. Their clinical presentations included global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy (HCM). HCM was identified in two of five patients. This study also reported two additional families with biallelic ATAD3A variants - one family with homozygous c.158C>T/ p.Thr53Ile variant and the unrelated newborn with biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. The newborn with the deletion variants had mild RVH with septal hypertrophy. PMID:28549128 (2017) reported five patients from four unrelated families with fatal congenital pontocerebellar hypoplasia and with large biallelic deletions that generate chimeric ATAD3B/ATAD3A fusion genes. Progressive cardiac hypertrophy was reported in one of five patients. PMID:31727539 (2019) reported the identification of a novel homozygous missense variant in ATAD3A gene (c.1217 T > G/ p.Leu406Arg) in four siblings from a consanguineous family presenting with fatal neonatal cerebellar hypoplasia, seizures, axial hypotonia, HCM, hepatomegaly, congenital cataract, and dysmorphic facies. HCM was reported in all four patients. PMID:32004445 (2020) reported five unrelated neonates with a heterozygous 67-kb duplication at 1p36.33 creating an in-frame ATAD3A–ATAD3C fusion gene. They presented with a disorder characterised by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures. HCM and DCM were reported in three and two patients respectively. PMID:33575671 (2021) reported the investigation of 17 patients from 16 unrelated families, where six different de novo duplications in the ATAD3 gene locus (ATAD3A–ATAD3C fusion duplications) were reported. They presented with lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently corneal clouding or cataracts and encephalopathy. PMID:37095554 (2023) reported four patients from two families with compound heterozygous c.229C>G (p.Leu77Val) variant and 3-4 exon deletion in ATAD3A gene. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. Two patients from one of these two families were reported with mild HCM. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which two paediatric patients with unspecified cardiomyopathy were identified with de novo heterozygous duplication in ATAD3 gene cluster via reanalysis of data from trio genome sequencing. Both monoallelic and biallelic variants in ATAD3A gene have been reported with relevant phenotypes in both OMIM (MIM #617183) and Gene2Phenotype (definitive rating for monoallelic and strong rating for biallelic on the DD panel). Records from both resources include hypertrophic cardiomyopathy as part of the phenotype. This gene is also green on the 'Cardiomyopathy_Paediatric' panel on PanelApp Australia. Sources: Literature
02 Sep 2025	DDG2P v6.3	ELFN1	Arina Puzriakova Publications for gene: ELFN1 were set to 34509675
02 Sep 2025	DDG2P v6.2	ELFN1	Arina Puzriakova Classified gene: ELFN1 as Red List (low evidence)
02 Sep 2025	DDG2P v6.2	ELFN1	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support this gene disease association, however, the content of this panel reflects genes and classifications assigned by Gene2Phenotype on their DDG2P panel. 'ELFN1-related intellectual disability and epilepsy' is currently classified as 'limited' (https://www.ebi.ac.uk/gene2phenotype/gene/ELFN1) which maps to the PanelApp rating of Red - therefore this rating will be maintained on this panel. This gene has been added to other GMS panels with a green recommendation (ID and epilepsy) to capture the evidence and ensure inclusion of ELFN1 in the NHS GMS.
02 Sep 2025	DDG2P v6.2	ELFN1	Arina Puzriakova Gene: elfn1 has been classified as Red List (Low Evidence).
02 Sep 2025	Intellectual disability v9.68	ELFN1	Arina Puzriakova Classified gene: ELFN1 as Amber List (moderate evidence)
02 Sep 2025	Intellectual disability v9.68	ELFN1	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
02 Sep 2025	Intellectual disability v9.68	ELFN1	Arina Puzriakova Gene: elfn1 has been classified as Amber List (Moderate Evidence).
02 Sep 2025	Early onset or syndromic epilepsy v8.25	ELFN1	Arina Puzriakova Classified gene: ELFN1 as Amber List (moderate evidence)
02 Sep 2025	Early onset or syndromic epilepsy v8.25	ELFN1	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
02 Sep 2025	Early onset or syndromic epilepsy v8.25	ELFN1	Arina Puzriakova Gene: elfn1 has been classified as Amber List (Moderate Evidence).
02 Sep 2025	Early onset or syndromic epilepsy v8.24	ELFN1	Arina Puzriakova gene: ELFN1 was added gene: ELFN1 was added to Early onset or syndromic epilepsy. Sources: Literature Q3_25_promote_green tags were added to gene: ELFN1. Mode of inheritance for gene: ELFN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ELFN1 were set to 40576023; 34509675; 34452636 Phenotypes for gene: ELFN1 were set to Neurodevelopmental disorder, MONDO:0700092 Review for gene: ELFN1 was set to GREEN Added comment: Total of 14 individuals from 7 unrelated families with biallelic loss of function variants in ELFN1 and a neurodevelopmental disorder comprising DD/ID ranging from moderate to severe (13/13) and epilepsy (12/13). Other features included dysmorphic features, behavioural disturbances, ADHD, ASD, hypotonia, muscle weakness, ataxia. Knockout and haploinsufficiency studies in mice resulted in detectable phenotypes compatible with ELFN1 deficiency disorder. Sources: Literature
02 Sep 2025	Intellectual disability v9.67	ELFN1	Arina Puzriakova gene: ELFN1 was added gene: ELFN1 was added to Intellectual disability. Sources: Literature Q3_25_promote_green tags were added to gene: ELFN1. Mode of inheritance for gene: ELFN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ELFN1 were set to 40576023; 34509675; 34452636 Phenotypes for gene: ELFN1 were set to Neurodevelopmental disorder, MONDO:0700092 Review for gene: ELFN1 was set to GREEN Added comment: Total of 14 individuals from 7 unrelated families with biallelic loss of function variants in ELFN1 and a neurodevelopmental disorder comprising DD/ID ranging from moderate to severe (13/13) and epilepsy (12/13). Other features included dysmorphic features, behavioural disturbances, ADHD, ASD, hypotonia, muscle weakness, ataxia. Knockout and haploinsufficiency studies in mice resulted in detectable phenotypes compatible with ELFN1 deficiency disorder. Sources: Literature
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.67	FGFR3	Achchuthan Shanmugasundram Classified gene: FGFR3 as Red List (low evidence)
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.67	FGFR3	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is no evidence directly linking FGFR3 variants to any cardiac phenotype except one patient reported from the reanalysis of the UK 100,000 genomes cohort. The phenotype was not fully explained by the genotype in this patient. Hence, there is no reliable evidence for this association and the gene should be rated red.
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.67	FGFR3	Achchuthan Shanmugasundram Gene: fgfr3 has been classified as Red List (Low Evidence).
02 Sep 2025	Paediatric or syndromic cardiomyopathy v7.66	FGFR3	Achchuthan Shanmugasundram gene: FGFR3 was added gene: FGFR3 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: FGFR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FGFR3 were set to 39472908 Review for gene: FGFR3 was set to RED Added comment: All reported FGFR3 variants cause skeletal or craniofacial syndromes (e.g. achondroplasia, thanatophoric dysplasia) and there are no reports of FGFR3 variants causing cardiomyopathy as a direct phenotype. It is reported in Rare disease advisor (https://www.rarediseaseadvisor.com/disease-info-pages/achondroplasia-comorbidities/) that some children with achondroplasia (MIM #100800) develop hypertrophic cardiomyopathy or heart failure secondary to severe obstructive sleep apnea and obesity – but the FGFR3 variant itself only indirectly contributes via these complications . Lethal de novo FGFR3 variants cause perinatal dwarfism syndromes; affected infants die from respiratory insufficiency before cardiomyopathy could manifest, and no survivors with these variants have been reported to develop cardiomyopathy. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with dilated cardiomyopathy was identified with heterozygous missense variant in FGFR3 gene (c.667C>T/ p.Arg223Cys) via reanalysis of data from trio genome sequencing. This variant was reported as hot VUS and the publication states that the cardiomyopathy phenotype was not fully explained by the genotype. Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.65	TKFC	Achchuthan Shanmugasundram Classified gene: TKFC as Amber List (moderate evidence)
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.65	TKFC	Achchuthan Shanmugasundram Added comment: Comment on list classification: Three unrelated cases reported with TKFC variants (two missense and one nonsense) and cardiomyopathy. However, the phenotype did not completely segregate with variant in one family. This gene should be rated amber with the current evidence. The 'watchlist' tag has been added to review the gene in future in light of new evidence.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.65	TKFC	Achchuthan Shanmugasundram Gene: tkfc has been classified as Amber List (Moderate Evidence).
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.64	TKFC	Achchuthan Shanmugasundram gene: TKFC was added gene: TKFC was added to Paediatric or syndromic cardiomyopathy. Sources: Literature watchlist tags were added to gene: TKFC. Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TKFC were set to 32004446; 39251934; 39472908 Phenotypes for gene: TKFC were set to Triokinase and FMN cyclase deficiency syndrome, OMIM:618805; triokinase and FMN cyclase deficiency syndrome, MONDO:0032927; cardiomyopathy, MONDO:0004994 Review for gene: TKFC was set to AMBER Added comment: PMID:32004446 (2020) reported four affected individuals from 2 consanguineous families with congenital cataracts, developmental delay, liver dysfunction and microcytic anaemia. One of the infants also had fatal dilated cardiomyopathy (DCM) and lactic acidosis following a febrile illness. Both families were identified with homozygous missense variants in TKFC gene, and c.1628G>T (p.Arg543Ile) variant was present in the infant with DCM. PMID:39251934 (2024) reported two deceased neonate siblings presenting with oculocutaneous albinism type1 (OCA1). They had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy (HCM). Upon performing WES and segregation analysis, positive co-segregation of nonsense homozygous c.346C > T (p.Arg116Ter) variant in TYR gene and missense homozygous c.598G > A (p.Val200Ile) variant in TKFC gene were identified in the two affected patients. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with DCM was identified with homozygous missense variant in TKFC gene (c.1628G>T/ p.Arg543Ile) via reanalysis of data from trio genome sequencing. This variant is reported as likely pathogenic and the publication states that the phenotype is explained by the genotype. This gene has been associated with Triokinase and FMN cyclase deficiency syndrome (MIM #618805) in OMIM (phenotype accessed in OMIM on 01 September 2025), which includes DCM as one of the clinical manifestations. Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.63	TREX1	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases reported with cardiomyopathy (one with fetal CM abdominal other being paediatric). The paediatric case was from the UK 100,000 genomes cohort and with a missense variant. In addition, there is functional evidence from knockout mouse model. This gene should be rated amber with the current evidence. However, the 'watchlist' tag has been added to review this gene in the future in light of new evidence.; to: Comment on list classification: There are two unrelated cases reported with cardiomyopathy (one with fetal CM abdominal other being paediatric). The paediatric case was from the UK 100,000 genomes cohort and with a missense hot VUS variant. In addition, there is functional evidence from knockout mouse model. This gene should be rated amber with the current evidence. However, the 'watchlist' tag has been added to review this gene in the future in light of new evidence.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.63	TREX1	Achchuthan Shanmugasundram Classified gene: TREX1 as Amber List (moderate evidence)
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.63	TREX1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases reported with cardiomyopathy (one with fetal CM abdominal other being paediatric). The paediatric case was from the UK 100,000 genomes cohort and with a missense variant. In addition, there is functional evidence from knockout mouse model. This gene should be rated amber with the current evidence. However, the 'watchlist' tag has been added to review this gene in the future in light of new evidence.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.63	TREX1	Achchuthan Shanmugasundram Gene: trex1 has been classified as Amber List (Moderate Evidence).
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.62	TREX1	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 01 September 2025.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.62	TREX1	Achchuthan Shanmugasundram Phenotypes for gene: TREX1 were changed from Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750; Aicardi-Goutieres syndrome 1, MONDO:0009165 to Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750; Aicardi-Goutieres syndrome 1, MONDO:0009165; cardiomyopathy, MONDO:0004994
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.61	TREX1	Achchuthan Shanmugasundram edited their review of gene: TREX1: Changed phenotypes to: Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750, Aicardi-Goutieres syndrome 1, MONDO:0009165, cardiomyopathy, MONDO:0004994
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.61	TREX1	Achchuthan Shanmugasundram gene: TREX1 was added gene: TREX1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature watchlist tags were added to gene: TREX1. Mode of inheritance for gene: TREX1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TREX1 were set to 15254239; 36581356; 39472908 Phenotypes for gene: TREX1 were set to Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750; Aicardi-Goutieres syndrome 1, MONDO:0009165 Review for gene: TREX1 was set to AMBER Added comment: PMID:36581356 (2022) reported a case of fetal cardiomyopathy whose postnatal symptoms resembled TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes and syphilis) infection. The mother had a history of two lost pregnancies due to fetal cardiomyopathy and the same was identified in the current pregnancy. A homozygous single base pair insertion in exon 2 of the TREX1 gene (chr3:g.48466711_48466712insG/ p.Glu20GlyfsTer82) was identified in the neonate and the parents were positive for the same heterozygous pathological variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with unspecified cardiomyopathy was identified with homozygous missense variant in TREX1 gene (c.45C>G/ p.Ile15Met) via reanalysis of data from trio genome sequencing. This variant is reported to be a hot VUS in the publication, which also stated that the phenotype was explained by the genotype. PMID:15254239 (2004) reported the generation of Trex1(-/-) null mice, which exhibited a dramatically reduced survival, and developed inflammatory myocarditis leading to progressive, often dilated cardiomyopathy and circulatory failure. Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.60	KLHL24	Achchuthan Shanmugasundram changed review comment from: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature; to: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. This variant was reported as hot VUS in the publication Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.60	KLHL24	Achchuthan Shanmugasundram Classified gene: KLHL24 as Amber List (moderate evidence)
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.60	KLHL24	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic KLHL24 variants with dilated cardiomyopathy/ hypertrophic cardiopmyopathy. Hence, this gene can be promoted to green rating in the next GMS update.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.60	KLHL24	Achchuthan Shanmugasundram Gene: klhl24 has been classified as Amber List (Moderate Evidence).
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.59	KLHL24	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: KLHL24.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.59	KLHL24	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 01 September 2025.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.59	KLHL24	Achchuthan Shanmugasundram Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372 to Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.58	KLHL24	Achchuthan Shanmugasundram Publications for gene: KLHL24 were set to 27889062; 29779254; 30120936; 31649980; 32870709; 35975634; 36672924; 3947290
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.57	KLHL24	Achchuthan Shanmugasundram edited their review of gene: KLHL24: Changed publications to: 27889062, 29779254, 30120936, 31649980, 32870709, 35975634, 36672924, 39472908
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.57	KLHL24	Achchuthan Shanmugasundram changed review comment from: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature; to: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.57	KLHL24	Achchuthan Shanmugasundram gene: KLHL24 was added gene: KLHL24 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: KLHL24 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: KLHL24 were set to 27889062; 29779254; 30120936; 31649980; 32870709; 35975634; 36672924; 3947290 Phenotypes for gene: KLHL24 were set to Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372 Mode of pathogenicity for gene: KLHL24 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: KLHL24 was set to GREEN Added comment: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.56	SCN8A	Achchuthan Shanmugasundram Classified gene: SCN8A as Red List (low evidence)
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.56	SCN8A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case available in support of the association of monoallelic SCN8A variants with cardiomyopathy from UK 100,000 genomes cohort. The cardiomyopathy phenotype is not explained by the genotype in this patient. Hence, there is no reliable evidence for this association and this gene should be rated red on this panel.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.56	SCN8A	Achchuthan Shanmugasundram Gene: scn8a has been classified as Red List (Low Evidence).
01 Sep 2025	Primary lymphoedema v4.7	UNC45A	Matthew Edwards gene: UNC45A was added gene: UNC45A was added to Primary lymphoedema. Sources: Expert Review Mode of inheritance for gene: UNC45A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNC45A were set to PMID: 37328071; PMID: 39887522 Phenotypes for gene: UNC45A were set to lymphedema in the lower and upper limbs; cholestasis; hyperbilirubinemia; increased concentrations of bile acids in blood Penetrance for gene: UNC45A were set to unknown Review for gene: UNC45A was set to GREEN Added comment: Confirmed cause of Aagenaes syndrome/lymphedema cholestasis syndrome 1. 4. Primary lymphoedema may be presenting feature Sources: Expert Review
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.55	SCN8A	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 01 September 2025.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.55	SCN8A	Achchuthan Shanmugasundram Phenotypes for gene: SCN8A were changed from Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364 to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.54	SCN8A	Achchuthan Shanmugasundram changed review comment from: SCN8A is a well-established gene for complex neurodevelopmental disorder including early-onset epilepsy and developmental impairments. SCN8A has been associated with relevant phenotypes in OMIM (MIMs #614306, #614558, #617080 & #618364), Gene2Phenotype (with 'definitive' rating on the DD panel) and ClinGen ('definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Epilepsy GCEP). There is significant evidence that SCN8A variants can lead to cardiac arrhythmias (e.g. bradycardia) during epileptic seizures and increase risk for Sudden Unexpected Death in Epilepsy. However, there is no published evidence associating SCN8A variants to cardiomyopathy except for a single patient reported in PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous missense variant in SCN8A gene (c.3967G>A/ p.Ala1323Thr) via reanalysis of data from trio genome sequencing. This variant is reported to be likely pathogenic in the publication. However, the publication states that the cardiomyopathy phenotype is not explained by the genotype. In addition, no cardiac presentations has been recorded as part of the OMIM phenotypes. Sources: Literature; to: SCN8A is a well-established gene for complex neurodevelopmental disorder including early-onset epilepsy and developmental impairments. SCN8A has been associated with relevant phenotypes in OMIM (MIMs #614306, #614558, #617080 & #618364), Gene2Phenotype (with 'definitive' rating on the DD panel) and ClinGen ('definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Epilepsy GCEP). There is significant evidence that SCN8A variants can lead to cardiac arrhythmias (e.g. bradycardia) during epileptic seizures and increase risk for Sudden Unexpected Death in Epilepsy. However, there is no published evidence associating SCN8A variants to cardiomyopathy except for a single patient reported in PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous missense variant in SCN8A gene (c.3967G>A/ p.Ala1323Thr) via reanalysis of data from trio genome sequencing. This variant is reported to be likely pathogenic in the publication. However, the publication states that the cardiomyopathy phenotype is not explained by the genotype. In addition, no cardiac presentations have been recorded as clinical manifestations for the OMIM phenotypes. Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.54	SCN8A	Achchuthan Shanmugasundram gene: SCN8A was added gene: SCN8A was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: SCN8A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SCN8A were set to 3947290 Phenotypes for gene: SCN8A were set to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364 Review for gene: SCN8A was set to RED Added comment: SCN8A is a well-established gene for complex neurodevelopmental disorder including early-onset epilepsy and developmental impairments. SCN8A has been associated with relevant phenotypes in OMIM (MIMs #614306, #614558, #617080 & #618364), Gene2Phenotype (with 'definitive' rating on the DD panel) and ClinGen ('definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Epilepsy GCEP). There is significant evidence that SCN8A variants can lead to cardiac arrhythmias (e.g. bradycardia) during epileptic seizures and increase risk for Sudden Unexpected Death in Epilepsy. However, there is no published evidence associating SCN8A variants to cardiomyopathy except for a single patient reported in PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous missense variant in SCN8A gene (c.3967G>A/ p.Ala1323Thr) via reanalysis of data from trio genome sequencing. This variant is reported to be likely pathogenic in the publication. However, the publication states that the cardiomyopathy phenotype is not explained by the genotype. In addition, no cardiac presentations has been recorded as part of the OMIM phenotypes. Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.53	NPHP3	Achchuthan Shanmugasundram Classified gene: NPHP3 as Red List (low evidence)
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.53	NPHP3	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is primarily associated with nephronophthisis in > 20 unrelated cases. There is only one patient reported with a NPHP3 synonymous variant from UK 100,000 genomes cohort and the phenotype was not explained by the variant. Hence, this gene does not have any evidence of reliable association with cardiomyopathy and should be rated red.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.53	NPHP3	Achchuthan Shanmugasundram Gene: nphp3 has been classified as Red List (Low Evidence).
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.52	NPHP3	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 01 September 2025.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.52	NPHP3	Achchuthan Shanmugasundram Phenotypes for gene: NPHP3 were changed from Renal-hepatic-pancreatic dysplasia 1, OMIM:208540; Nephronophthisis 3, OMIM:604387; Meckel syndrome 7, OMIM:267010 to Renal-hepatic-pancreatic dysplasia 1, OMIM:208540; Nephronophthisis 3, OMIM:604387; Meckel syndrome 7, OMIM:267010
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.51	NPHP3	Achchuthan Shanmugasundram gene: NPHP3 was added gene: NPHP3 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: NPHP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPHP3 were set to 34212438; 39472908 Phenotypes for gene: NPHP3 were set to Renal-hepatic-pancreatic dysplasia 1, OMIM:208540; Nephronophthisis 3, OMIM:604387; Meckel syndrome 7, OMIM:267010 Review for gene: NPHP3 was set to RED Added comment: There are >20 unrelated patients reported with biallelic variants in NPHP3 and with nephronophthisis. occasionally, patients have presented with extra-renal features, including rare congenital heart defects in a small number of cases. There are three OMIM phenotypes associated with this gene, of which Renal-hepatic-pancreatic dysplasia 1 (MIM #208540) had recorded atrial septal defect, aortic stenosis, or situs abnormalities as potential cardiovascular presentations. The only patient that was reported with cardiomyopathy was from PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous synonymous variant in NPHP3 gene (c.2805C>T/ p.Gly935=) via reanalysis of data from duo genome sequencing. The publication states that the cardiomyopathy phenotype is not explained by the genotype. This variant was previously reported to be responsible for hepatorenal fibrocystic disease from PMID:34212438 in five unrelated families. The two patients from the UK 100,000 genomes cohort reported in this publication also had valvular cardiopathy. Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.50	JAK1	Achchuthan Shanmugasundram changed review comment from: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort. One of these patients with dilated cardiomyopathy was identified with de novo heterozygous missense variant in JAK1 gene (c.2666T>C/ p.Val889Ala) via reanalysis of data from trio genome sequencing, as this gene was not originally included in the panel. This variant was reported as a likely pathogenic in the publication. PMID:40744288 (2025) reported a mouse model with cardiomyocyte-specific deletion of JAK1, where JAK1 loss in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. In addition, cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterised by substantial myocardial fibrosis. Sources: Literature; to: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort. One of these patients with dilated cardiomyopathy was identified with de novo heterozygous missense variant in JAK1 gene (c.2666T>C/ p.Val889Ala) via reanalysis of data from trio genome sequencing, as this gene was not originally included in the panel. This variant was reported as likely pathogenic in the publication. PMID:40744288 (2025) reported a mouse model with cardiomyocyte-specific deletion of JAK1, where JAK1 loss in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. In addition, cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterised by substantial myocardial fibrosis. Sources: Literature
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.50	JAK1	Achchuthan Shanmugasundram Classified gene: JAK1 as Amber List (moderate evidence)
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.50	JAK1	Achchuthan Shanmugasundram Added comment: Comment on list classification: Monoallelic variants in JAK1 gene are primarily associated with 'Autoinflammation, immune dysregulation, and eosinophilia' (MIM #618999, accessed on 01 September 2025). However, there is only one case from the UK 100,000 genomes cohort and functional evidence from mouse models in support of the association of monoallelic variants in this gene with dilated cardiomyopathy. Hence, this gene can only be rated amber with the current evidence.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.50	JAK1	Achchuthan Shanmugasundram Gene: jak1 has been classified as Amber List (Moderate Evidence).
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.49	JAK1	Achchuthan Shanmugasundram Deleted their comment
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.49	JAK1	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 01 September 2025.
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.49	JAK1	Achchuthan Shanmugasundram Phenotypes for gene: JAK1 were changed from Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999; autoinflammation, immune dysregulation, and eosinophilia, MONDO:0033558; dilated cardiomyopathy, MONDO:0005021 to Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999; autoinflammation, immune dysregulation, and eosinophilia, MONDO:0033558; dilated cardiomyopathy, MONDO:0005021
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.48	JAK1	Achchuthan Shanmugasundram gene: JAK1 was added gene: JAK1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: JAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: JAK1 were set to 39472908; 40744288 Phenotypes for gene: JAK1 were set to Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999; autoinflammation, immune dysregulation, and eosinophilia, MONDO:0033558; dilated cardiomyopathy, MONDO:0005021 Review for gene: JAK1 was set to AMBER Added comment: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort. One of these patients with dilated cardiomyopathy was identified with de novo heterozygous missense variant in JAK1 gene (c.2666T>C/ p.Val889Ala) via reanalysis of data from trio genome sequencing, as this gene was not originally included in the panel. This variant was reported as a likely pathogenic in the publication. PMID:40744288 (2025) reported a mouse model with cardiomyocyte-specific deletion of JAK1, where JAK1 loss in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. In addition, cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterised by substantial myocardial fibrosis. Sources: Literature
01 Sep 2025	Intellectual disability v9.66	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, OMIM:252940 to Mucopolysaccharidosis type IIID, OMIM:252940
01 Sep 2025	Likely inborn error of metabolism v8.56	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from MPS IIID, Sanfilippo D disease (Mucopolysaccharidoses); Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis Type III; Mucopolysaccharidosis, Type III to Mucopolysaccharidosis type IIID, OMIM:252940
01 Sep 2025	Mucopolysaccharideosis, Gaucher, Fabry v1.4	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis, Type III; Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis Type III to Mucopolysaccharidosis type IIID, OMIM:252940
01 Sep 2025	Skeletal dysplasia v8.7	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID 252940 to Mucopolysaccharidosis type IIID, OMIM:252940
01 Sep 2025	Lysosomal storage disorder v3.4	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID 252940 to Mucopolysaccharidosis type IIID, OMIM:252940
01 Sep 2025	Intellectual disability v9.65	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, 252940; MUCOPOLYSACCHARIDOSIS TYPE 3D (MPS3D) to Mucopolysaccharidosis type IIID, OMIM:252940
01 Sep 2025	Undiagnosed metabolic disorders v1.631	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from MPS IIID, Sanfilippo D disease (Mucopolysaccharidoses); Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis, Type III; Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis Type III to Mucopolysaccharidosis type IIID, OMIM:252940
01 Sep 2025	Fetal anomalies v6.20	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from MUCOPOLYSACCHARIDOSIS TYPE 3D to Mucopolysaccharidosis type IIID, OMIM:252940
01 Sep 2025	Paediatric or syndromic cardiomyopathy v7.47	GNS	Arina Puzriakova Phenotypes for gene: GNS were changed from Mucopolysaccharidosis type IIID, 252940; Mucopolysaccharidosis, Type III; MPS IIID, Sanfilippo D disease (Mucopolysaccharidoses); Mucopolysaccharidosis Type IIID; Mucopolysaccharidosis Type III to Mucopolysaccharidosis type IIID, OMIM:252940
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.46	NF1	Achchuthan Shanmugasundram Classified gene: NF1 as Amber List (moderate evidence)
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.46	NF1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with monoallelic NF1 gene deletions and hypertrophic cardiomyopathy. In addition, three patients were reported with monoallelic NF1 small variants and cardiomyopathy. Hence, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.46	NF1	Achchuthan Shanmugasundram Gene: nf1 has been classified as Amber List (Moderate Evidence).
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.45	NF1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NF1.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.45	NF1	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 29 August 2025.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.45	NF1	Achchuthan Shanmugasundram Phenotypes for gene: NF1 were changed from Neurofibromatosis, type 1 162200; Noonan syndrome; Neurofibromatosis syndrome 1; Neurofibromatosis-Noonan syndrome 601321; Neurofibromatosis Noonan syndrome; Neurofibromatosis-Noonan Syndrome to Neurofibromatosis, type 1, OMIM:162200; Neurofibromatosis, familial spinal, OMIM:162210; Neurofibromatosis-Noonan syndrome, OMIM:601321; Watson syndrome, OMIM:193520; cardiomyopathy, MONDO:0004994
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.44	NF1	Achchuthan Shanmugasundram edited their review of gene: NF1: Changed phenotypes to: Neurofibromatosis, type 1, OMIM:162200, Neurofibromatosis, familial spinal, OMIM:162210, Neurofibromatosis-Noonan syndrome, OMIM:601321, Watson syndrome, OMIM:193520, cardiomyopathy, MONDO:0004994
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.44	NF1	Achchuthan Shanmugasundram Publications for gene: NF1 were set to 12707950; 16380919; 19845691
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.43	NF1	Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278345, 30919579, 38654147, 39472908; Phenotypes: Neurofibromatosis, type 1, OMIM:162200, neurofibromatosis type 1, MONDO:0018975, cardiomyopathy, MONDO:0004994; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.43	NAA15	Achchuthan Shanmugasundram changed review comment from: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous frameshift variant in NAA15 gene (c.174_177del/ p.Arg313Pro & c.1232C>T/ p.Cys58TrpfsTer15). Only the patient genome was sequenced.; to: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous frameshift variant in NAA15 gene (c.174_177del/ p.Cys58TrpfsTer15). Only the patient genome was sequenced.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.43	NAA15	Achchuthan Shanmugasundram Classified gene: NAA15 as Amber List (moderate evidence)
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.43	NAA15	Achchuthan Shanmugasundram Added comment: Comment on list classification: The majority of the cases reported with heterozygous NAA15 variants do not present with cardiomyopathy, while a significant proportion of cases had congenital cardiac defects. There were >50 cases reported in total. However, only three unrelated cases were reported with cardiomyopathy (two frameshift variants and one missense variant), of which one of the cases were from the UK 100,000 genomes project cohort. Hence, this gene should remain as amber. The 'watchlist' tag has been added to review new evidence in the future.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.43	NAA15	Achchuthan Shanmugasundram Gene: naa15 has been classified as Amber List (Moderate Evidence).
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.42	NAA15	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 August 2025.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.42	NAA15	Achchuthan Shanmugasundram Phenotypes for gene: NAA15 were changed from hypertrophic cardiomyopathy, MONDO:0005045 to Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities, OMIM:617787; hypertrophic cardiomyopathy, MONDO:0005045
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.41	NAA15	Achchuthan Shanmugasundram Publications for gene: NAA15 were set to 33103328
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.40	NAA15	Achchuthan Shanmugasundram Tag watchlist tag was added to gene: NAA15.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.40	NAA15	Achchuthan Shanmugasundram edited their review of gene: NAA15: Added comment: PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous frameshift variant in NAA15 gene (c.174_177del/ p.Arg313Pro & c.1232C>T/ p.Cys58TrpfsTer15). Only the patient genome was sequenced.; Changed publications to: 33103328, 39472908
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.40	NAA15	Achchuthan Shanmugasundram changed review comment from: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated cases reported with paediatric hypertrophic cardiomyopathy. PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively. Although none of the patients reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects. Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).; to: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated cases reported with paediatric hypertrophic cardiomyopathy. PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively. Although none of the patients were reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects. Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.40	NAA15	Achchuthan Shanmugasundram changed review comment from: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated c cases reported with paediatric hypertrophic cardiomyopathy. PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively. Although none of the patients reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects. Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).; to: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated cases reported with paediatric hypertrophic cardiomyopathy. PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively. Although none of the patients reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects. Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).
29 Aug 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.13	GUK1	Arina Puzriakova Tag Q3_25_NHS_review was removed from gene: GUK1.
29 Aug 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.13	GUK1	Arina Puzriakova Entity copied from Mitochondrial disorders v9.26
29 Aug 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.13	GUK1	Arina Puzriakova gene: GUK1 was added gene: GUK1 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature,Expert Review Amber Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: GUK1. Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GUK1 were set to 39230499 Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome 21, OMIM:621071
29 Aug 2025	Mitochondrial disorders v9.26	GUK1	Arina Puzriakova Classified gene: GUK1 as Amber List (moderate evidence)
29 Aug 2025	Mitochondrial disorders v9.26	GUK1	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 4 individuals from 3 unrelated families with biallelic variants leading to GUK1 deficiency. Muscle biopsies showed mtDNA depletion and/or deletions and reduced activities of mitochondrial respiratory chain enzymes.
29 Aug 2025	Mitochondrial disorders v9.26	GUK1	Arina Puzriakova Gene: guk1 has been classified as Amber List (Moderate Evidence).
29 Aug 2025	Mitochondrial disorders v9.25	GUK1	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: GUK1. Tag Q3_25_NHS_review tag was added to gene: GUK1.
29 Aug 2025	Mitochondrial disorders v9.25	GUK1	Arina Puzriakova Publications for gene: GUK1 were set to PMID: 39230499
29 Aug 2025	Mitochondrial disorders v9.24	GUK1	Arina Puzriakova Phenotypes for gene: GUK1 were changed from Mitochondrial DNA depletion syndrome 21 to Mitochondrial DNA depletion syndrome 21, OMIM:621071
29 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.41	EFL1	Arina Puzriakova Phenotypes for gene: EFL1 were changed from Shwachman-Diamond syndrome 2, MIM# 617941 to Shwachman-Diamond syndrome 2, OMIM:617941
29 Aug 2025	Cytopenia - NOT Fanconi anaemia v4.22	EFL1	Arina Puzriakova Phenotypes for gene: EFL1 were changed from Shwachman-Diamond syndrome 2, 617941; 617941 Shwachman-Diamond syndrome 2 to Shwachman-Diamond syndrome 2, OMIM:617941
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.40	MTO1	Achchuthan Shanmugasundram Classified gene: MTO1 as Amber List (moderate evidence)
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.40	MTO1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are > 30 cases reported with biallelic MTO1 variants and hypertrophic cardiomyopathy as one of the hallmark presentations. Hence, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.40	MTO1	Achchuthan Shanmugasundram Gene: mto1 has been classified as Amber List (Moderate Evidence).
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.39	MTO1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: MTO1.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.39	MTO1	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM (MIM #614702) and Gene2Phenotype (with 'definitive' rating on the DD panel). OMIM phenotype was accessed on 29 August 2025.
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.39	MTO1	Achchuthan Shanmugasundram Phenotypes for gene: MTO1 were changed from Combined oxidative phosphorylation deficiency 10, OMIM:614702; mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, MONDO:0013865 to Combined oxidative phosphorylation deficiency 10, OMIM:614702; mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, MONDO:0013865
29 Aug 2025	Paediatric or syndromic cardiomyopathy v7.38	MTO1	Achchuthan Shanmugasundram gene: MTO1 was added gene: MTO1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: MTO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTO1 were set to 22608499; 23929671; 34547275; 34990597; 39472908 Phenotypes for gene: MTO1 were set to Combined oxidative phosphorylation deficiency 10, OMIM:614702; mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, MONDO:0013865 Review for gene: MTO1 was set to GREEN Added comment: PMID:22608499 (2012) reported two infant siblings and an unrelated child of Italian descent with hypertrophic cardiomyopathy and neonatal lactic acidosis. The siblings died early in their life (when 19 days and 40 days old). The affected siblings were identified with compound heterozygous variants in MTO1 gene – a maternal frameshift variant (c.1858dup/ p.Arg620Lysfs(∗)8) and a paternal missense variant (c.1282G>A/ p.Ala428Thr). The unrelated patient was homozygous for the same missense variant (c.1282G>A). PMID:23929671 (2013) reported five additional patients from three unrelated families, who also presented with hypertrophic cardiomyopathy and lactic acidosis, in addition to other variable phenotypes including psychomotor delay, hypotonia, feeding difficulties and respiratory illness. The two sibling pairs were identified with homozygous missense variants (c.1232C>T/ p.Thr411Ile), while the unrelated patient was reported with compound heterozygous missense variants (c.1402G>A/ p.Ala428Thr & c.1430G>A/ p.Arg477His). PMID:34547275 (2021) reported the identification of compound heterozygous variants in MTO1 gene in a Chinese patient with complex oxidative phosphorylation deficiency type 10 (COXPD10). This patient had lactic acidosis and cardia abnormalities such as myocarditis and tachycardia, but not hypertrophic cardiomyopathy. The identified variants are c.344delA (p.Asn115Thrfs*11, frameshift) and c.1055C>T (p.Thr352Met, missense). PMID:34990597 (2022) reported a patient with COXPD10 presenting with multiple organ failure, severe pneumonia, sepsis, hyperlactatemia, metabolic acidosis, and moderate anaemia. The patient was identified with compound heterozygous variants in MTO1 gene (c.1291C > T/ p.Arg431Trp and c.1390C > T/ p.Arg464Cys). The patient also showed HCM. This study also reviewed previously published cases of confirmed MTO1 deficiency. Of 42 total cases including the patient reported in this study, 32 patients were reported with HCM and one additional patient was reported with dilated cardiomyopathy. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient with unspecified cardiomyopathy was identified with compound heterozygous missense variants in MTO1 gene (c.938G>C/ p.Arg313Pro & c.1232C>T/ p.Thr411Ile). There is also functional evidence available in support of the disease association. Sources: Literature
29 Aug 2025	Arthrogryposis v9.7	AGRN	Arina Puzriakova Classified gene: AGRN as Amber List (moderate evidence)
29 Aug 2025	Arthrogryposis v9.7	AGRN	Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber as two families have now been identified with FADS which presents with multiple joint contractures (PMID: 31730230; 39807604)
29 Aug 2025	Arthrogryposis v9.7	AGRN	Arina Puzriakova Gene: agrn has been classified as Amber List (Moderate Evidence).
29 Aug 2025	Fetal anomalies v6.19	AGRN	Arina Puzriakova Publications for gene: AGRN were set to 31730230
29 Aug 2025	Arthrogryposis v9.6	AGRN	Arina Puzriakova Publications for gene: AGRN were set to 31730230
29 Aug 2025	Fetal anomalies v6.18	AGRN	Arina Puzriakova Phenotypes for gene: AGRN were changed from Fetal akinesia deformation sequence (FADS) to Fetal akinesia deformation sequence, MONDO:0008824
29 Aug 2025	Arthrogryposis v9.5	AGRN	Arina Puzriakova Phenotypes for gene: AGRN were changed from Fetal akinesia deformation sequence (FADS) to Fetal akinesia deformation sequence, MONDO:0008824
29 Aug 2025	Arthrogryposis v9.4	AGRN	Arina Puzriakova edited their review of gene: AGRN: Added comment: PMID: 39807604 (2025) - biallelic null variants in AGRN leading to a fetal akinesia deformation sequence (FADS) identified in a second family affecting three pregnancies. WES revealed a maternally inherited heterozygous variant c.952+1_952+3del and split-read analysis identified a paternally inherited heterozygous 41.33 kb deletion, encompassing exons 1 and 2 of AGRN.; Changed publications to: 31730230, 39807604; Changed phenotypes to: Fetal akinesia deformation sequence, MONDO:0008824
29 Aug 2025	Retinal disorders v8.23	SPG11	Achchuthan Shanmugasundram Classified gene: SPG11 as Amber List (moderate evidence)
29 Aug 2025	Retinal disorders v8.23	SPG11	Achchuthan Shanmugasundram Gene: spg11 has been classified as Amber List (Moderate Evidence).
29 Aug 2025	Retinal disorders v8.22	SPG11	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 August 2025.
29 Aug 2025	Retinal disorders v8.22	SPG11	Achchuthan Shanmugasundram Phenotypes for gene: SPG11 were changed from Retinal dystrophy; spastic paraplegia to Spastic paraplegia 11, autosomal recessive, OMIM:604360; retinal disorder, MONDO:0005283
29 Aug 2025	Retinal disorders v8.21	SPG11	Achchuthan Shanmugasundram Publications for gene: SPG11 were set to PMID: 19194956, 36343909, 38613257,21035867
29 Aug 2025	Retinal disorders v8.20	SPG11	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SPG11. Tag Q3_25_NHS_review tag was added to gene: SPG11.
29 Aug 2025	Retinal disorders v8.20	DYRK1A	Achchuthan Shanmugasundram Classified gene: DYRK1A as Amber List (moderate evidence)
29 Aug 2025	Retinal disorders v8.20	DYRK1A	Achchuthan Shanmugasundram Gene: dyrk1a has been classified as Amber List (Moderate Evidence).
29 Aug 2025	Retinal disorders v8.19	DYRK1A	Achchuthan Shanmugasundram Tag Q3_25_NHS_review tag was added to gene: DYRK1A.
29 Aug 2025	Retinal disorders v8.19	DYRK1A	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: DYRK1A.
29 Aug 2025	Retinal disorders v8.19	DYRK1A	Achchuthan Shanmugasundram Phenotypes for gene: DYRK1A were changed from FEVR to Intellectual developmental disorder, autosomal dominant 7, OMIM:614104; Retinal disorder, MONDO:0005283
29 Aug 2025	Retinal disorders v8.18	DYRK1A	Achchuthan Shanmugasundram Publications for gene: DYRK1A were set to PMID: 40405340; 36736451
29 Aug 2025	Neurological ciliopathies v6.1	EVC2	Ida Ertmanska commented on gene: EVC2: Comment on mode of inheritance: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
29 Aug 2025	Neurological ciliopathies v6.1	EVC2	Ida Ertmanska reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38531627, 23220543, 19810119, 16404586; Phenotypes: Weyers acrofacial dysostosis, OMIM:193530, acrofacial dysostosis, Weyers type, MONDO:0008673; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
29 Aug 2025	Skeletal ciliopathies v6.1	EVC2	Ida Ertmanska commented on gene: EVC2: Comment on mode of inheritance: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
29 Aug 2025	Retinal disorders v8.17	CFI	Achchuthan Shanmugasundram Classified gene: CFI as Red List (low evidence)
29 Aug 2025	Retinal disorders v8.17	CFI	Achchuthan Shanmugasundram Gene: cfi has been classified as Red List (Low Evidence).
29 Aug 2025	Skeletal ciliopathies v6.1	EVC2	Ida Ertmanska reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38531627, 23220543, 19810119, 16404586; Phenotypes: Weyers acrofacial dysostosis, OMIM:193530, acrofacial dysostosis, Weyers type, MONDO:0008673; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
29 Aug 2025	Retinal disorders v8.16	CFI	Achchuthan Shanmugasundram Publications for gene: CFI were set to
29 Aug 2025	Retinal disorders v8.15	CFI	Achchuthan Shanmugasundram Phenotypes for gene: CFI were changed from Early Onset Drsen Maculopathy to Macular degeneration, age related, 13, susceptibility to, OMIM:615439; retinal disorder, MONDO:0005283
29 Aug 2025	Skeletal dysplasia v8.6	EVC2	Ida Ertmanska changed review comment from: Comment on list classification: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.; to: Comment on mode of inheritance: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
29 Aug 2025	Fetal anomalies v6.17	EVC2	Ida Ertmanska changed review comment from: Comment on list classification: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.; to: Comment on mode of inheritance: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
29 Aug 2025	Fetal anomalies v6.17	EVC2	Ida Ertmanska commented on gene: EVC2: Comment on list classification: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
29 Aug 2025	Fetal anomalies v6.17	EVC2	Ida Ertmanska reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38531627, 23220543, 19810119, 16404586; Phenotypes: Weyers acrofacial dysostosis, OMIM:193530, acrofacial dysostosis, Weyers type, MONDO:0008673; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
29 Aug 2025	Fetal anomalies v6.17	ACO2	Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BIALLELIC, autosomal or pseudoautosomal' as isolated optic atrophy caused by heterozygous variants in this gene is not relevant to the fetal panel. Extraocular features are rare in dominant cases (11%) and would also not be relevant to this panel (e.g. hearing loss, ataxia, nystagmus, metabolic dysfunction) (PMID: 34056600)
29 Aug 2025	Fetal anomalies v6.17	ACO2	Arina Puzriakova Mode of inheritance for gene: ACO2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
29 Aug 2025	Fetal anomalies v6.16	ACO2	Arina Puzriakova Phenotypes for gene: ACO2 were changed from INFANTILE CEREBELLAR-RETINAL DEGENERATION to Infantile cerebellar-retinal degeneration, OMIM:614559
29 Aug 2025	Skeletal dysplasia v8.6	EVC2	Ida Ertmanska commented on gene: EVC2: Comment on list classification: There are at least five unrelated families reported in literature with Weyers acrofacial dysostosis (rare skeletal dysplasia) and heterozygous variants in exon 22 of EVC2. While biallelic variants in EVC2 are associated with Ellis-van Creveld syndrome, Weyers acrofacial dysostosis is dominantly inherited. MOI should be changed from BIALLELIC to BOTH monoallelic and biallelic in the next GMS panel update.
29 Aug 2025	Skeletal dysplasia v8.6	EVC2	Ida Ertmanska reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38531627, 23220543, 19810119, 16404586; Phenotypes: Weyers acrofacial dysostosis, OMIM:193530, acrofacial dysostosis, Weyers type, MONDO:0008673; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
29 Aug 2025	Retinal disorders v8.14	DYRK1A	Ida Ertmanska commented on gene: DYRK1A: Comment on list classification: DYRK1A syndrome patients may present with vision abnormalities, including retinal involvement. There is sufficient evidence available (4 unrelated patients with a retinal phenotype) for the association of monoallelic DYRK1A variants with retinal disorders, which fits into the scope of this panel. Hence, this gene can be promoted to green rating in the next GMS update.
29 Aug 2025	Retinal disorders v8.14	DYRK1A	Ida Ertmanska reviewed gene: DYRK1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33159716, 36736451, 40405340, 19081073; Phenotypes: Intellectual developmental disorder, autosomal dominant 7, OMIM:614104, Retinal disorder, MONDO:0005283; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
29 Aug 2025	Retinal disorders v8.14	SPG11	Ida Ertmanska reviewed gene: SPG11: Rating: GREEN; Mode of pathogenicity: None; Publications: 19194956, 36343909, 38613257, 39391989; Phenotypes: Spastic paraplegia 11, autosomal recessive, OMIM:604360, retinal disorder, MONDO:0005283; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
29 Aug 2025	Retinal disorders v8.14	CFI	Ida Ertmanska commented on gene: CFI: Comment on list classification: Macular degeneration was reported in two Tunisian patients, heterozygous for a CFI variant. The reported variant is also common in healthy Tunisian controls. Hence, the gene can only be rated as Red with the current evidence.
29 Aug 2025	Retinal disorders v8.14	CFI	Ida Ertmanska changed review comment from: PMID: 25986072 – Two families with carriers of CFI:c.1234G>A p.(Val412Met). 24yo heterozygous carrier Fam3-01 displayed early-onset drusen maculopathy. Individual Fam1-01, 68yo, had advanced age-related macular degeneration – time of onset unknown. 10/200 unrelated Tunisian Jewish controls were reported to carry for the variant (5% allele freq) - too high to cause the disorder. The variant is also present in gnomAD v4.1.0: highest allele freq = 0.0004954 (Middle Eastern population; no homozygotes). OMIM reports a gene association with disease susceptibility (OMIM:615439 Macular degeneration, age related, 13, susceptibility to; accessed 20th Aug 2025).; to: PMID: 25986072 – Two families with carriers of CFI:c.1234G>A p.(Val412Met). 24yo heterozygous carrier Fam3-01 displayed early-onset drusen maculopathy. Individual Fam1-01, 68yo, had advanced age-related macular degeneration – time of onset unknown. 10/200 unrelated Tunisian Jewish controls were reported to carry for the variant (5% allele freq) - too high to cause the disorder. The variant is also present in gnomAD v4.1.0: highest allele freq = 0.0004954 (Middle Eastern population; no homozygotes). OMIM reports a gene association with disease susceptibility (OMIM:615439 Macular degeneration, age related, 13, susceptibility to; accessed 20th Aug 2025).
29 Aug 2025	Retinal disorders v8.14	CFI	Ida Ertmanska reviewed gene: CFI: Rating: RED; Mode of pathogenicity: None; Publications: 25986072; Phenotypes: Macular degeneration, age related, 13, susceptibility to, OMIM:615439, retinal disorder, MONDO:0005283; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
29 Aug 2025	Retinal disorders v8.14	CFI	Ida Ertmanska Deleted their review
29 Aug 2025	Retinal disorders v8.14	CFI	Ida Ertmanska reviewed gene: CFI: Rating: RED; Mode of pathogenicity: None; Publications: 25986072; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
28 Aug 2025	Paediatric or syndromic cardiomyopathy v7.37	NEB	Achchuthan Shanmugasundram Classified gene: NEB as Red List (low evidence)
28 Aug 2025	Paediatric or syndromic cardiomyopathy v7.37	NEB	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only patient reported in a large cohort study (UK 100,000 genomes project) with unspecified cardiomyopathy and homozygous NEB variant. No further phenotypic information was reported in the publication (PMID:39472908). All other reported cases did not have confirmed cardiomyopathy (despite some cardiac involvement in a few cases) or had Nemaline myopathy and cardiomyopathy with variants in other genes (e.g. ACTA1). There is no functional evidence to suggest the association of NEB with cardiomyopathy. Hence, this gene should be rated red.
28 Aug 2025	Paediatric or syndromic cardiomyopathy v7.37	NEB	Achchuthan Shanmugasundram Gene: neb has been classified as Red List (Low Evidence).
28 Aug 2025	Paediatric or syndromic cardiomyopathy v7.36	NEB	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 28 August 2025.
28 Aug 2025	Paediatric or syndromic cardiomyopathy v7.36	NEB	Achchuthan Shanmugasundram Phenotypes for gene: NEB were changed from Nemaline myopathy 2, autosomal recessive, OMIM:256030 to Nemaline myopathy 2, autosomal recessive, OMIM:256030
28 Aug 2025	Paediatric or syndromic cardiomyopathy v7.35	NEB	Achchuthan Shanmugasundram gene: NEB was added gene: NEB was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: NEB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEB were set to 23650303; 26321576; 28131200; 29070751; 29070751; 39472908 Phenotypes for gene: NEB were set to Nemaline myopathy 2, autosomal recessive, OMIM:256030 Review for gene: NEB was set to RED Added comment: Biallelic variants in NEB are reported to cause Nemaline myopathy 2 (MIM #256030), which is a skeletal muscle disorder with a wide range of severity and age-of-onset. The most common clinical presentation is early-onset (in infancy or childhood) muscle weakness predominantly affecting proximal limb muscles. The OMIM record (MIM #256030) does not list any cardiac presentations as part of the phenotype. Cardiac involvement has only been reported in very few cases with NEB-related nemaline myopathy in the literature. However, there is no evidence available to suggest that these patients presented with cardiomyopathy (PMIDs: 28131200 (2016); 29070751 (2017, Article in Japanese); 29070751 (2020). Although a 9-year-old male patient with nemaline myopathy with dilated cardiomyopathy reported in PMID:23650303 (2013), the patient harboured a novel heterozygous ACTA1 variant, which is causative of the disease. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one male patient with unspecified cardiomyopathy was identified with a homozygous splice donor variant in NEB gene (c.2415+1G>A). However, no further information on patient phenotypes was provided in the patient. Nebulin is primarily expressed in skeletal muscles and expressed at very low levels in heart. In addition, no cardiac phenotype was reported in NEB knockout mouse models (PMID: 26321576, 2015), suggesting that the any cardiac failure in patients with NEB-related Nemaline myopathy may be secondary to respiratory failure. Sources: Literature
28 Aug 2025	Rare genetic inflammatory skin disorders v4.1	FECH	Sharon Whatley gene: FECH was added gene: FECH was added to Rare genetic inflammatory skin disorders. Sources: Literature Mode of inheritance for gene: FECH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FECH were set to 7857832; 16911284; 39969427; 32873934; 38940544; 11753383; 16385445 Phenotypes for gene: FECH were set to 177000 Penetrance for gene: FECH were set to Complete Review for gene: FECH was set to GREEN Added comment: Relevant metabolic investigation: Erythrocyte metal free protoporphyrin PMID: 7857832 Todd reports that erythropoietic protoporphyria (EPP) is a rare disorder caused by the partial deficiency of ferrochelatase, the terminal enzyme of haem biosynthesis that is coded by the FECH gene. This results in an increase in protoporphyrin IX that is released from erythroid cells into the vascular endothelium and surrounding tissues. It is activated by visible light, triggering oxidative stress and inflammation. Affected patients usually present with episodes of severe phototoxic pain in light exposed skin. PMID: 16911284 Holme found the median age of presentation to be less than one year of age although diagnosis was delayed until a median age of 12 years. Infants are extremely sensitive to sunlight, experiencing pain, burning, and swelling of the skin and may present with crying or screaming after being exposed. This acute photosensitivity of sun exposed areas is lifelong. PMID: 39969427 Levy reported that the accumulation of protoporphyrin in the liver caused cholestatic liver injury in 3.4% of 322 patients with EPP and progressed to severe liver failure in 2.5%. PMID: 32873934 Dickey reports the EPP prevalence to be 0.0059% (~1 in 17,000) from the UK biobank and suggests that the disorder is underreported. Among more than 155 family cohorts of EPP patients that have been published in the literature, no occurrence of a nonpenetrant disease-associated genotype has been reported. It is therefore assumed that EPP is fully penetrant. PMID: 38940544 Aarsand reports that the genetics of EPP is complex with ~5% of cases of unknown genomic pathology. There are several different known genetic mechanisms that cause the EPP phenotype including defects in other genes such as ALAS2 found in 2-10% of EPP patients and ALAS2 together with CLPX identified in one patient. Rarely EPP can develop in later life due to genomic instability affecting the FECH gene in myelodysplastic syndromes. Approximately 4% of EPP patients have biallelic pathogenic variants in the FECH gene while most EPP cases are due to a pathogenic FECH variant trans to an intronic variant (c.315-48T>C) that causes low expression of that allele. PMID: 11753383 Gouya discovered an intronic single nucleotide change c.315-48T>C in intron 3 of the FECH gene that modulates the use of an aberrant splice acceptor site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, producing a decreased level of mRNA. This, in trans to a pathogenic variant was found to cause phenotypic expression of EPP. PMID: 16385445 Gouya reports that this intronic variant is present in >90% of EPP patients. The FECH low-expression variant c.315-48T>C has a total allele frequency of 0.06713 and an allele frequency of 0.3803 in those of East Asian ancestry with ~7% of these being homozygotes (GnomAD v4.10). However clinical detection of EPP remains low. Even taking into account underreporting, this suggests that the low expression variant in the homozygous form causes a reduction in the ferrochelatase enzyme activity but not to a level that causes disease, otherwise EPP would be much more common. It is essential that any genetic sequencing includes the region of intron 3 (c.315-48T>C) that harbours the low expression variant. Sources: Literature
28 Aug 2025	Childhood onset dystonia, chorea or related movement disorder v7.3	FECH	Sharon Whatley reviewed gene: FECH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
28 Aug 2025	Likely inborn error of metabolism v8.55	FECH	Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 16911284, 39969427, 32873934, 38940544, 11753383, 16385445; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
28 Aug 2025	Undiagnosed metabolic disorders v1.630	FECH	Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 16911284, 39969427, 32873934, 38940544, 11753383, 16385445; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
28 Aug 2025	Iron metabolism disorders - NOT common HFE mutations v3.1	FECH	Sharon Whatley reviewed gene: FECH: Rating: RED; Mode of pathogenicity: None; Publications: 28185024; Phenotypes: ; Mode of inheritance: None
28 Aug 2025	Vascular skin disorders v2.1	FECH	Sharon Whatley reviewed gene: FECH: Rating: RED; Mode of pathogenicity: None; Publications: 7857832; Phenotypes: ; Mode of inheritance: None
28 Aug 2025	Cutaneous photosensitivity with a likely genetic cause v3.9	FECH	Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 16911284, 39969427, 32873934, 38940544, 11753383, 16385445; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
28 Aug 2025	Non-acute porphyrias v1.26	FECH	Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 16911284, 39969427, 32873934, 38940544, 11753383, 16385445; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
28 Aug 2025	Erythropoietic protoporphyria, mild variant v1.3	FECH	Sharon Whatley reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 7857832, 18760763, 33596641; Phenotypes: 177000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
28 Aug 2025	Paediatric or syndromic cardiomyopathy v7.34	PLD1	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort. As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has recently been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.; to: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort. As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.
28 Aug 2025	Paediatric or syndromic cardiomyopathy v7.34	NDUFA4	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there are at least three unrelated patients reported with biallelic variants in NDUFA4 gene, only one patient (one from 100,000 genomes project) presented with cardiomyopathy. Hence, this gene can only be rated red with the current evidence.; to: Comment on list classification: Although there are at least three unrelated patients reported with biallelic variants in NDUFA4 gene, only one patient (one from the UK 100,000 genomes project) presented with cardiomyopathy. Hence, this gene can only be rated red with the current evidence.
27 Aug 2025	Neurological segmental overgrowth v3.1	PIK3CA	Eleanor Williams Tag mosaicism tag was added to gene: PIK3CA. Tag somatic tag was added to gene: PIK3CA.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.34	SGCG	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.; to: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies. There is also functional evidence from mice model, which supports the association of SGCG gene with cardiomyopathy. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.34	SGCG	Achchuthan Shanmugasundram Publications for gene: SGCG were set to 10942431; 11053682; 24464767; 39472908
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.33	SGCG	Achchuthan Shanmugasundram edited their review of gene: SGCG: Changed publications to: 10942431, 11053682, 14991064, 24464767, 39472908
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.33	SGCG	Achchuthan Shanmugasundram changed review comment from: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT). PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction. PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%). PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited. This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation). Sources: Literature; to: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT). PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction. PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%). PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited. This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation). PMID:14991064 provided functional evidence from Sgcg knockout mice, which develop a progressive cardiomyopathy characterised by focal myocardial degeneration and fibrosis. Transgenic rescue experiments in mice showed that re-expressing SGCG only in cardiac muscle (but not in vascular muscle) was sufficient to prevent the cardiomyopathy in Sgcg-null mice. Sources: Literature
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.33	SGCG	Achchuthan Shanmugasundram Classified gene: SGCG as Amber List (moderate evidence)
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.33	SGCG	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.33	SGCG	Achchuthan Shanmugasundram Gene: sgcg has been classified as Amber List (Moderate Evidence).
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.32	SGCG	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SGCG.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.32	SGCG	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 26 August 2025.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.32	SGCG	Achchuthan Shanmugasundram Phenotypes for gene: SGCG were changed from Muscular dystrophy, limb-girdle, autosomal recessive 5, OMIM:253700; autosomal recessive limb-girdle muscular dystrophy type 2C, MONDO:0009677 to Muscular dystrophy, limb-girdle, autosomal recessive 5, OMIM:253700; autosomal recessive limb-girdle muscular dystrophy type 2C, MONDO:0009677
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.31	SGCG	Achchuthan Shanmugasundram gene: SGCG was added gene: SGCG was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: SGCG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SGCG were set to 10942431; 11053682; 24464767; 39472908 Phenotypes for gene: SGCG were set to Muscular dystrophy, limb-girdle, autosomal recessive 5, OMIM:253700; autosomal recessive limb-girdle muscular dystrophy type 2C, MONDO:0009677 Review for gene: SGCG was set to GREEN Added comment: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT). PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction. PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%). PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited. This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation). Sources: Literature
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.30	PLD1	Achchuthan Shanmugasundram Classified gene: PLD1 as Amber List (moderate evidence)
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.30	PLD1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort. As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has recently been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.30	PLD1	Achchuthan Shanmugasundram Gene: pld1 has been classified as Amber List (Moderate Evidence).
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.29	PLD1	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 26 August 2025.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.29	PLD1	Achchuthan Shanmugasundram Phenotypes for gene: PLD1 were changed from Cardiac valvular dysplasia 1, OMIM:212093; cardiac valvular defect, developmental, MONDO:0008913; neonatal cardiomyopathy to Cardiac valvular dysplasia 1, OMIM:212093; cardiac valvular defect, developmental, MONDO:0008913; neonatal cardiomyopathy
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.28	PLD1	Achchuthan Shanmugasundram Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093; neonatal cardiomyopathy to Cardiac valvular dysplasia 1, OMIM:212093; cardiac valvular defect, developmental, MONDO:0008913; neonatal cardiomyopathy
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.27	PLD1	Achchuthan Shanmugasundram Publications for gene: PLD1 were set to 27799408; 33645542
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.26	PLD1	Achchuthan Shanmugasundram reviewed gene: PLD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39472908; Phenotypes: Cardiac valvular dysplasia 1, OMIM:212093, cardiac valvular defect, developmental, MONDO:0008913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.26	NDUFA4	Achchuthan Shanmugasundram Classified gene: NDUFA4 as Red List (low evidence)
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.26	NDUFA4	Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are at least three unrelated patients reported with biallelic variants in NDUFA4 gene, only one patient (one from 100,000 genomes project) presented with cardiomyopathy. Hence, this gene can only be rated red with the current evidence.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.26	NDUFA4	Achchuthan Shanmugasundram Gene: ndufa4 has been classified as Red List (Low Evidence).
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.25	NDUFA4	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 26 August 2025.
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.25	NDUFA4	Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.24	NDUFA4	Achchuthan Shanmugasundram Publications for gene: NDUFA4 were set to 23746447, 29636225
26 Aug 2025	Paediatric or syndromic cardiomyopathy v7.23	NDUFA4	Achchuthan Shanmugasundram reviewed gene: NDUFA4: Rating: RED; Mode of pathogenicity: None; Publications: 23746447, 38674434, 39472908; Phenotypes: ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065, mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.23	NAXD	Achchuthan Shanmugasundram Classified gene: NAXD as Amber List (moderate evidence)
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.23	NAXD	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >10 unrelated patients reported with biallelic NAXD variants and with 'Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2' (MIM #618321). However, the disease has a variable presentation and cardiomyopathy was reported in four unrelated patients. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.23	NAXD	Achchuthan Shanmugasundram Gene: naxd has been classified as Amber List (Moderate Evidence).
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.22	NAXD	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NAXD.
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.22	NAXD	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 25 August 2025.
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.22	NAXD	Achchuthan Shanmugasundram Phenotypes for gene: NAXD were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321; NAD(P)HX dehydratase deficiency, MONDO:0034121 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321; NAD(P)HX dehydratase deficiency, MONDO:0034121
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.21	NAXD	Achchuthan Shanmugasundram gene: NAXD was added gene: NAXD was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAXD were set to 30576410; 32462209; 39472908; 39822994 Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321; NAD(P)HX dehydratase deficiency, MONDO:0034121 Review for gene: NAXD was set to GREEN Added comment: PMID:30576410 (2019) reported six unrelated individuals with biallelic NAXD variants, and with encephalopathy precipitated by febrile illnesses. They all had severe neurological deterioration and died in early childhood. One of these six patients, who is a girl of Indian descent developed dilated cardiomyopathy and heart failure, and was identified with homozygous c.54_57delAAGA (p.Ala20Phefs9) variant. PMID: 32462209 (2020) reported a seven-year-old male patient that experienced rapid deterioration and after gastroenteritis and died suddenly. An autopsy imaging CT scan showed thickening of the myocardial wall and gross hypertrophic cardiomyopathy in the patient. His paternal uncle also died due to acute myocardial infarction at the age of 28. Biallelic variants (c.44delG/ p.Arg15Glnfs3 & c.54_57delAAGA/ p.Ala20Phefs*9) were identified by WES in the patient and these variants are present in heterozygous state in the parents. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one female patient with dilated cardiomyopathy was identified with homozygous variant in NAXD gene (c.54_57del/ p.Ala20PhefsTer9). PMID:39822994 (2024) reported a 47-month-old male patient of Chinese descent that experienced a sharp deterioration after febrile illness, causing heart failure, cardiogenic shock, and ultimately death. This patient was diagnosed with myocarditis and dilated cardiomyopathy and was identified with compound heterozygous variants in NAXD gene (c.43C>T/ p.Arg15Ter & c.781G>T/ p.Gly261Cys). This gene has been associated with MIM #618321 in OMIM, which mentions cardiomyopathy as one of the clinical presentations that is observed in some patients. Sources: Literature
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.20	AIFM1	Achchuthan Shanmugasundram Classified gene: AIFM1 as Amber List (moderate evidence)
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.20	AIFM1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >20 unrelated patients reported with hemizygous AIFM1 variants and with Combined oxidative phosphorylation deficiency 6 (MIM #300816). However, the disease has a variable presentation and cardiomyopathy was reported in four unrelated patients. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.20	AIFM1	Achchuthan Shanmugasundram Gene: aifm1 has been classified as Amber List (Moderate Evidence).
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.19	AIFM1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: AIFM1.
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.19	AIFM1	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 25 August 2025.
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.19	AIFM1	Achchuthan Shanmugasundram Phenotypes for gene: AIFM1 were changed from Combined oxidative phosphorylation deficiency 6, OMIM:300816 to Combined oxidative phosphorylation deficiency 6, OMIM:300816; severe X-linked mitochondrial encephalomyopathy, MONDO:0010437
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.18	AIFM1	Achchuthan Shanmugasundram edited their review of gene: AIFM1: Changed phenotypes to: Combined oxidative phosphorylation deficiency 6, OMIM:300816, severe X-linked mitochondrial encephalomyopathy, MONDO:0010437
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.18	AIFM1	Achchuthan Shanmugasundram gene: AIFM1 was added gene: AIFM1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: AIFM1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: AIFM1 were set to 22019070; 28967629; 34117073; 39472908 Phenotypes for gene: AIFM1 were set to Combined oxidative phosphorylation deficiency 6, OMIM:300816 Review for gene: AIFM1 was set to GREEN Added comment: PMID:22019070 (2011) reported three siblings of Palestinian descent with early prenatal verntriculomegaly, of which two brothers were investigated further. The two brothers presented with infantile encephalomyopathy. One of them died at the age of 4 years due to cardiac failure secondary to aspiration pneumonia, and the other died at 3 months of age because of hypertrophic cardiomyopathy and aspiration pneumonia. Using linkage analysis in the family, followed by whole exome sequencing, a pathogenic variant in the AIFM1 gene was identified in patient B (c.923G > A/ p.Gly308Glu), which segregated with the disease state and was absent in 86 anonymous controls. PMID:28967629 (2018) reported two unrelated male patients with AIFM1 variants and they displayed distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. Cardiomyopathy was only reported in patient 2, who also displayed severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, and hyporeflexia. The c.422C > T (p.Thr141Ile) hemizygous variant was identified in this patient via WES and validated by Sanger sequencing and was confirmed de novo. PMID:34117073 (2021) reported three affected males (proband, brother and maternal uncle) exhibiting severe multisystem pathology, metabolic acidosis, and early demise. Biventricular hypertrophy was observed via foetal heart echocardiogram in the proband, and by limited autopsy in the maternal uncle. A missense hemizygous AIFM1 variant (c.506C > T/ p.Pro169Leu) was identified in the proband and sibling and this variant is absent in reference population databases, as discussed in this publication. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient was identified with hemizygous variant in AIFM1 gene (c.603_605del/ p.Arg201del?). This gene is associated with Combined oxidative phosphorylation deficiency 6 (MIM #300816) in OMIM, which includes hypertrophic cardiomyopathy as one of the variable clinical presentations. Sources: Literature
25 Aug 2025	Paediatric or syndromic cardiomyopathy v7.17	FBXL4	Achchuthan Shanmugasundram changed review comment from: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1. PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter]. PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function. PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)). PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748). Sources: Literature; to: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1. PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter]. PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function. PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)). PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter). There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748). Sources: Literature
25 Aug 2025	Hereditary neuropathy or pain disorder v7.5	COX18	Alexander Rossor gene: COX18 was added gene: COX18 was added to Hereditary neuropathy or pain disorder. Sources: Literature Mode of inheritance for gene: COX18 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COX18 were set to 40830826 Phenotypes for gene: COX18 were set to peripheral neuropathy Penetrance for gene: COX18 were set to Complete Review for gene: COX18 was set to GREEN Added comment: 8 individuals from 3 families Sources: Literature
21 Aug 2025	Paediatric or syndromic cardiomyopathy v7.17	FBXL4	Achchuthan Shanmugasundram Classified gene: FBXL4 as Amber List (moderate evidence)
21 Aug 2025	Paediatric or syndromic cardiomyopathy v7.17	FBXL4	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >90 patients reported with biallelic FBXL4 variants and mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) (MIM #615471). Of these, ~20% of patients are reported with early-onset hypertrophic cardiomyopathy. As there are >15 patients reported with cardiomyopathy, this gene can be promoted to green rating in the next GMS update.
21 Aug 2025	Paediatric or syndromic cardiomyopathy v7.17	FBXL4	Achchuthan Shanmugasundram Gene: fbxl4 has been classified as Amber List (Moderate Evidence).
21 Aug 2025	Paediatric or syndromic cardiomyopathy v7.16	FBXL4	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: FBXL4.
21 Aug 2025	Paediatric or syndromic cardiomyopathy v7.16	FBXL4	Achchuthan Shanmugasundram gene: FBXL4 was added gene: FBXL4 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: FBXL4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FBXL4 were set to 23993193; 23993194; 25868664; 26404457; 28940506; 38359748; 39472908 Phenotypes for gene: FBXL4 were set to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), OMIM:615471 Review for gene: FBXL4 was set to GREEN Added comment: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1. PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter]. PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function. PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)). PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748). Sources: Literature
20 Aug 2025	Intellectual disability v9.64	UPF1	Karen Stals changed review comment from: At least 4 individuals reported in the literature with de novo variants in this gene and a neurodevelopmental disorder. Additional patient identified in Exeter. Moderate gene-disease association in Gene2Phenotype.; to: At least 4 individuals described in the literature with de novo variants in this gene and a neurodevelopmental disorder. Additional patient identified in Exeter. Moderate gene-disease association in Gene2Phenotype.
20 Aug 2025	Intellectual disability v9.64	UPF1	Karen Stals reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39993774, PMID: 39571789, PMID: 28539120; Phenotypes: Developmental delay, autism, intellectual disability, speech delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
19 Aug 2025	Autoinflammatory disorders v2.29	ITCH	Nicholas Head gene: ITCH was added gene: ITCH was added to Autoinflammatory disorders. Sources: Other Mode of inheritance for gene: ITCH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ITCH were set to PMID: 36338154 Phenotypes for gene: ITCH were set to Autoimmune disease, multisystem, with facial dysmorphism, 613385 Review for gene: ITCH was set to GREEN gene: ITCH was marked as current diagnostic Added comment: Currently listed as a green gene on R15 panel. Causes a autoinflammatory disorder with multisystem involvement. Sources: Other
15 Aug 2025	Paediatric or syndromic cardiomyopathy v7.15	FLII	Achchuthan Shanmugasundram changed review comment from: PMID:32870709 (2020) reported a large cohort of 205 unrelated patients with various forms of childhood-onset cardiomyopathy (CM), in which two unrelated patients of Saudi Arabian decent with infantile-onset dilated CM were identified with homozygous missense variants (p.Leu674Val & p.Arg1240Cys). PMID:37561591 (2023) identified biallelic variants in FLII gene in three unrelated families with idiopathic, early-onset dilated CM of which two patients were the ones that were already reported in PMID:32870709. The third patient was a girl of Dutch decent that had onset of CM at around 2 months of age. This patient was identified with compound heterozygous variants (p.Gln454Ter & p.Arg1168Trp). Introduction of patient-specific FLII variants into the zebrafish genome using CRISPR/Cas9 genome editing resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in the patients. In addition, functional studies also provided insights into the function of Flii during ventricular chamber morphogenesis that involves myocardial cell adhesion and myofibril organisation. This gene has been associated with dilated CM phenotype in OMIM (MIM #620635).; to: PMID:32870709 (2020) reported a large cohort of 205 unrelated patients with various forms of childhood-onset cardiomyopathy (CM), in which two unrelated patients of Saudi Arabian descent with infantile-onset dilated CM were identified with homozygous missense variants (p.Leu674Val & p.Arg1240Cys). PMID:37561591 (2023) identified biallelic variants in FLII gene in three unrelated families with idiopathic, early-onset dilated CM of which two patients were the ones that were already reported in PMID:32870709. The third patient was a girl of Dutch descent that had onset of CM at around 2 months of age. This patient was identified with compound heterozygous variants (p.Gln454Ter & p.Arg1168Trp). Introduction of patient-specific FLII variants into the zebrafish genome using CRISPR/Cas9 genome editing resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in the patients. In addition, functional studies also provided insights into the function of Flii during ventricular chamber morphogenesis that involves myocardial cell adhesion and myofibril organisation. This gene has been associated with dilated CM phenotype in OMIM (MIM #620635).
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.40	REXO2	Achchuthan Shanmugasundram Classified gene: REXO2 as Amber List (moderate evidence)
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.40	REXO2	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one patient reported with monoallelic variant in REXO2, and functional evidence is available in support of the association. Hence, this gene should be rated amber with the current evidence.
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.40	REXO2	Achchuthan Shanmugasundram Gene: rexo2 has been classified as Amber List (Moderate Evidence).
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.39	REXO2	Achchuthan Shanmugasundram Phenotypes for gene: REXO2 were changed from to type 1 interferonopathy, MONDO:0700264
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.38	REXO2	Achchuthan Shanmugasundram Publications for gene: REXO2 were set to PMID: 39107301
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.37	REXO2	Achchuthan Shanmugasundram reviewed gene: REXO2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 39107301; Phenotypes: type 1 interferonopathy, MONDO:0700264; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.37	GTF3A	Achchuthan Shanmugasundram Classified gene: GTF3A as Amber List (moderate evidence)
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.37	GTF3A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one family reported with immunodeficiency and biallelic GTF3A variants, and functional evidenced available in support of the association. Hence, this gene can be rated amber with current evidence.
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.37	GTF3A	Achchuthan Shanmugasundram Gene: gtf3a has been classified as Amber List (Moderate Evidence).
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.36	GTF3A	Achchuthan Shanmugasundram Phenotypes for gene: GTF3A were changed from CVID with HSV encephalitis to common variable immunodeficiency, MONDO:001551
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.35	GTF3A	Achchuthan Shanmugasundram Publications for gene: GTF3A were set to PMID: 36399538
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.34	GTF3A	Achchuthan Shanmugasundram reviewed gene: GTF3A: Rating: AMBER; Mode of pathogenicity: None; Publications: 36399538; Phenotypes: common variable immunodeficiency, MONDO:0015517; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.34	GTF3AP5	Achchuthan Shanmugasundram Classified gene: GTF3AP5 as No list
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.34	GTF3AP5	Achchuthan Shanmugasundram Added comment: Comment on list classification: PMID:36399538 reports the association of GTF3A to immunodeficiency rather than GTF3AP5. Hence, the reviewer removed their review. This gene is therefore rated grey on this panel.
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.34	GTF3AP5	Achchuthan Shanmugasundram Gene: gtf3ap5 has been removed from the panel.
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.33	GTF3AP5	Achchuthan Shanmugasundram Tag curated_removed tag was added to gene: GTF3AP5.
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.33	GTF3AP5	Achchuthan Shanmugasundram Classified gene: GTF3AP5 as No list
15 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.33	GTF3AP5	Achchuthan Shanmugasundram Gene: gtf3ap5 has been removed from the panel.
15 Aug 2025	Paediatric or syndromic cardiomyopathy v7.15	FLII	Achchuthan Shanmugasundram Classified gene: FLII as Amber List (moderate evidence)
15 Aug 2025	Paediatric or syndromic cardiomyopathy v7.15	FLII	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.
15 Aug 2025	Paediatric or syndromic cardiomyopathy v7.15	FLII	Achchuthan Shanmugasundram Gene: flii has been classified as Amber List (Moderate Evidence).
15 Aug 2025	Paediatric or syndromic cardiomyopathy v7.14	FLII	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: FLII.
15 Aug 2025	Paediatric or syndromic cardiomyopathy v7.14	FLII	Achchuthan Shanmugasundram Phenotypes for gene: FLII were changed from Dilated cardiomyopathy, MONDO:0005021 to Cardiomyopathy, dilated, 2J, OMIM:620635
15 Aug 2025	Paediatric or syndromic cardiomyopathy v7.13	FLII	Achchuthan Shanmugasundram Publications for gene: FLII were set to 32870709
15 Aug 2025	Paediatric or syndromic cardiomyopathy v7.12	FLII	Achchuthan Shanmugasundram reviewed gene: FLII: Rating: GREEN; Mode of pathogenicity: None; Publications: 32870709, 37561591; Phenotypes: Cardiomyopathy, dilated, 2J, OMIM:620635; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
15 Aug 2025	Structural eye disease v4.20	HNRNPC	Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) missense variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations. PMID:40004505 reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature; to: PMID:37541189 (2023) reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) missense variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations. PMID:40004505 (2025) reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature
15 Aug 2025	Structural eye disease v4.20	HNRNPC	Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations. PMID:40004505 reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) missense variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations. PMID:40004505 reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature
15 Aug 2025	Structural eye disease v4.20	HNRNPC	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are only two unrelated patients reported with monoallelic HNRNPC variants and bilateral colobomatous microphthalmia. They were both identified with the same missense variant and only in silico structural modelling data available for the variant. Hence, this gene can only be rated amber with the current evidence.; to: Comment on list classification: There are only two unrelated patients reported with monoallelic HNRNPC variants and bilateral colobomatous microphthalmia. They were both identified with the same missense variant, the only functional evidence available for this variant is from in silico structural modelling. Hence, this gene can only be rated amber with the current evidence.
15 Aug 2025	Structural eye disease v4.20	HNRNPC	Achchuthan Shanmugasundram Classified gene: HNRNPC as Amber List (moderate evidence)
15 Aug 2025	Structural eye disease v4.20	HNRNPC	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated patients reported with monoallelic HNRNPC variants and bilateral colobomatous microphthalmia. They were both identified with the same missense variant and only in silico structural modelling data available for the variant. Hence, this gene can only be rated amber with the current evidence.
15 Aug 2025	Structural eye disease v4.20	HNRNPC	Achchuthan Shanmugasundram Gene: hnrnpc has been classified as Amber List (Moderate Evidence).
15 Aug 2025	Structural eye disease v4.19	HNRNPC	Achchuthan Shanmugasundram gene: HNRNPC was added gene: HNRNPC was added to Structural eye disease. Sources: Literature Mode of inheritance for gene: HNRNPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HNRNPC were set to 37541189; 40004505 Phenotypes for gene: HNRNPC were set to Intellectual developmental disorder, autosomal dominant 74, OMIM:620688; microphthalmia, isolated, with coloboma, MONDO:0000170 Review for gene: HNRNPC was set to AMBER Added comment: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. The only patient with the p.(Arg99Gln) variant had bilateral colobomatous microphthalmia and bilateral cochlear malformations. PMID:40004505 reported the identification of the same missense variant (p.(Arg99Gln)) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. The clinical phenotype of this individual fit that of the previously described individual with the same variant from PMID:37541189, and only partially overlaps with the clinical spectrum of the disease. There is some functional evidence available for this variant from in silico structural modelling. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature
15 Aug 2025	Intellectual disability v9.64	HNRNPC	Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant and only partially overlaps with the clinical spectrum of the disease. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant, and only partially overlaps with the clinical spectrum of the disease. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature
15 Aug 2025	Intellectual disability v9.64	HNRNPC	Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals. PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual with the same variant and only partially overlaps with the clinical spectrum of the disease. This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype. Sources: Literature
15 Aug 2025	Intellectual disability v9.64	UNC13A	Achchuthan Shanmugasundram edited their review of gene: UNC13A: Changed rating: GREEN
14 Aug 2025	Early onset or syndromic epilepsy v8.23	UNC13A	Achchuthan Shanmugasundram Classified gene: UNC13A as Amber List (moderate evidence)
14 Aug 2025	Early onset or syndromic epilepsy v8.23	UNC13A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated patients and functional studies) for the promotion of this gene to green rating in the next GMS update.
14 Aug 2025	Early onset or syndromic epilepsy v8.23	UNC13A	Achchuthan Shanmugasundram Gene: unc13a has been classified as Amber List (Moderate Evidence).
14 Aug 2025	Early onset or syndromic epilepsy v8.22	UNC13A	Achchuthan Shanmugasundram gene: UNC13A was added gene: UNC13A was added to Early onset or syndromic epilepsy. Sources: Literature Q3_25_promote_green tags were added to gene: UNC13A. Mode of inheritance for gene: UNC13A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UNC13A were set to 28192369; 39634123 Phenotypes for gene: UNC13A were set to developmental and epileptic encephalopathy, MONDO:0100620 Review for gene: UNC13A was set to GREEN Added comment: PMID:28192369 (2017) reported a 6-year-old male patient presenting with a disorder characterised by a dyskinetic movement disorder, developmental delay, and autism, and identified with a rare de novo heterozygous missense variant (p.Pro814Leu) in UNC13A gene. Sanger sequencing was done in parents and de novo inheritance was confirmed. This patient also presented with febrile seizures. PMID:39634123 (2024) reported three unrelated patients presenting with clinical phenotypes consistent with developmental and epileptic encephalopathy including status epilepticus, focal onset seizures in both febrile and afebrile states, and intellectual disability. They were identified with three different de novo heterozygous missense variants (p.Met631Lys, p.Phe649Leu & p.Pro814Leu) based on trio exome sequencing. There is also functional evidence available from CRISPR/Cas9 zebrafish mutants in support of the association of UNC13A to epilepsy. This gene is currently associated with congenital nervous system disorder (MONDO:0002320) in ClinGen with 'Limited' rating by Syndromic Disorders expert panel (https://search.clinicalgenome.org/CCID:008453). Sources: Literature
14 Aug 2025	Intellectual disability v9.64	UNC13A	Achchuthan Shanmugasundram Classified gene: UNC13A as Amber List (moderate evidence)
14 Aug 2025	Intellectual disability v9.64	UNC13A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with three different monoallelic UNC13A variants and with intellectual disability/ developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
14 Aug 2025	Intellectual disability v9.64	UNC13A	Achchuthan Shanmugasundram Gene: unc13a has been classified as Amber List (Moderate Evidence).
14 Aug 2025	Intellectual disability v9.63	UNC13A	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UNC13A. Tag Q3_25_NHS_review tag was added to gene: UNC13A.
14 Aug 2025	Intellectual disability v9.63	UNC13A	Achchuthan Shanmugasundram Phenotypes for gene: UNC13A were changed from to developmental and epileptic encephalopathy, MONDO:0100620
14 Aug 2025	Intellectual disability v9.62	UNC13A	Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369
14 Aug 2025	Intellectual disability v9.61	UNC13A	Achchuthan Shanmugasundram reviewed gene: UNC13A: Rating: ; Mode of pathogenicity: None; Publications: 28192369, 39634123; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
14 Aug 2025	Childhood onset hereditary spastic paraplegia v8.8	INPP4A	Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
14 Aug 2025	Childhood onset hereditary spastic paraplegia v8.8	INPP4A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (10 patients from 9 families and functional studies) for the promotion of this gene to green rating in the next GMS update.
14 Aug 2025	Childhood onset hereditary spastic paraplegia v8.8	INPP4A	Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
14 Aug 2025	Childhood onset hereditary spastic paraplegia v8.7	INPP4A	Achchuthan Shanmugasundram gene: INPP4A was added gene: INPP4A was added to Childhood onset hereditary spastic paraplegia. Sources: Literature Q3_25_promote_green tags were added to gene: INPP4A. Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INPP4A were set to 39315527; 40748307; 40772914 Phenotypes for gene: INPP4A were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: INPP4A was set to GREEN Added comment: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Nine patients from eight families were reported with spasticity, of which six had LoF variants downstream of exon 4 and the remaining three had missense variants. Although age of onset was not provided for these patients, the age of last examination for eight of nine patients were below 16. There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder. PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. This patient had spasticity. Sources: Literature
13 Aug 2025	Severe microcephaly v8.11	INPP4A	Achchuthan Shanmugasundram changed review comment from: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants. PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report. PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies. Sources: Literature; to: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants. There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder. PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report. PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies. Sources: Literature
13 Aug 2025	Ataxia and cerebellar anomalies - narrow panel v8.15	INPP4A	Achchuthan Shanmugasundram changed review comment from: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants. PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs22). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies. Sources: Literature; to: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants. There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder. PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs22). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies. Sources: Literature
13 Aug 2025	Severe microcephaly v8.11	INPP4A	Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
13 Aug 2025	Severe microcephaly v8.11	INPP4A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 11 patients from eight unrelated families reported with biallelic INPP4A variants and severe microcephaly. Hence, this gene can be promoted to green rating in the next GMS update.
13 Aug 2025	Severe microcephaly v8.11	INPP4A	Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
13 Aug 2025	Ataxia and cerebellar anomalies - narrow panel v8.15	INPP4A	Achchuthan Shanmugasundram changed review comment from: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants. PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalied hypotonia, and mild limb weakness. They both had cerebellar anomalies. Sources: Literature; to: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants. PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies. Sources: Literature
13 Aug 2025	Severe microcephaly v8.10	INPP4A	Achchuthan Shanmugasundram gene: INPP4A was added gene: INPP4A was added to Severe microcephaly. Sources: Literature Q3_25_promote_green tags were added to gene: INPP4A. Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INPP4A were set to 39315527; 40748307; 40772914 Phenotypes for gene: INPP4A were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149 Review for gene: INPP4A was set to GREEN Added comment: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants. PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report. PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies. Sources: Literature
13 Aug 2025	Ataxia and cerebellar anomalies - narrow panel v8.15	INPP4A	Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
13 Aug 2025	Ataxia and cerebellar anomalies - narrow panel v8.15	INPP4A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (15 patients from 11 families) for the promotion of this gene to green rating in the next GMS update.
13 Aug 2025	Ataxia and cerebellar anomalies - narrow panel v8.15	INPP4A	Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
13 Aug 2025	Ataxia and cerebellar anomalies - narrow panel v8.14	INPP4A	Achchuthan Shanmugasundram gene: INPP4A was added gene: INPP4A was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Q3_25_promote_green tags were added to gene: INPP4A. Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INPP4A were set to 39315527; 40748307; 40772914 Phenotypes for gene: INPP4A were set to neurodevelopmental disorder, MONDO:0700092; Cerebellar hypoplasia, HP:0001321 Review for gene: INPP4A was set to GREEN Added comment: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants. PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalied hypotonia, and mild limb weakness. They both had cerebellar anomalies. Sources: Literature
13 Aug 2025	Early onset or syndromic epilepsy v8.21	INPP4A	Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
13 Aug 2025	Early onset or syndromic epilepsy v8.21	INPP4A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are a total of 33 patients from 19 unrelated families reported with biallelic INPP4A variants and a neurodevelopmental disorder. Of these, 13 patients from 12 families presented with seizures. Hence, this gene should be promoted to green rating in the next GMS update.
13 Aug 2025	Early onset or syndromic epilepsy v8.21	INPP4A	Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
13 Aug 2025	Early onset or syndromic epilepsy v8.20	INPP4A	Achchuthan Shanmugasundram edited their review of gene: INPP4A: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
13 Aug 2025	Early onset or syndromic epilepsy v8.20	INPP4A	Achchuthan Shanmugasundram Phenotypes for gene: INPP4A were changed from Intellectual disability; Seizures to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
13 Aug 2025	Early onset or syndromic epilepsy v8.19	INPP4A	Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678
13 Aug 2025	Early onset or syndromic epilepsy v8.18	INPP4A	Achchuthan Shanmugasundram reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39315527, 40748307, 40772914; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
13 Aug 2025	Intellectual disability v9.61	INPP4A	Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
13 Aug 2025	Intellectual disability v9.61	INPP4A	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are a total of 33 patients from 19 unrelated families reported with biallelic INPP4A variants and a neurodevelopmental disorder. Of these, 29 patients presented with severe or profound intellectual disability/ global developmental delay. Hence, this gene should be promoted to green rating in the next GMS update.
13 Aug 2025	Intellectual disability v9.61	INPP4A	Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
13 Aug 2025	Intellectual disability v9.60	INPP4A	Achchuthan Shanmugasundram edited their review of gene: INPP4A: Changed publications to: 39315527, 40748307, 40772914
13 Aug 2025	Intellectual disability v9.60	INPP4A	Achchuthan Shanmugasundram Phenotypes for gene: INPP4A were changed from Intellectual disability; Seizures to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
13 Aug 2025	Intellectual disability v9.59	INPP4A	Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678; 39315527; 4074830740772914
13 Aug 2025	Intellectual disability v9.58	INPP4A	Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678
13 Aug 2025	Intellectual disability v9.57	INPP4A	Achchuthan Shanmugasundram reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39315527, 4074830740772914; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
13 Aug 2025	Structural eye disease v4.18	NTN1	Hannah Knight gene: NTN1 was added gene: NTN1 was added to Structural eye disease. Sources: Literature Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NTN1 were set to PMID: 39648562 Phenotypes for gene: NTN1 were set to Chorioretinal Coloboma; Sensorineural Hearing Loss; Polydactyly Review for gene: NTN1 was set to AMBER Added comment: PMID: 39648562 reported a patient with chorioretinal coloboma and microphthalmia who carried a heterozygous NTN1 variant, c.1483T>A p.(Tyr495Asn). Patient also had bilateral sensorineural hearing loss which was investigated by examining the sensory hair cells of ntn1a morphant zebrafish, suggesting a role for netrin‐1 in hair cell development. NTN1 was previously identified as a mediator of optic fissure closure from transcriptome analyses of chick and zebrafish and was shown to cause ocular coloboma when knocked out in both mouse and zebrafish. Sources: Literature
13 Aug 2025	Structural eye disease v4.18	MYH10	Hannah Knight gene: MYH10 was added gene: MYH10 was added to Structural eye disease. Sources: Literature Mode of inheritance for gene: MYH10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYH10 were set to PMID: 40044823 Phenotypes for gene: MYH10 were set to Autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features Review for gene: MYH10 was set to GREEN Added comment: PMID: 40044823 reported six individuals from 3 unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features suggesting Baraitser-Winter cerebrofrontofacial syndrome. No neurodevelopmental features. 3 novel heterozygous variants in the MYH10 gene reported. Sources: Literature
12 Aug 2025	Primary ciliary disorders v1.47	HYDIN	Arina Puzriakova Publications for gene: HYDIN were set to
12 Aug 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.46	HYDIN	Arina Puzriakova Publications for gene: HYDIN were set to
12 Aug 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.45	HYDIN	Arina Puzriakova Phenotypes for gene: HYDIN were changed from Ciliary dyskinesia, primary, 5, 608647 to Ciliary dyskinesia, primary, 5, OMIM:608647
12 Aug 2025	Primary ciliary disorders v1.46	HYDIN	Arina Puzriakova Phenotypes for gene: HYDIN were changed from Ciliary dyskinesia, primary, 5, 608647 to Ciliary dyskinesia, primary, 5, OMIM:608647
10 Aug 2025	Childhood onset dystonia, chorea or related movement disorder v7.3	ADCY5	Cassandra Smith reviewed gene: ADCY5: Rating: GREEN; Mode of pathogenicity: None; Publications: 28971144, 30975617, 34631954, 33704598; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
08 Aug 2025	Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2	LINC01082	Hannah Robinson gene: LINC01082 was added gene: LINC01082 was added to Alveolar capillary dysplasia with misalignment of pulmonary veins. Sources: NHS GMS Mode of inheritance for gene: LINC01082 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317 Phenotypes for gene: LINC01082 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins Penetrance for gene: LINC01082 were set to Complete Review for gene: LINC01082 was set to GREEN gene: LINC01082 was marked as current diagnostic Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele. Sources: NHS GMS
08 Aug 2025	Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2	LINC01081	Hannah Robinson gene: LINC01081 was added gene: LINC01081 was added to Alveolar capillary dysplasia with misalignment of pulmonary veins. Sources: NHS GMS Mode of inheritance for gene: LINC01081 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317 Phenotypes for gene: LINC01081 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins Penetrance for gene: LINC01081 were set to Complete Review for gene: LINC01081 was set to GREEN gene: LINC01081 was marked as current diagnostic Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele. Sources: NHS GMS
08 Aug 2025	Fetal anomalies v6.15	LINC01082	Hannah Robinson gene: LINC01082 was added gene: LINC01082 was added to Fetal anomalies. Sources: NHS GMS Mode of inheritance for gene: LINC01082 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317 Phenotypes for gene: LINC01082 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins Penetrance for gene: LINC01082 were set to Complete Review for gene: LINC01082 was set to GREEN gene: LINC01082 was marked as current diagnostic Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele. Sources: NHS GMS
08 Aug 2025	Fetal anomalies v6.15	LINC01081	Hannah Robinson gene: LINC01081 was added gene: LINC01081 was added to Fetal anomalies. Sources: NHS GMS Mode of inheritance for gene: LINC01081 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317 Phenotypes for gene: LINC01081 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins Penetrance for gene: LINC01081 were set to Complete Review for gene: LINC01081 was set to GREEN gene: LINC01081 was marked as current diagnostic Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele. Sources: NHS GMS
08 Aug 2025	Non-syndromic familial congenital anorectal malformations v1.9	LINC01082	Hannah Robinson gene: LINC01082 was added gene: LINC01082 was added to Non-syndromic familial congenital anorectal malformations. Sources: NHS GMS Mode of inheritance for gene: LINC01082 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317 Phenotypes for gene: LINC01082 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins Penetrance for gene: LINC01082 were set to Complete Review for gene: LINC01082 was set to GREEN gene: LINC01082 was marked as current diagnostic Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele. Sources: NHS GMS
08 Aug 2025	Non-syndromic familial congenital anorectal malformations v1.9	LINC01081	Hannah Robinson gene: LINC01081 was added gene: LINC01081 was added to Non-syndromic familial congenital anorectal malformations. Sources: NHS GMS Mode of inheritance for gene: LINC01081 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317 Phenotypes for gene: LINC01081 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins Penetrance for gene: LINC01081 were set to Complete Review for gene: LINC01081 was set to GREEN gene: LINC01081 was marked as current diagnostic Added comment: LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele. Sources: NHS GMS
07 Aug 2025	Clefting v6.9	MED16	Achchuthan Shanmugasundram Classified gene: MED16 as Amber List (moderate evidence)
07 Aug 2025	Clefting v6.9	MED16	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (seven unrelated families) available for the promotion of this gene to green rating in the next GMS update.
07 Aug 2025	Clefting v6.9	MED16	Achchuthan Shanmugasundram Gene: med16 has been classified as Amber List (Moderate Evidence).
07 Aug 2025	Clefting v6.8	MED16	Achchuthan Shanmugasundram gene: MED16 was added gene: MED16 was added to Clefting. Sources: Literature Q3_25_promote_green tags were added to gene: MED16. Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED16 were set to 40081376 Phenotypes for gene: MED16 were set to Guillouet-Gordon syndrome, OMIM:621220 Review for gene: MED16 was set to GREEN Added comment: PMID:40081376 (2025) reported 25 patients from 18 families with biallelic MED16 variants and multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. There were a total of 8 predicted protein-truncating and 18 missense or in-frame duplication variants identified from these patients. Clefting was reported in eight patients from seven different families. This gene has been associated with relevant phenotypes in OMIM (MIM #621220), but not yet in Gene2Phenotype. Sources: Literature
07 Aug 2025	Intellectual disability v9.57	MED16	Achchuthan Shanmugasundram Classified gene: MED16 as Amber List (moderate evidence)
07 Aug 2025	Intellectual disability v9.57	MED16	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (10 unrelated families) available for the promotion of this gene to green rating in the next GMS update.
07 Aug 2025	Intellectual disability v9.57	MED16	Achchuthan Shanmugasundram Gene: med16 has been classified as Amber List (Moderate Evidence).
07 Aug 2025	Intellectual disability v9.56	MED16	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: MED16. Tag Q3_25_NHS_review tag was added to gene: MED16.
07 Aug 2025	Intellectual disability v9.56	MED16	Achchuthan Shanmugasundram Phenotypes for gene: MED16 were changed from developmental delay; multiple congenital abnormalities; Medopathy to Guillouet-Gordon syndrome, OMIM:621220
07 Aug 2025	Intellectual disability v9.56	MED16	Achchuthan Shanmugasundram Publications for gene: MED16 were set to PMID: 40081376
07 Aug 2025	Intellectual disability v9.55	MED16	Achchuthan Shanmugasundram reviewed gene: MED16: Rating: GREEN; Mode of pathogenicity: None; Publications: 40081376; Phenotypes: Guillouet-Gordon syndrome, OMIM:621220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Aug 2025	Possible mitochondrial disorder - nuclear genes v4.8	PDE12	Achchuthan Shanmugasundram changed review comment from: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature; to: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature
07 Aug 2025	Fetal anomalies v6.15	PDE12	Achchuthan Shanmugasundram Classified gene: PDE12 as Amber List (moderate evidence)
07 Aug 2025	Fetal anomalies v6.15	PDE12	Achchuthan Shanmugasundram Added comment: Comment on list classification: Of the three unrelated families reported with biallelic PDE12 variants, foetal anomalies were reported in two families. There is also functional and in silico evidence available. Hence, this gene can be promoted to green rating in the next GMS update.
07 Aug 2025	Fetal anomalies v6.15	PDE12	Achchuthan Shanmugasundram Gene: pde12 has been classified as Amber List (Moderate Evidence).
07 Aug 2025	Fetal anomalies v6.14	PDE12	Achchuthan Shanmugasundram changed review comment from: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature; to: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Of these, the patient from family 2 (died on day 2 after birth), and the two foetuses from family 3 had foetal anomalies detected via prenatal ultrasound. The patient from family 2 had brain anomalies. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature
07 Aug 2025	Mitochondrial disorders v9.23	PDE12	Achchuthan Shanmugasundram changed review comment from: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
07 Aug 2025	Possible mitochondrial disorder - nuclear genes v4.8	PDE12	Achchuthan Shanmugasundram Classified gene: PDE12 as Amber List (moderate evidence)
07 Aug 2025	Possible mitochondrial disorder - nuclear genes v4.8	PDE12	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated families and functional evidence) available for the association of biallelic variants in this gene with mitochondrial disease. Hence, this gene can be promoted to green rating in the next GMS update.
07 Aug 2025	Possible mitochondrial disorder - nuclear genes v4.8	PDE12	Achchuthan Shanmugasundram Gene: pde12 has been classified as Amber List (Moderate Evidence).
07 Aug 2025	Fetal anomalies v6.14	PDE12	Achchuthan Shanmugasundram gene: PDE12 was added gene: PDE12 was added to Fetal anomalies. Sources: Literature Q3_25_promote_green tags were added to gene: PDE12. Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE12 were set to 39567835 Phenotypes for gene: PDE12 were set to mitochondrial disease, MONDO:0044970 Review for gene: PDE12 was set to GREEN Added comment: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature
07 Aug 2025	Possible mitochondrial disorder - nuclear genes v4.7	PDE12	Achchuthan Shanmugasundram gene: PDE12 was added gene: PDE12 was added to Possible mitochondrial disorder - nuclear genes. Sources: Literature Q3_25_promote_green tags were added to gene: PDE12. Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE12 were set to 39567835 Phenotypes for gene: PDE12 were set to mitochondrial disease, MONDO:0044970 Review for gene: PDE12 was set to GREEN Added comment: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature
07 Aug 2025	Mitochondrial disorders v9.23	PDE12	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PDE12. Tag Q3_25_NHS_review tag was added to gene: PDE12.
07 Aug 2025	Mitochondrial disorders v9.23	PDE12	Achchuthan Shanmugasundram Classified gene: PDE12 as Amber List (moderate evidence)
07 Aug 2025	Mitochondrial disorders v9.23	PDE12	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Karen Stals, there is sufficient evidence (three unrelated families and functional evidence) available for the association of biallelic variants in this gene with mitochondrial disease. Hence, this gene can be promoted to green rating in the next GMS update.
07 Aug 2025	Mitochondrial disorders v9.23	PDE12	Achchuthan Shanmugasundram Gene: pde12 has been classified as Amber List (Moderate Evidence).
07 Aug 2025	Mitochondrial disorders v9.22	PDE12	Achchuthan Shanmugasundram Phenotypes for gene: PDE12 were changed from to mitochondrial disease, MONDO:0044970
07 Aug 2025	Mitochondrial disorders v9.21	PDE12	Achchuthan Shanmugasundram Publications for gene: PDE12 were set to 29903433; 28745585
07 Aug 2025	Mitochondrial disorders v9.20	PDE12	Achchuthan Shanmugasundram Mode of inheritance for gene: PDE12 was changed from to BIALLELIC, autosomal or pseudoautosomal
07 Aug 2025	Mitochondrial disorders v9.19	PDE12	Achchuthan Shanmugasundram reviewed gene: PDE12: Rating: GREEN; Mode of pathogenicity: None; Publications: 39567835; Phenotypes: mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Aug 2025	Congenital myopathy v6.35	DST	Cassandra Smith gene: DST was added gene: DST was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DST were set to 40497796 Review for gene: DST was set to GREEN Added comment: 9 affected individuals from 14 unrelated families, with variants in exons 40-41, specific to the DST-b isoform expressed in muscle. Phenotype: "severe neonatal myopathy characterized by arthrogryposis, hypotonia, and dilated cardiomyopathy" Sources: Literature
06 Aug 2025	Retinal disorders v8.14	CYP2U1	Arina Puzriakova Publications for gene: CYP2U1 were set to PMID: 26914923; 34828401; 39605873
05 Aug 2025	Monogenic short stature v1.22	RREB1	Achchuthan Shanmugasundram edited their review of gene: RREB1: Changed rating: RED
05 Aug 2025	Monogenic short stature v1.22	RREB1	Achchuthan Shanmugasundram Classified gene: RREB1 as Red List (low evidence)
05 Aug 2025	Monogenic short stature v1.22	RREB1	Achchuthan Shanmugasundram Added comment: Comment on list classification: The eligibility criteria for R453 in the National Genomic Test Directory specifies that the patients should have the height at <-3 SD below mean for the age to be included on this panel. As the reported patients do not meet this criteria, this gene has been rated red with the current evidence. This gene has already been proposed for green rating on R29 Intellectual disability panel and hence will feed into R27 Paediatric disorders.
05 Aug 2025	Monogenic short stature v1.22	RREB1	Achchuthan Shanmugasundram Gene: rreb1 has been classified as Red List (Low Evidence).
05 Aug 2025	Monogenic short stature v1.21	RREB1	Achchuthan Shanmugasundram Phenotypes for gene: RREB1 were changed from Rasopathy; Noonan-like; developmental disorder to RASopathy, MONDO:0021060
05 Aug 2025	Monogenic short stature v1.20	RREB1	Achchuthan Shanmugasundram Publications for gene: RREB1 were set to PMID: 40418122
05 Aug 2025	Monogenic short stature v1.19	RREB1	Achchuthan Shanmugasundram changed review comment from: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms. The height and weight of the patient was <3 centile at 3.25 years of age. PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). Although all reported patients had relative short stature, only one patient had -2SD below mean for the age. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms. The height and weight of the patient was <3 centile at 3.25 years of age. PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). Only one of the six reported patients had the height of ~-2SD below mean for the age. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
05 Aug 2025	Monogenic short stature v1.19	RREB1	Achchuthan Shanmugasundram reviewed gene: RREB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 38332451, 40418122; Phenotypes: RASopathy, MONDO:0021060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Aug 2025	Intellectual disability v9.55	RREB1	Achchuthan Shanmugasundram changed review comment from: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms. PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms. PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
05 Aug 2025	Intellectual disability v9.55	RREB1	Achchuthan Shanmugasundram changed review comment from: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs20). The patient presented with severe intellectual disability and general muscular hypotonia among other features. PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms. PMID:40418122 reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
05 Aug 2025	Intellectual disability v9.55	RREB1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: RREB1. Tag Q3_25_NHS_review tag was added to gene: RREB1.
05 Aug 2025	Intellectual disability v9.55	RREB1	Achchuthan Shanmugasundram Classified gene: RREB1 as Amber List (moderate evidence)
05 Aug 2025	Intellectual disability v9.55	RREB1	Achchuthan Shanmugasundram Added comment: Comment on list classification: Of the seven unrelated patients reported with monoallelic single nucleotide variants in RREB1 gene, three were reported with either intellectual disability or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
05 Aug 2025	Intellectual disability v9.55	RREB1	Achchuthan Shanmugasundram Gene: rreb1 has been classified as Amber List (Moderate Evidence).
05 Aug 2025	Intellectual disability v9.54	RREB1	Achchuthan Shanmugasundram Publications for gene: RREB1 were set to 38332451; 40418122
05 Aug 2025	Intellectual disability v9.53	RREB1	Achchuthan Shanmugasundram Phenotypes for gene: RREB1 were changed from Rasopathy; Noonan-like; developmental disorder to RASopathy, MONDO:0021060
05 Aug 2025	Intellectual disability v9.53	RREB1	Achchuthan Shanmugasundram Publications for gene: RREB1 were set to PMID: 40418122
05 Aug 2025	Intellectual disability v9.52	RREB1	Achchuthan Shanmugasundram reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38332451, 40418122; Phenotypes: RASopathy, MONDO:0021060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
05 Aug 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	DNAJB13	Steven Cowman reviewed gene: DNAJB13: Rating: GREEN; Mode of pathogenicity: None; Publications: 40637281; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.32	IRF1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: IRF1. Tag Q3_25_NHS_review tag was added to gene: IRF1.
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.32	IRF1	Achchuthan Shanmugasundram Classified gene: IRF1 as Amber List (moderate evidence)
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.32	IRF1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two unrelated cases and functional evidence in support of the association of biallelic IRF1 variants to immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS update.
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.32	IRF1	Achchuthan Shanmugasundram Gene: irf1 has been classified as Amber List (Moderate Evidence).
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.31	IRF1	Achchuthan Shanmugasundram Phenotypes for gene: IRF1 were changed from Immunodeficiency 117, mycobacteriosis, autosomal recessive to Immunodeficiency 117, mycobacteriosis, autosomal recessive, OMIM:620668
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.30	IRF1	Achchuthan Shanmugasundram Publications for gene: IRF1 were set to PMID: 36736301
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.29	IRF1	Achchuthan Shanmugasundram reviewed gene: IRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36736301; Phenotypes: Immunodeficiency 117, mycobacteriosis, autosomal recessive, OMIM:620668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Aug 2025	Monogenic short stature v1.19	QSOX2	Achchuthan Shanmugasundram Classified gene: QSOX2 as Amber List (moderate evidence)
05 Aug 2025	Monogenic short stature v1.19	QSOX2	Achchuthan Shanmugasundram Added comment: Comment on list classification: Although all three families were reported with short stature in PMID:39341815, there was only one family reported with height < -3 SD below mean (the eligibility criteria specified in the National Genomic Test Directory). There is also functional evidence available. Hence, this gene can be rated amber with current evidence.
05 Aug 2025	Monogenic short stature v1.19	QSOX2	Achchuthan Shanmugasundram Gene: qsox2 has been classified as Amber List (Moderate Evidence).
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.29	QSOX2	Achchuthan Shanmugasundram Classified gene: QSOX2 as Amber List (moderate evidence)
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.29	QSOX2	Achchuthan Shanmugasundram Added comment: Comment on list classification: Although recurrent respiratory infections and atopic eczema were reported in all three unrelated families from PMID:39341815, immunological profile showing immunodeficiency was reported only in one family. As there is functional evidence available in addition to human cases, this gene can be rated amber with the current evidence.
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.29	QSOX2	Achchuthan Shanmugasundram Gene: qsox2 has been classified as Amber List (Moderate Evidence).
05 Aug 2025	Monogenic short stature v1.18	QSOX2	Achchuthan Shanmugasundram gene: QSOX2 was added gene: QSOX2 was added to Monogenic short stature. Sources: Literature Mode of inheritance for gene: QSOX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: QSOX2 were set to 39341815 Phenotypes for gene: QSOX2 were set to Maharaj Storr Syndrome Review for gene: QSOX2 was set to AMBER Added comment: PMID:39341815 reported five patients from three unrelated families presenting with short stature, immune dysfunction, atopic eczema and gastrointestinal dysmotility. They were identified with biallelic QSOX2 variants via whole exome/genome sequencing. A total of six different variants were identified from these patients. Although all five patients were reported with short stature, only the twins from family 1 had height < -3 SD below mean for the age. Recurrent respiratory infections and atopic eczema was reported in four patients from three families, while this was absent in the father of family 2. Low IgM levels and abnormalities in some other immunological markers were only reported in twins from family 1. There is also functional evidence available. Patient-derived fibroblasts showed defective STAT5B nuclear translocation despite enhanced phosphorylation, and demonstrated growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Sources: Literature
05 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.28	QSOX2	Achchuthan Shanmugasundram gene: QSOX2 was added gene: QSOX2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: QSOX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: QSOX2 were set to 39341815 Phenotypes for gene: QSOX2 were set to Maharaj Storr Syndrome Review for gene: QSOX2 was set to AMBER Added comment: PMID:39341815 reported five patients from three unrelated families presenting with short stature, immune dysfunction, atopic eczema and gastrointestinal dysmotility. They were identified with biallelic QSOX2 variants via whole exome/genome sequencing. A total of six different variants were identified from these patients. Although all five patients were reported with short stature, only the twins from family 1 had height < -3 SD below mean for the age. Recurrent respiratory infections and atopic eczema was reported in four patients from three families, while this was absent in the father of family 2. Low IgM levels and abnormalities in some other immunological markers were only reported in twins from family 1. There is also functional evidence available. Patient-derived fibroblasts showed defective STAT5B nuclear translocation despite enhanced phosphorylation, and demonstrated growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Sources: Literature
04 Aug 2025	Congenital myopathy v6.35	SRPK3	Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the diagnostic panel (no evidence for monogenic association).; to: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the panel as Green (no evidence for monogenic association).
04 Aug 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.12	SRPK3	Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the diagnostic panel (no evidence for monogenic association).; to: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the panel as Green (no evidence for monogenic association).
04 Aug 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.12	SRPK3	Arina Puzriakova Classified gene: SRPK3 as Amber List (moderate evidence)
04 Aug 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.12	SRPK3	Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the diagnostic panel (no evidence for monogenic association).
04 Aug 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.12	SRPK3	Arina Puzriakova Gene: srpk3 has been classified as Amber List (Moderate Evidence).
04 Aug 2025	Congenital myopathy v6.35	SRPK3	Arina Puzriakova Classified gene: SRPK3 as Amber List (moderate evidence)
04 Aug 2025	Congenital myopathy v6.35	SRPK3	Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the diagnostic panel (no evidence for monogenic association).
04 Aug 2025	Congenital myopathy v6.35	SRPK3	Arina Puzriakova Gene: srpk3 has been classified as Amber List (Moderate Evidence).
04 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.27	FLT3LG	Arina Puzriakova Publications for gene: FLT3LG were set to 38701783
04 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.26	FLT3LG	Arina Puzriakova Classified gene: FLT3LG as Amber List (moderate evidence)
04 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.26	FLT3LG	Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further evidence - only a single family reported to date but phenotype is recapitulated by null mouse model. - PMID: 38701783 (2024) - three sibs from a consanguineous family with a homozygous frameshift variant and recurrent infections, including severe cutaneous warts, and hypoplastic bone marrow. - PMID: 10828034 (2000) - null mouse model recapitulates bone marrow findings
04 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.26	FLT3LG	Arina Puzriakova Gene: flt3lg has been classified as Amber List (Moderate Evidence).
04 Aug 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.25	FLT3LG	Arina Puzriakova Phenotypes for gene: FLT3LG were changed from Immunodeficiency; warts to ?Immunodeficiency 125 , OMIM:620926
04 Aug 2025	Hereditary diffuse gastric cancer v2.2	CDH1	Arina Puzriakova Phenotypes for gene: CDH1 were changed from to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
04 Aug 2025	Adult solid tumours cancer susceptibility v2.30	CDH1	Arina Puzriakova Phenotypes for gene: CDH1 were changed from Hereditary Diffuse Gastric Cancer, Familial Lobular Breast Cancer to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
04 Aug 2025	Inherited ovarian cancer (without breast cancer) v4.7	CDH1	Arina Puzriakova Phenotypes for gene: CDH1 were changed from Endometrial carcinoma, somatic, 608089; Ovarian carcinoma, somatic, 167000; {Breast cancer, lobular}, 114480; Gastric cancer, familial diffuse, with or without cleft lip and/or palate, 137215; {Prostate cancer, susceptibility to}, 176807; High Risk Breast Cancer; Breast and Ovarian Cancer to Ovarian cancer, somatic, OMIM:167000
04 Aug 2025	Adult solid tumours for rare disease v1.41	CDH1	Arina Puzriakova Phenotypes for gene: CDH1 were changed from Hereditary Diffuse Gastric Cancer, Familial Lobular Breast Cancer to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
04 Aug 2025	Clefting v6.7	CDH1	Arina Puzriakova Phenotypes for gene: CDH1 were changed from BLEPHAROCHEILODONTIC; Blepharocheilodontic syndrome 1 to Blepharocheilodontic syndrome 1, OMIM:119580; Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
04 Aug 2025	Fetal anomalies v6.13	CDH1	Arina Puzriakova Phenotypes for gene: CDH1 were changed from Blepharo-cheiro-dontic syndrome to Blepharocheilodontic syndrome 1, OMIM:119580
04 Aug 2025	Familial breast cancer v1.27	CDH1	Arina Puzriakova Phenotypes for gene: CDH1 were changed from Endometrial carcinoma, somatic, 608089; Ovarian carcinoma, somatic, 167000; {Breast cancer, lobular}, 114480; Gastric cancer, familial diffuse, with or without cleft lip and/or palate, 137215; {Prostate cancer, susceptibility to}, 176807; High Risk Breast Cancer; Breast and Ovarian Cancer; lobular breast cancer to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
04 Aug 2025	Familial breast cancer v1.26	CDH1	Arina Puzriakova Publications for gene: CDH1 were set to
04 Aug 2025	Familial breast cancer v1.25	CDH1	Arina Puzriakova Classified gene: CDH1 as Green List (high evidence)
04 Aug 2025	Familial breast cancer v1.25	CDH1	Arina Puzriakova Added comment: Comment on list classification: Rating Green as this is a well established breast cancer gene. Germline heterozygous variants have been found in diffuse gastric and lobular breast cancer syndrome. Patients may develop lobular breast cancer only or lobular breast cancer with gastric cancer. Lobular carcinoma of the breast has been reported in up to 60% of female carriers.
04 Aug 2025	Familial breast cancer v1.25	CDH1	Arina Puzriakova Gene: cdh1 has been classified as Green List (High Evidence).
04 Aug 2025	Breast cancer pertinent cancer susceptibility v2.14	CDH1	Arina Puzriakova changed review comment from: Comment on list classification: Updated rating from Red to Amber in line with review by Dmitrijs Rots - well-known for the breast cancer; to: Comment on list classification: Updated rating from Red to Amber in line with review by Dmitrijs Rots - well established breast cancer gene but appropriate for breast cancer susceptibility panel
04 Aug 2025	Breast cancer pertinent cancer susceptibility v2.14	CDH1	Arina Puzriakova edited their review of gene: CDH1: Changed rating: AMBER
04 Aug 2025	Breast cancer pertinent cancer susceptibility v2.14	CDH1	Arina Puzriakova Classified gene: CDH1 as Amber List (moderate evidence)
04 Aug 2025	Breast cancer pertinent cancer susceptibility v2.14	CDH1	Arina Puzriakova Added comment: Comment on list classification: Updated rating from Red to Amber in line with review by Dmitrijs Rots - well-known for the breast cancer
04 Aug 2025	Breast cancer pertinent cancer susceptibility v2.14	CDH1	Arina Puzriakova Gene: cdh1 has been classified as Amber List (Moderate Evidence).
04 Aug 2025	Monogenic diabetes v3.3	POC5	Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
04 Aug 2025	Monogenic diabetes v3.3	POC5	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
04 Aug 2025	Monogenic diabetes v3.3	POC5	Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
04 Aug 2025	Severe insulin resistance and lipodystrophy syndromes v4.62	POC5	Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
04 Aug 2025	Severe insulin resistance and lipodystrophy syndromes v4.62	POC5	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
04 Aug 2025	Severe insulin resistance and lipodystrophy syndromes v4.62	POC5	Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
04 Aug 2025	Ophthalmological ciliopathies v5.3	POC5	Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
04 Aug 2025	Ophthalmological ciliopathies v5.3	POC5	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. This disorder is also relevant to the R27 Paediatric disorders superpanel, which will be added through inclusion on the Ophthalmological ciliopathies panel.
04 Aug 2025	Ophthalmological ciliopathies v5.3	POC5	Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
04 Aug 2025	Monogenic diabetes v3.2	POC5	Arina Puzriakova gene: POC5 was added gene: POC5 was added to Monogenic diabetes. Sources: Literature Q3_25_promote_green tags were added to gene: POC5. Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POC5 were set to 29272404; 40590205 Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology Review for gene: POC5 was set to GREEN Added comment: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature
04 Aug 2025	Severe insulin resistance and lipodystrophy syndromes v4.61	POC5	Arina Puzriakova gene: POC5 was added gene: POC5 was added to Lipodystrophy - childhood onset. Sources: Literature Q3_25_promote_green tags were added to gene: POC5. Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POC5 were set to 29272404; 40590205 Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology Review for gene: POC5 was set to GREEN Added comment: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature
04 Aug 2025	Ophthalmological ciliopathies v5.2	POC5	Arina Puzriakova gene: POC5 was added gene: POC5 was added to Ophthalmological ciliopathies. Sources: Literature Q3_25_promote_green tags were added to gene: POC5. Mode of inheritance for gene: POC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POC5 were set to 29272404; 40590205 Phenotypes for gene: POC5 were set to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology Review for gene: POC5 was set to GREEN Added comment: Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model. Sources: Literature
04 Aug 2025	Retinal disorders v8.13	POC5	Arina Puzriakova Classified gene: POC5 as Amber List (moderate evidence)
04 Aug 2025	Retinal disorders v8.13	POC5	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Total of 12 families reported in PMID:40590205 and PMID:29272404 with biallelic LOF variants in the POC5 gene presenting with retinal dystrophy (11/12), diabetes mellitus (10/12), lipodystrophy (6/12), kidney disease (7/12), and muscle cramps (8/12). Two variants were found in multiple unrelated families from different ethnic and geographic backgrounds. Aberrant localization of POC5 at the basal body of the cilium, provides evidence that the described syndrome is a ciliopathy. Supportive zebrafish knockdown model.
04 Aug 2025	Retinal disorders v8.13	POC5	Arina Puzriakova Gene: poc5 has been classified as Amber List (Moderate Evidence).
04 Aug 2025	Retinal disorders v8.12	POC5	Arina Puzriakova Phenotypes for gene: POC5 were changed from to Retinal dystrophy; diabetes mellitus; lipodystrophy; renal failure; abnormal muscle physiology
04 Aug 2025	Retinal disorders v8.11	POC5	Arina Puzriakova Publications for gene: POC5 were set to
04 Aug 2025	Retinal disorders v8.10	POC5	Arina Puzriakova Mode of inheritance for gene: POC5 was changed from to BIALLELIC, autosomal or pseudoautosomal
04 Aug 2025	Retinal disorders v8.9	POC5	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: POC5. Tag Q3_25_NHS_review tag was added to gene: POC5.
01 Aug 2025	Paediatric or syndromic cardiomyopathy v7.12	EYA4	Arina Puzriakova Classified gene: EYA4 as Red List (low evidence)
01 Aug 2025	Paediatric or syndromic cardiomyopathy v7.12	EYA4	Arina Puzriakova Gene: eya4 has been classified as Red List (Low Evidence).
01 Aug 2025	Paediatric or syndromic cardiomyopathy v7.11	EYA4	Arina Puzriakova Classified gene: EYA4 as Amber List (moderate evidence)
01 Aug 2025	Paediatric or syndromic cardiomyopathy v7.11	EYA4	Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red - only single report of a case of DCM preceded by sensorineural hearing loss (possibly) associated with a deletion in EYA4 (PMID: 10769282). No other evidence of link with DCM, only definitive association is with non-syndromic hearing loss. Association is classified as provisional in OMIM and limited in ClinGen.
01 Aug 2025	Paediatric or syndromic cardiomyopathy v7.11	EYA4	Arina Puzriakova Gene: eya4 has been classified as Amber List (Moderate Evidence).
01 Aug 2025	Dilated Cardiomyopathy and conduction defects v1.96	EYA4	Arina Puzriakova Classified gene: EYA4 as Red List (low evidence)
01 Aug 2025	Dilated Cardiomyopathy and conduction defects v1.96	EYA4	Arina Puzriakova Added comment: Comment on list classification: Demoting from Green to Red - only single report of a case of DCM preceded by sensorineural hearing loss (possibly) associated with a deletion in EYA4 (PMID: 10769282). No other evidence of link with DCM, only definitive association is with non-syndromic hearing loss. Association is classified as provisional in OMIM and limited in ClinGen.
01 Aug 2025	Dilated Cardiomyopathy and conduction defects v1.96	EYA4	Arina Puzriakova Gene: eya4 has been classified as Red List (Low Evidence).
01 Aug 2025	Paediatric or syndromic cardiomyopathy v7.10	EYA4	Arina Puzriakova Phenotypes for gene: EYA4 were changed from Cardiomyopathy, dilated, 1J to ?Cardiomyopathy, dilated, 1J, OMIM:605362
01 Aug 2025	Dilated and arrhythmogenic cardiomyopathy v3.2	EYA4	Arina Puzriakova Phenotypes for gene: EYA4 were changed from ?Cardiomyopathy, dilated, 1J (605362); Cardiomyopathy, dilated, 1J; Deafness, autosomal dominant 10 (601316) to ?Cardiomyopathy, dilated, 1J, OMIM:605362
01 Aug 2025	Dilated Cardiomyopathy and conduction defects v1.95	EYA4	Arina Puzriakova Phenotypes for gene: EYA4 were changed from ?Cardiomyopathy, dilated, 1J (605362); Deafness, autosomal dominant 10 (601316); Cardiomyopathy, dilated, 1J to ?Cardiomyopathy, dilated, 1J, OMIM:605362
01 Aug 2025	Monogenic hearing loss v5.23	EYA4	Arina Puzriakova Phenotypes for gene: EYA4 were changed from hearing loss; Nonsyndromic Hearing Loss, Dominant; Deafness, autosomal dominant 10, 601316; Cardiomyopathy, dilated, 1J, 605362 to Deafness, autosomal dominant 10, OMIM:601316
01 Aug 2025	Hereditary neuropathy or pain disorder v7.5	RCC1	Arina Puzriakova Phenotypes for gene: RCC1 were changed from to Severe, acute-onset axonal neuropathy following infection
01 Aug 2025	Hereditary neuropathy v1.500	RCC1	Arina Puzriakova Phenotypes for gene: RCC1 were changed from axonal neuropathy; encephalopathy; infection-induced neuropathy to Severe, acute-onset axonal neuropathy following infection
01 Aug 2025	Hereditary neuropathy or pain disorder v7.4	RCC1	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RCC1. Tag Q3_25_NHS_review tag was added to gene: RCC1.
01 Aug 2025	Hereditary neuropathy or pain disorder v7.4	RCC1	Arina Puzriakova Publications for gene: RCC1 were set to
01 Aug 2025	Hereditary neuropathy v1.499	RCC1	Arina Puzriakova Publications for gene: RCC1 were set to PMID: 40683276
01 Aug 2025	Hereditary neuropathy v1.498	RCC1	Arina Puzriakova Classified gene: RCC1 as Green List (high evidence)
01 Aug 2025	Hereditary neuropathy v1.498	RCC1	Arina Puzriakova Added comment: Comment on list classification: Rating Green on this 100K panel as there is a sufficient number of unrelated cases with the same phenotype and functional data to support this gene-disease association. At least 12 unrelated families reported (PMID: 40683276) with biallelic variants in this gene associated with severe, acute-onset axonal neuropathy following infection. Eight different missense variants were identified. In vitro studies indicate that variants reduced the thermal stability of the RCC1 protein and some variants decreased GDP-to-GTP exchange activity. Patient fibroblasts under stress, revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model demonstrated that altered Rcc1 function leads to fatal intolerance to oxidative stress.
01 Aug 2025	Hereditary neuropathy v1.498	RCC1	Arina Puzriakova Gene: rcc1 has been classified as Green List (High Evidence).
01 Aug 2025	Hereditary neuropathy or pain disorder v7.3	RCC1	Arina Puzriakova Classified gene: RCC1 as Amber List (moderate evidence)
01 Aug 2025	Hereditary neuropathy or pain disorder v7.3	RCC1	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - number of cases with the same phenotype and functional support. At least 12 unrelated families reported (PMID: 40683276) with biallelic variants in this gene associated with severe, acute-onset axonal neuropathy following infection. Eight different missense variants were identified. In vitro studies indicate that variants reduced the thermal stability of the RCC1 protein and some variants decreased GDP-to-GTP exchange activity. Patient fibroblasts under stress, revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model demonstrated that altered Rcc1 function leads to fatal intolerance to oxidative stress.
01 Aug 2025	Hereditary neuropathy or pain disorder v7.3	RCC1	Arina Puzriakova Gene: rcc1 has been classified as Amber List (Moderate Evidence).
01 Aug 2025	Paediatric disorders - additional genes v7.5	GPKOW	Arina Puzriakova Classified gene: GPKOW as Amber List (moderate evidence)
01 Aug 2025	Paediatric disorders - additional genes v7.5	GPKOW	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with a multisystemic disorder due to hypomorphic or possible dominant-negative variants in this gene (PMID: 28612833; 40221893).
01 Aug 2025	Paediatric disorders - additional genes v7.5	GPKOW	Arina Puzriakova Gene: gpkow has been classified as Amber List (Moderate Evidence).
01 Aug 2025	Severe microcephaly v8.9	GPKOW	Arina Puzriakova edited their review of gene: GPKOW: Changed rating: AMBER
01 Aug 2025	Severe microcephaly v8.9	GPKOW	Arina Puzriakova Tag watchlist tag was added to gene: GPKOW.
01 Aug 2025	Severe microcephaly v8.9	GPKOW	Arina Puzriakova Classified gene: GPKOW as Amber List (moderate evidence)
01 Aug 2025	Severe microcephaly v8.9	GPKOW	Arina Puzriakova Added comment: Comment on list classification: Rating Amber as severity of microcephaly is not within the scope of this panel (> -3SD) in all cases. Particularly, in family 1 from PMID: 40221893 where head size increased following birth. This classification could be reviewed if additional cases of severe microcephaly associated with this gene emerge in the future (adding watchlist tag). PMID: 28612833 - 5 affected males from one family with microcephaly that could be considered within the scope of the panel where biparietal diameter (BPD) is specified (see supplemental). PMID: 40221893 - 3 affected males from 2 families: F1, in individual 1 HC was −2.4 SD at birth, changing to −1.3 SD at a later examination at 7 weeks, while individual 2 had a HC −3.47 SD at birth and −2.22 SD at 3 months; in F2, individual 3 had HC −3.47 SD at 33-weeks when the pregnancy was terminated. Heterozygous female carriers in F2 also had severe microcephaly, including the mother and sister of individual 3.
01 Aug 2025	Severe microcephaly v8.9	GPKOW	Arina Puzriakova Gene: gpkow has been classified as Amber List (Moderate Evidence).
01 Aug 2025	Paediatric disorders - additional genes v7.4	GPKOW	Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: GPKOW. Tag Q3_25_promote_green tag was added to gene: GPKOW.
01 Aug 2025	Severe microcephaly v8.8	GPKOW	Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: GPKOW.
01 Aug 2025	Paediatric disorders - additional genes v7.4	GPKOW	Arina Puzriakova Entity copied from Fetal anomalies v6.12
01 Aug 2025	Paediatric disorders - additional genes v7.4	GPKOW	Arina Puzriakova gene: GPKOW was added gene: GPKOW was added to Paediatric disorders - additional genes. Sources: Expert Review Amber,PAGE Additional Gene List Q2_25_ promote_green tags were added to gene: GPKOW. Mode of inheritance for gene: GPKOW was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: GPKOW were set to 28612833; 40221893 Phenotypes for gene: GPKOW were set to microcephaly with intrauterine growth restriction
01 Aug 2025	Severe microcephaly v8.8	GPKOW	Arina Puzriakova Entity copied from Fetal anomalies v6.12
01 Aug 2025	Severe microcephaly v8.8	GPKOW	Arina Puzriakova gene: GPKOW was added gene: GPKOW was added to Severe microcephaly. Sources: Expert Review Amber,PAGE Additional Gene List Q2_25_ promote_green tags were added to gene: GPKOW. Mode of inheritance for gene: GPKOW was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: GPKOW were set to 28612833; 40221893 Phenotypes for gene: GPKOW were set to microcephaly with intrauterine growth restriction
31 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.24	ASXL1	Boaz Palterer gene: ASXL1 was added gene: ASXL1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: ASXL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ASXL1 were set to 40742536 Phenotypes for gene: ASXL1 were set to chronic viral infections; viral-associated malignancies; combined immune deficiency Penetrance for gene: ASXL1 were set to unknown Review for gene: ASXL1 was set to RED Added comment: Fu et al. present a single case report with biallelic germline missense variants in ASXL1. The patient had a history of hematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction, confirming the patient variants’ pathogenicity. Sources: Literature
31 Jul 2025	Rhabdomyolysis and metabolic muscle disorders v5.7	AMPD1	Arina Puzriakova Phenotypes for gene: AMPD1 were changed from Rhabdomyolysis; Myopathy due to myoadenylate deaminase deficiency 615511 to Myopathy due to myoadenylate deaminase deficiency, OMIM:615511
31 Jul 2025	Acute rhabdomyolysis v2.2	AMPD1	Arina Puzriakova Classified gene: AMPD1 as Green List (high evidence)
31 Jul 2025	Acute rhabdomyolysis v2.2	AMPD1	Arina Puzriakova Added comment: Comment on list classification: This gene was promoted to Green and added to the diagnostic panel, however as per review by Zornitza Stark (below), it has since come to light that several variants reported in patients have a high frequency in the general population, calling into question their pathogenicity. Hence, tagging for GMS expert review to determine whether this gene should be demoted on this panel. Copied from Zornitza Stark (Australian Genomics) review on Rhabdomyolysis and metabolic muscle disorders (66) panel (v3.35): Variable age of onset ranging from infancy to adulthood (OMIM), however, no new publications supporting gene disease association. PMID: 21343608: Reported an infancy presenting with congenital hypotonia and muscle weakness. Variant reported in as VUS in ClinVar (as Q45*) and present in gnomad (1470 homozygotes) PMID: 11102975: Adult patient reported however variants reported R425H (also R458H) present in gnomad (3 homozygotes) and R388W (also R421W) present in gnomad (2 homozygotes). The observation of a high number of homozygotes in gnomad together with the absence of new reports raises significant concerns about the pathogenicity of these variants.
31 Jul 2025	Acute rhabdomyolysis v2.2	AMPD1	Arina Puzriakova Gene: ampd1 has been classified as Green List (High Evidence).
31 Jul 2025	Acute rhabdomyolysis v2.1	AMPD1	Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: AMPD1. Tag Q3_25_demote_red tag was added to gene: AMPD1.
31 Jul 2025	Rhabdomyolysis and metabolic muscle disorders v5.6	AMPD1	Arina Puzriakova Classified gene: AMPD1 as Green List (high evidence)
31 Jul 2025	Rhabdomyolysis and metabolic muscle disorders v5.6	AMPD1	Arina Puzriakova Added comment: Comment on list classification: This gene was promoted to Green and added to the diagnostic panel, however as per review by Zornitza Stark, it has since come to light that several variants reported in patients have a high frequency in the general population, calling into question their pathogenicity. Hence, tagging for GMS expert review to determine whether this gene should be demoted on this panel.
31 Jul 2025	Rhabdomyolysis and metabolic muscle disorders v5.6	AMPD1	Arina Puzriakova Gene: ampd1 has been classified as Green List (High Evidence).
31 Jul 2025	Rhabdomyolysis and metabolic muscle disorders v5.5	AMPD1	Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: AMPD1. Tag Q3_25_demote_red tag was added to gene: AMPD1.
31 Jul 2025	Fetal anomalies v6.12	MYH3	Arina Puzriakova Phenotypes for gene: MYH3 were changed from DISTAL ARTHROGRYPOSIS TYPE 2B; DISTAL ARTHROGRYPOSIS TYPE 2A to Arthrogryposis, distal, type 2A (Freeman-Sheldon), OMIM:193700 (AD); Arthrogryposis, distal, type 2B3 (Sheldon-Hall), OMIM:618436 (AD); Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110 (AD); Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469 (AR)
31 Jul 2025	Fetal anomalies v6.11	MYH3	Arina Puzriakova Publications for gene: MYH3 were set to
31 Jul 2025	Fetal anomalies v6.10	MYH3	Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next GMS panel update. Monoallelic variants are associated with distal arthrogryposis conditions including Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Monoallelic and biallelic variants also underlie Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterised by extensive bony abnormalities in addition to congenital contractures. These features could be detected prenatally and therefore are relevant to this panel. At least 3 unrelated recessive CPSFS cases have been reported with multiple contractures (PMID: 29805041). Additionally, two sibs from one family have been reported with distal arthrogryposis without additional features of CPSFS, who harboured two homozygous ultra-rare MYH3 variants (PMID: 38856159). Their presentation was assessed in a prenatal diagnostic setting. Overall this evidence supports an MOI of 'both mono- and biallelic' on this panel.
31 Jul 2025	Fetal anomalies v6.10	MYH3	Arina Puzriakova Mode of inheritance for gene: MYH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
31 Jul 2025	Intellectual disability v9.52	MYH3	Arina Puzriakova Mode of inheritance for gene: MYH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
31 Jul 2025	Fetal anomalies v6.9	MYH3	Arina Puzriakova Tag Q3_25_MOI tag was added to gene: MYH3.
31 Jul 2025	Arthrogryposis v9.4	MYH3	Arina Puzriakova Publications for gene: MYH3 were set to
31 Jul 2025	Arthrogryposis v9.3	MYH3	Arina Puzriakova Tag Q3_25_MOI tag was added to gene: MYH3.
31 Jul 2025	Arthrogryposis v9.3	MYH3	Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next GMS panel update. Monoallelic variants are associated with distal arthrogryposis conditions including Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Monoallelic and biallelic variants also underlie Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterised by extensive bony abnormalities in addition to congenital contractures - a phenotype relevant to this panel. At least 3 unrelated recessive CPSFS cases have been reported with multiple contractures (PMID: 29805041). Additionally, two sibs from one family have been reported with distal arthrogryposis without additional features of CPSFS, who harboured two homozygous ultra-rare MYH3 variants (PMID: 38856159). Overall this evidence supports an MOI of 'both mono- and biallelic' on this panel.
31 Jul 2025	Arthrogryposis v9.3	MYH3	Arina Puzriakova Mode of inheritance for gene: MYH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
31 Jul 2025	Arthrogryposis v9.2	MYH3	Arina Puzriakova Phenotypes for gene: MYH3 were changed from Arthrogryposis, distal, type 2A, 193700; Arthrogryposis, distal, type 2B, 601680; Arthrogryposis Multiplex Congenita to Arthrogryposis, distal, type 2A (Freeman-Sheldon), OMIM:193700 (AD); Arthrogryposis, distal, type 2B3 (Sheldon-Hall), OMIM:618436 (AD); Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110 (AD); Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469 (AR)
30 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.13	ZFHX3	Arina Puzriakova Classified gene: ZFHX3 as Red List (low evidence)
30 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.13	ZFHX3	Arina Puzriakova Gene: zfhx3 has been classified as Red List (Low Evidence).
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.24	HSPA1L	Arina Puzriakova Classified gene: HSPA1L as Green List (high evidence)
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.24	HSPA1L	Arina Puzriakova Added comment: Comment on list classification: This gene was recently promoted to Green and added to the diagnostic panel, however as per review by Zornitza Stark, it has since come to light that several variants reported in patients have a high frequency in the general population, calling into question their pathogenicity. Hence, tagging for GMS expert review to determine whether this gene should be demoted on this panel.
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.24	HSPA1L	Arina Puzriakova Gene: hspa1l has been classified as Green List (High Evidence).
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.23	HSPA1L	Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: HSPA1L. Tag Q3_25_demote_amber tag was added to gene: HSPA1L.
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.23	AMFR	Arina Puzriakova changed review comment from: Comment on list classification: Rating Red as currently there is only a single human case report linking this gene to immune dysfunction. Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.; to: Comment on list classification: Rating Red as currently there is only a single human case report linking this gene to immune dysfunction (PMID:38277122). Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.23	AMFR	Arina Puzriakova changed review comment from: Comment on list classification: Rating Red as currently there is only a single report linking this gene to immune dysfunction. Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.; to: Comment on list classification: Rating Red as currently there is only a single human case report linking this gene to immune dysfunction. Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.23	AMFR	Arina Puzriakova Classified gene: AMFR as Red List (low evidence)
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.23	AMFR	Arina Puzriakova Added comment: Comment on list classification: Rating Red as currently there is only a single report linking this gene to immune dysfunction. Also unaffected carriers call into question the association but good functional work. Additional cases required to ascertain pathogenicity.
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.23	AMFR	Arina Puzriakova Gene: amfr has been classified as Red List (Low Evidence).
30 Jul 2025	Early onset or syndromic epilepsy v8.18	MT-TK	Arina Puzriakova Classified gene: MT-TK as Amber List (moderate evidence)
30 Jul 2025	Early onset or syndromic epilepsy v8.18	MT-TK	Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
30 Jul 2025	Early onset or syndromic epilepsy v8.18	MT-TK	Arina Puzriakova Gene: mt-tk has been classified as Amber List (Moderate Evidence).
30 Jul 2025	Early onset or syndromic epilepsy v8.17	MT-TK	Arina Puzriakova Classified gene: MT-TK as Amber List (moderate evidence)
30 Jul 2025	Early onset or syndromic epilepsy v8.17	MT-TK	Arina Puzriakova Gene: mt-tk has been classified as Amber List (Moderate Evidence).
30 Jul 2025	Early onset or syndromic epilepsy v8.16	MT-TK	Arina Puzriakova gene: MT-TK was added gene: MT-TK was added to Early onset or syndromic epilepsy. Sources: Literature locus-type-rna-transfer, Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: MT-TK. Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL Publications for gene: MT-TK were set to 1463006; 8228033; 18651333; 29663531; 33766967 Phenotypes for gene: MT-TK were set to MERRF syndrome, MONDO:0010790 Review for gene: MT-TK was set to GREEN Added comment: Adding MT-TK to this panel by suggestion of North East and Yorkshire GLH where a patient was identified with a tier 3 diagnostic MT-TK variant due to absence of the gene on this applied panel. MT-TK gene has been associated with severe mitochondrial diseases which includes myoclonic epilepsy - multiple (at least 8) unrelated cases with epilepsy as a presenting feature have been reported in the literature (PMID: 1463006; 8228033; 18651333; 29663531; 33766967) Sources: Literature
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.22	DPP9	Arina Puzriakova Classified gene: DPP9 as Amber List (moderate evidence)
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.22	DPP9	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Three unrelated families with four individuals with an immune disorder characterised by failure to thrive, skin manifestations, pancytopenia, recurrent fevers and recurrent infections. Supporting mouse and zebrafish models (PMID: 36112693)
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.22	DPP9	Arina Puzriakova Gene: dpp9 has been classified as Amber List (Moderate Evidence).
30 Jul 2025	Laterality disorders and isomerism v4.3	MNS1	Karen Stals reviewed gene: MNS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38920647; Phenotypes: Laterality defects, ciliopathy disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
30 Jul 2025	Mitochondrial disorders v9.19	PDE12	Karen Stals reviewed gene: PDE12: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:39567835; Phenotypes: Neonatal mitochondrial disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.21	DPP9	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DPP9. Tag Q3_25_NHS_review tag was added to gene: DPP9.
30 Jul 2025	Intellectual disability v9.51	MED16	Karen Stals gene: MED16 was added gene: MED16 was added to Intellectual disability. Sources: NHS GMS Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED16 were set to PMID: 40081376 Phenotypes for gene: MED16 were set to developmental delay; multiple congenital abnormalities; Medopathy Penetrance for gene: MED16 were set to unknown Review for gene: MED16 was set to GREEN gene: MED16 was marked as current diagnostic Added comment: 25 individuals from 18 families reported with biallelic MED16 variants with multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. 8 predicted protein-truncating and 18 missense or in-frame duplication variants identified. Sources: NHS GMS
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.21	DPP9	Arina Puzriakova Publications for gene: DPP9 were set to PMID: 36112693
30 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.20	DPP9	Arina Puzriakova Phenotypes for gene: DPP9 were changed from Hatipoglu immunodeficiency syndrome to Hatipoglu immunodeficiency syndrome, OMIM:620331
30 Jul 2025	Fetal hydrops v1.89	RASA1	Karen Stals reviewed gene: RASA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36980822; Phenotypes: hydrops, chylothorax, Capillary malformation-arteriovenous malformation 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
30 Jul 2025	Intellectual disability v9.51	RREB1	Karen Stals gene: RREB1 was added gene: RREB1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RREB1 were set to PMID: 40418122 Phenotypes for gene: RREB1 were set to Rasopathy; Noonan-like; developmental disorder Penetrance for gene: RREB1 were set to Complete Review for gene: RREB1 was set to GREEN Added comment: 6 additional individuals with truncating variants in RREB1 gene and a Rasopathy phenotype, features including congenital heart disease, developmental delay, short stature, and dysmorphic facial features (PMID: 40418122). RREB1 encodes a transcriptional repressor of Ras-MAPK signalling. Supporting functional evidence and animal models. Sources: Literature
30 Jul 2025	Monogenic short stature v1.17	RREB1	Karen Stals gene: RREB1 was added gene: RREB1 was added to Monogenic short stature. Sources: Literature Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RREB1 were set to PMID: 40418122 Phenotypes for gene: RREB1 were set to Rasopathy; Noonan-like; developmental disorder Penetrance for gene: RREB1 were set to Complete Review for gene: RREB1 was set to GREEN Added comment: 6 additional individuals with truncating variants in RREB1 gene and a Rasopathy phenotype, features including congenital heart disease, developmental delay, short stature, and dysmorphic facial features (PMID: 40418122). RREB1 encodes a transcriptional repressor of Ras-MAPK signalling. Supporting functional evidence and animal models. Sources: Literature
30 Jul 2025	RASopathies v1.83	RREB1	Karen Stals reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40418122; Phenotypes: Rasopathy, Noonan-like, developmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
30 Jul 2025	Paediatric disorders - additional genes v7.3	MC4R	Arina Puzriakova Classified gene: MC4R as Amber List (moderate evidence)
30 Jul 2025	Paediatric disorders - additional genes v7.3	MC4R	Arina Puzriakova Added comment: Comment on list classification: This gene should be promote to Green at the next GMS panel update. There is sufficient evidence to support this gene-disease association (variants in the MC4R gene are the most common cause of monogenic obesity, >3 cases). As highlighted in the review by Ian Berry, the R27 panel represents an alternative test to R149 that may be requested for these patients which warrants inclusion of the MC4R gene on this panel.
30 Jul 2025	Paediatric disorders - additional genes v7.3	MC4R	Arina Puzriakova Gene: mc4r has been classified as Amber List (Moderate Evidence).
30 Jul 2025	Paediatric disorders - additional genes v7.2	MC4R	Arina Puzriakova Phenotypes for gene: MC4R were changed from to Obesity (BMIQ20), OMIM:618406; {Obesity, resistence to (BMIQ20)}, OMIM:618306
30 Jul 2025	Paediatric disorders - additional genes v7.1	MC4R	Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MC4R. Tag Q3_25_NHS_review tag was added to gene: MC4R.
30 Jul 2025	Structural eye disease v4.18	FOXE3	Arina Puzriakova Phenotypes for gene: FOXE3 were changed from Anterior segment mesenchymal dysgenesis, OMIM:107250; Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256 to Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Cataract 34, multiple types, OMIM:612968
30 Jul 2025	Structural eye disease v4.17	FOXE3	Arina Puzriakova Tag Q3_25_promote_green was removed from gene: FOXE3. Tag Q3_25_MOI tag was added to gene: FOXE3.
30 Jul 2025	Structural eye disease v4.17	FOXE3	Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from ' BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' at the next GMS panel update. As highlighted in review by Dorine Bax, at least 6 cases with heterozygous variants and cataracts and/or anterior segment dysgenesis have been reported, which appear to represent a spectrum of disease rather than separate disease entities. Both presentations are relevant to this panel and therefore should be included. AD inheritance is discussed in ClinGen and OMIM curations of this gene-disease association. Cases with AR inheritance generally have more severe presentation.
30 Jul 2025	Structural eye disease v4.17	FOXE3	Arina Puzriakova Mode of inheritance for gene: FOXE3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
30 Jul 2025	Structural eye disease v4.16	FOXE3	Arina Puzriakova Tag watchlist_moi was removed from gene: FOXE3. Tag Q3_25_promote_green tag was added to gene: FOXE3. Tag Q3_25_NHS_review tag was added to gene: FOXE3.
28 Jul 2025	Hereditary neuropathy v1.497	RCC1	Bill Newman gene: RCC1 was added gene: RCC1 was added to Hereditary neuropathy. Sources: Expert list Mode of inheritance for gene: RCC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RCC1 were set to PMID: 40683276 Phenotypes for gene: RCC1 were set to axonal neuropathy; encephalopathy; infection-induced neuropathy Penetrance for gene: RCC1 were set to Complete Review for gene: RCC1 was set to GREEN Added comment: We have just described 12 families withbiallelic hylomorphic variants in this gene associated with acute onset axonal neuropathy mimicking Guillain Barre syndrome (ie post infective onset) Sources: Expert list
28 Jul 2025	Early onset or syndromic epilepsy v8.15	RNU5B-1	Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with variable degrees of intellectual disability reported in almost all cases. This disorder to relevant to the R27 Paediatric disorders superpanel, which will be added through inclusion on the Intellectual disability panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with seizures reported in 6 unrelated cases which can be an early presenting feature.
28 Jul 2025	Early onset or syndromic epilepsy v8.15	RNU5B-1	Arina Puzriakova Entity copied from Intellectual disability v9.51
28 Jul 2025	Early onset or syndromic epilepsy v8.15	RNU5B-1	Arina Puzriakova gene: RNU5B-1 was added gene: RNU5B-1 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature locus-type-rna-small-nuclear, dd_review, Q3_25_promote_green tags were added to gene: RNU5B-1. Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RNU5B-1 were set to 40379786; 40442284 Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092
28 Jul 2025	Early onset or syndromic epilepsy v8.14	RNU5A-1	Arina Puzriakova Entity copied from Intellectual disability v9.51
28 Jul 2025	Early onset or syndromic epilepsy v8.14	RNU5A-1	Arina Puzriakova gene: RNU5A-1 was added gene: RNU5A-1 was added to Early onset or syndromic epilepsy. Sources: Expert Review Red,Literature locus-type-rna-small-nuclear tags were added to gene: RNU5A-1. Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RNU5A-1 were set to 40379786 Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder, MONDO:0700092
28 Jul 2025	Intellectual disability v9.51	RNU5A-1	Arina Puzriakova Classified gene: RNU5A-1 as Red List (low evidence)
28 Jul 2025	Intellectual disability v9.51	RNU5A-1	Arina Puzriakova Added comment: Comment on list classification: Rating Red awaiting further evidence - limited number of cases currently reported with variable neurodevelopmental phenotype. Variants have been classified as VUS and additional evidence is required to ascertain pathogenicity.
28 Jul 2025	Intellectual disability v9.51	RNU5A-1	Arina Puzriakova Gene: rnu5a-1 has been classified as Red List (Low Evidence).
28 Jul 2025	Intellectual disability v9.50	RNU5A-1	Arina Puzriakova gene: RNU5A-1 was added gene: RNU5A-1 was added to Intellectual disability. Sources: Literature locus-type-rna-small-nuclear tags were added to gene: RNU5A-1. Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RNU5A-1 were set to 40379786 Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder, MONDO:0700092 Added comment: PMID: 40379786 (2025) - three unrelated individuals with de novo variants in the RNU5A-1 gene (classified as VUS) and a neurodevelopmental disorder. Six individuals with rare de novo variants were identified in total but clinical details were only available for 3/6. Of these three individuals, two harboured the same variant (n.40_41insA) on the maternal allele, while the third individual harboured a different variant (n.39del) but also on the 5′ loop I domain of RNU5A-1. Clinical data showed neurodevelopmental abnormalities (mild ID (2), severe ID (1), epilepsy (2), brain MRI abnormalities (1)) with variable congenital malformations. Sources: Literature
28 Jul 2025	Intellectual disability v9.49	RNU2-2P	Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679; 40442284
28 Jul 2025	Intellectual disability v9.48	RNU5B-1	Arina Puzriakova Tag locus-type-rna-small-nuclear tag was added to gene: RNU5B-1. Tag dd_review tag was added to gene: RNU5B-1.
28 Jul 2025	Intellectual disability v9.48	RNU2-2P	Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679
28 Jul 2025	Early onset or syndromic epilepsy v8.13	RNU2-2P	Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679
28 Jul 2025	Intellectual disability v9.47	RNU5B-1	Arina Puzriakova Classified gene: RNU5B-1 as Amber List (moderate evidence)
28 Jul 2025	Intellectual disability v9.47	RNU5B-1	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with variable degrees of intellectual disability reported in almost all cases. This disorder to relevant to the R27 Paediatric disorders superpanel, which will be added through inclusion on the Intellectual disability panel.
28 Jul 2025	Intellectual disability v9.47	RNU5B-1	Arina Puzriakova Gene: rnu5b-1 has been classified as Amber List (Moderate Evidence).
28 Jul 2025	Intellectual disability v9.46	RNU5B-1	Arina Puzriakova gene: RNU5B-1 was added gene: RNU5B-1 was added to Intellectual disability. Sources: Literature Q3_25_promote_green tags were added to gene: RNU5B-1. Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RNU5B-1 were set to 40379786; 40442284 Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092 Review for gene: RNU5B-1 was set to GREEN Added comment: At least 19 individuals with de novo and/or recurrent variants in RNU5B-1 and a neurodevelopmental disorder characterised by ID/DD, brain MRI abnormalities, hypotonia, microcephaly or macrocephaly, failure to thrive, and in some cases seizures. PMID: 40379786 (2025) - 15 unrelated probands with heterozygous variants in RNU5B-1. Clinical data was available for 9 individuals who presented with a neurodevelopmental disorder including severe ID/DD (although one patient had normal cognition but attention difficulties) and brain MRI abnormalities. Other features were variable and include hypotonia, epilepsy, ocular abnormalities, acquired microcephaly or macrocephaly and other variable congenital abnormalities. Variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. Functional studies demonstrate variant-specific splicing abnormalities in patient-derived cells which may underline the clinical variability observed in patients. PMID: 40442284 (2025) - 9 unrelated individuals with de novo variants in RNU5B-1 and a neurodevelopmental disorder characterised by GDD/ID, macrocephaly, eye abnormalities, seizures, hypotonia and failure to thrive, among other variable features - based on 6 cases where phenotype information was available. Variants were again found in regions critical for splicing. Both studies investigated participants of the 100KGP and/or NHS GMS (6 in PMID: 40379786 and 5 in PMID: 40442284) so likely refer to the same individuals. Sources: Literature
28 Jul 2025	Congenital myaesthenic syndrome v5.1	UNC13A	Tom Hodgkinson reviewed gene: UNC13A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 28192369, 39634123.; Phenotypes: ; Mode of inheritance: None
28 Jul 2025	Intellectual disability v9.45	UNC13A	Tom Hodgkinson reviewed gene: UNC13A: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 8192369, 39634123; Phenotypes: ASD, dyskinetic movement disorder, febrile seizures, developmental delay, intellectual disability, ataxia; Mode of inheritance: None
28 Jul 2025	DDG2P v6.1	ELFN1	Rhys Dore reviewed gene: ELFN1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 40576023, 34509675, 34452636; Phenotypes: intellectual disability, developmental delay, epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
25 Jul 2025	Brugada syndrome and cardiac sodium channel disease v3.13	ANK2	Arina Puzriakova Tag disputed tag was added to gene: ANK2.
24 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.19	IRF1	Hannah Knight gene: IRF1 was added gene: IRF1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: IRF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IRF1 were set to PMID: 36736301 Phenotypes for gene: IRF1 were set to Immunodeficiency 117, mycobacteriosis, autosomal recessive Review for gene: IRF1 was set to GREEN Added comment: 2 unrelated children, each born of consanguineous parents of Latin American and Turkish descent, respectively, who presented in early childhood with recurrent and severe mycobacterial disease, including BCG infections and infections with M. avium complex. Two different homozygous nonsense variants in IRF1 (p.R129X and p.Q35X). Also supportive functional data Sources: Literature
24 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.19	DPP9	Hannah Knight gene: DPP9 was added gene: DPP9 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: DPP9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DPP9 were set to PMID: 36112693 Phenotypes for gene: DPP9 were set to Hatipoglu immunodeficiency syndrome Review for gene: DPP9 was set to GREEN Added comment: PMID: 36112693 reported four patients from three unrelated families with biallelic DPP9 variants causing Hatipoglu immunodeficiency syndrome: - A 6-year-old boy, born of unrelated parents of Ashkenazi Jewish descent, with compound heterozygous variants (p.S214X and p.G167S) - A 14-year-old boy, born of consanguineous Turkish parents, with a homozygous variant (p.Q851X) - Two male patients from a consanguineous Bedouin family in Israel, with a homozygous variant (p.R111X) Sources: Literature
24 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.19	CD274	Hannah Knight gene: CD274 was added gene: CD274 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: CD274 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD274 were set to PMID: 38634869 Phenotypes for gene: CD274 were set to ?Autoimmune disease, multisystem, infantile-onset, 5 Review for gene: CD274 was set to RED Added comment: In 2 sibs, born of consanguineous Moroccan parents, PMID: 38634869 identified a homozygous splice site mutation in the CD274 gene. Both presented with neonatal onset of type 1 diabetes mellitus. The male proband subsequently developed asthma at 5 months of age, autoimmune hypothyroidism at age 3 years, and growth hormone deficiency at age 10. The boy also had mildly impaired intellectual development and speech delay that was attributed to a de novo heterozygous duplication at 7q11.23, which is associated with neurologic phenotypes and growth hormone deficiency. The sister, who did not have this duplication, had no clinical manifestations other than type 1 diabetes Sources: Literature
23 Jul 2025	Hereditary neuropathy or pain disorder v7.2	RCC1	Cassandra Smith reviewed gene: RCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40683276; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
23 Jul 2025	Primary lymphoedema v4.7	HGF	Achchuthan Shanmugasundram Classified gene: HGF as Amber List (moderate evidence)
23 Jul 2025	Primary lymphoedema v4.7	HGF	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>10 unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.
23 Jul 2025	Primary lymphoedema v4.7	HGF	Achchuthan Shanmugasundram Gene: hgf has been classified as Amber List (Moderate Evidence).
23 Jul 2025	Primary lymphoedema v4.6	HGF	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: HGF.
23 Jul 2025	Primary lymphoedema v4.6	HGF	Achchuthan Shanmugasundram Phenotypes for gene: HGF were changed from to primary lymphedema, MONDO:0019175
23 Jul 2025	Primary lymphoedema v4.5	HGF	Achchuthan Shanmugasundram Publications for gene: HGF were set to 18564920
23 Jul 2025	Primary lymphoedema v4.4	HGF	Achchuthan Shanmugasundram Mode of inheritance for gene: HGF was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
23 Jul 2025	Primary lymphoedema v4.3	HGF	Achchuthan Shanmugasundram reviewed gene: HGF: Rating: GREEN; Mode of pathogenicity: None; Publications: 38676400, 38791500; Phenotypes: primary lymphedema, MONDO:0019175; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
23 Jul 2025	Intellectual disability v9.45	PRMT9	Achchuthan Shanmugasundram Phenotypes for gene: PRMT9 were changed from to neurodevelopmental disorder, MONDO:0700092
23 Jul 2025	Intellectual disability v9.44	PRMT9	Achchuthan Shanmugasundram Publications for gene: PRMT9 were set to 21937992
23 Jul 2025	Intellectual disability v9.43	PRMT9	Achchuthan Shanmugasundram reviewed gene: PRMT9: Rating: RED; Mode of pathogenicity: None; Publications: 21937992, 38561334; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
22 Jul 2025	Paediatric or syndromic cardiomyopathy v7.9	ASNA1	Achchuthan Shanmugasundram changed review comment from: As reviewed by Dmitrijs Rots, PMID:31461301 reported the identification of compound heterozygous variants in two siblings with early infantile-onset, rapidly progressive dilated cardiomyopathy. There were two variants reported on the paternal allele (p.Cys289Trp and p.Gln305Ter) and one variant on the maternal allele (p.Val163Ala). Unaffected sibling was heterozygous for maternal allele. Functional studies showed that Val163Ala variant leads to protein misfolding as well as less effective tail-anchored protein insertion. Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality. In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype. As there is only one case and functional evidence available in support of this association, this gene can only be rated amber now.; to: PMID:31461301 reported the identification of compound heterozygous variants in two siblings with early infantile-onset, rapidly progressive dilated cardiomyopathy. There were two variants reported on the paternal allele (p.Cys289Trp and p.Gln305Ter) and one variant on the maternal allele (p.Val163Ala). Unaffected sibling was heterozygous for maternal allele. Functional studies showed that Val163Ala variant leads to protein misfolding as well as less effective tail-anchored protein insertion. Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality. In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype. As there is only one case and functional evidence available in support of this association, this gene can only be rated amber now.
22 Jul 2025	Paediatric or syndromic cardiomyopathy v7.9	ASNA1	Achchuthan Shanmugasundram Classified gene: ASNA1 as Amber List (moderate evidence)
22 Jul 2025	Paediatric or syndromic cardiomyopathy v7.9	ASNA1	Achchuthan Shanmugasundram Gene: asna1 has been classified as Amber List (Moderate Evidence).
22 Jul 2025	Paediatric or syndromic cardiomyopathy v7.8	ASNA1	Achchuthan Shanmugasundram Phenotypes for gene: ASNA1 were changed from Rapidly Progressive Pediatric Cardiomyopathy to ?Cardiomyopathy, dilated, 2H, OMIM:620203
22 Jul 2025	Paediatric or syndromic cardiomyopathy v7.7	ASNA1	Achchuthan Shanmugasundram Publications for gene: ASNA1 were set to PMID: 31461301
22 Jul 2025	Paediatric or syndromic cardiomyopathy v7.6	ASNA1	Achchuthan Shanmugasundram reviewed gene: ASNA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31461301; Phenotypes: ?Cardiomyopathy, dilated, 2H, OMIM:620203; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
22 Jul 2025	Early onset or syndromic epilepsy v8.12	UBR5	Achchuthan Shanmugasundram Classified gene: UBR5 as Amber List (moderate evidence)
22 Jul 2025	Early onset or syndromic epilepsy v8.12	UBR5	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
22 Jul 2025	Early onset or syndromic epilepsy v8.12	UBR5	Achchuthan Shanmugasundram Gene: ubr5 has been classified as Amber List (Moderate Evidence).
22 Jul 2025	Early onset or syndromic epilepsy v8.11	UBR5	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UBR5.
22 Jul 2025	Intellectual disability v9.43	UBR5	Achchuthan Shanmugasundram Classified gene: UBR5 as Amber List (moderate evidence)
22 Jul 2025	Intellectual disability v9.43	UBR5	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
22 Jul 2025	Intellectual disability v9.43	UBR5	Achchuthan Shanmugasundram Gene: ubr5 has been classified as Amber List (Moderate Evidence).
22 Jul 2025	Intellectual disability v9.42	UBR5	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UBR5.
22 Jul 2025	Early onset or syndromic epilepsy v8.11	UBR5	Achchuthan Shanmugasundram gene: UBR5 was added gene: UBR5 was added to Early onset or syndromic epilepsy. Sources: Literature dd_review tags were added to gene: UBR5. Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UBR5 were set to 39721588 Phenotypes for gene: UBR5 were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: UBR5 was set to GREEN Added comment: PMID:39721588 reported 29 unrelated individuals with a complex neurodevelopmental syndrome, which includes developmental delay (26/28), autism (16/26), intellectual disability (14/25), epilepsy (11/27), movement disorders (6/26) and/ or genital anomalies (4/25) as presenting phenotypes. They were all identified with variants in UBR5 gene, of which 28 had monoallelic inheritance (24 with de novo, 1 with maternal, 1 with maternal mosaic and 2 with unknown inheritance), while one had recessive inheritance. Of the 28 patients with monoallelic variants, 16 had global developmental delay, 13 had ID and 10 patients had epilepsy/ seizures. The single patient with biallelic variant had severe/ profound ID, developmental delay and epileptic encephalopathy. Functional evidence is also available from C. elegans and in vitro ubiquitination assays. This gene is associated with phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM. Sources: Literature
22 Jul 2025	Intellectual disability v9.42	UBR5	Achchuthan Shanmugasundram gene: UBR5 was added gene: UBR5 was added to Intellectual disability. Sources: Literature dd_review tags were added to gene: UBR5. Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UBR5 were set to 39721588 Phenotypes for gene: UBR5 were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: UBR5 was set to GREEN Added comment: PMID:39721588 reported 29 unrelated individuals with a complex neurodevelopmental syndrome, which includes developmental delay (26/28), autism (16/26), intellectual disability (14/25), epilepsy (11/27), movement disorders (6/26) and/ or genital anomalies (4/25) as presenting phenotypes. They were all identified with variants in UBR5 gene, of which 28 had monoallelic inheritance (24 with de novo, 1 with maternal, 1 with maternal mosaic and 2 with unknown inheritance), while one had recessive inheritance. Of the 28 patients with monoallelic variants, 16 had global developmental delay, 13 had ID and 10 patients had epilepsy/ seizures. The single patient with biallelic variant had severe/ profound ID, developmental delay and epileptic encephalopathy. Functional evidence is also available from C. elegans and in vitro ubiquitination assays. This gene is associated with phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM. Sources: Literature
22 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.19	CSF3R	Arina Puzriakova Phenotypes for gene: CSF3R were changed from Neutropenia, severe congenital, 7, autosomal recessive, 617014; Neutropenia, severe congenital 7; Congenital neutropenia; N/A; Congenital defects of phagocyte number or function to Neutropenia, severe congenital, 7, autosomal recessive, OMIM:617014; Congenital defects of phagocyte number or function
22 Jul 2025	Cytopenia - NOT Fanconi anaemia v4.21	CSF3R	Arina Puzriakova Phenotypes for gene: CSF3R were changed from Neutropenia, severe congenital, 7, autosomal recessive, 617014; 617014 Neutropenia, severe congenital, 7; 617014 Neutropenia, severe congenital, 7, autosomal recessive; Severe congenital neutropenia to Neutropenia, severe congenital, 7, autosomal recessive, OMIM:617014
22 Jul 2025	Mitochondrial disorders v9.19	GUK1	Hannah Knight gene: GUK1 was added gene: GUK1 was added to Mitochondrial disorders. Sources: Literature Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GUK1 were set to PMID: 39230499 Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome 21 Review for gene: GUK1 was set to GREEN Added comment: Four patients from three families reported with mitochondrial disorders and biallelic GUK1 variants. Different variants in all three families. Key symptoms include ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy Sources: Literature
21 Jul 2025	Distal myopathies v6.8	NEB	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: NEB.
21 Jul 2025	Intellectual disability v9.41	CRNKL1	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
21 Jul 2025	Early onset or syndromic epilepsy v8.10	CRNKL1	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
21 Jul 2025	Severe microcephaly v8.7	CRNKL1	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
21 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.12	CRNKL1	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
21 Jul 2025	Intellectual disability v9.41	PDE1B	Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
21 Jul 2025	Intellectual disability v9.41	PDE1B	Achchuthan Shanmugasundram Added comment: Comment on list classification: Intellectual disability was reported with the severity of moderate or above in only one patient and was either mild or severity not reported in others. Hence, this gene can only be rated amber with the current evidence.
21 Jul 2025	Intellectual disability v9.41	PDE1B	Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
19 Jul 2025	Malformations of cortical development v7.6	NFIA	Achchuthan Shanmugasundram Classified gene: NFIA as Amber List (moderate evidence)
19 Jul 2025	Malformations of cortical development v7.6	NFIA	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
19 Jul 2025	Malformations of cortical development v7.6	NFIA	Achchuthan Shanmugasundram Gene: nfia has been classified as Amber List (Moderate Evidence).
19 Jul 2025	Malformations of cortical development v7.5	NFIA	Achchuthan Shanmugasundram Phenotypes for gene: NFIA were changed from to Brain malformations with or without urinary tract defects, OMIM:613735
19 Jul 2025	Malformations of cortical development v7.4	NFIA	Achchuthan Shanmugasundram Publications for gene: NFIA were set to 36553517,
19 Jul 2025	Malformations of cortical development v7.3	NFIA	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NFIA.
19 Jul 2025	Malformations of cortical development v7.3	NFIA	Achchuthan Shanmugasundram reviewed gene: NFIA: Rating: GREEN; Mode of pathogenicity: None; Publications: 27081522, 28452798, 33973697, 36553517; Phenotypes: Brain malformations with or without urinary tract defects, OMIM:613735; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
18 Jul 2025	Childhood onset dystonia, chorea or related movement disorder v7.3	PDE1B	Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
18 Jul 2025	Childhood onset dystonia, chorea or related movement disorder v7.3	PDE1B	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with childhood onset dystonia. Hence, this gene can be promoted to green rating in the next GMS update.
18 Jul 2025	Childhood onset dystonia, chorea or related movement disorder v7.3	PDE1B	Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
18 Jul 2025	Childhood onset dystonia, chorea or related movement disorder v7.2	PDE1B	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PDE1B.
18 Jul 2025	Childhood onset dystonia, chorea or related movement disorder v7.2	PDE1B	Achchuthan Shanmugasundram gene: PDE1B was added gene: PDE1B was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE1B were set to 40492975 Phenotypes for gene: PDE1B were set to movement disorder, MONDO:0005395 Review for gene: PDE1B was set to GREEN Added comment: As reviewed by Sarah Dixon, PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs*6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total. They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability. Dystonia has been reported in five patients from four families. Functional evidence is also available for these variants. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen. Sources: Literature
18 Jul 2025	Intellectual disability v9.40	PDE1B	Achchuthan Shanmugasundram changed review comment from: As reviewed by Sarah Dixon, PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total. They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability (ID). ID was moderate in one patient, mild in three and severity not reported in one (ID noticed at the age of three years), while ID was not reported in two patients. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; to: As reviewed by Sarah Dixon, PMID:40492975 reported seven individuals from five unrelated families identified with biallelic PDE1B variants. Three truncating (p.Gln45Ter, p.Gln86Ter, p.Ser298Alafs6) and three splicing variants (c.594 + 2 T>G, c.735 + 5G>A, c.837-1G>C) were identified from these patients in total. They presented with an early-onset movement disorder characterised by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with motor and speech delay, and intellectual disability (ID). ID was moderate in one patient, mild in three and severity not reported in one patient (ID noticed at the age of three years). This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.
18 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.12	PDE1B	Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
18 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.12	PDE1B	Achchuthan Shanmugasundram Added comment: Comment on list classification: Ataxia has been reported in four unrelated families and hence this gene can be promoted to green rating in the next GMS update.
18 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.12	PDE1B	Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
18 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.11	PDE1B	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PDE1B. Tag Q3_25_NHS_review tag was added to gene: PDE1B.
18 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.11	PDE1B	Achchuthan Shanmugasundram Phenotypes for gene: PDE1B were changed from hypotonia; ataxia; dystonia; developmental delay; intellectual disability to movement disorder, MONDO:0005395
18 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.10	PDE1B	Achchuthan Shanmugasundram Publications for gene: PDE1B were set to PMID: 40492975
18 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.9	PDE1B	Achchuthan Shanmugasundram reviewed gene: PDE1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 40492975; Phenotypes: movement disorder, MONDO:0005395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
18 Jul 2025	Intellectual disability v9.40	PDE1B	Achchuthan Shanmugasundram Classified gene: PDE1B as Amber List (moderate evidence)
18 Jul 2025	Intellectual disability v9.40	PDE1B	Achchuthan Shanmugasundram Gene: pde1b has been classified as Amber List (Moderate Evidence).
18 Jul 2025	Intellectual disability v9.39	PDE1B	Achchuthan Shanmugasundram Phenotypes for gene: PDE1B were changed from hypotonia; ataxia; dystonia; developmental delay; intellectual disability to movement disorder, MONDO:0005395; intellectual disability, MONDO:0001071
18 Jul 2025	Intellectual disability v9.38	PDE1B	Achchuthan Shanmugasundram edited their review of gene: PDE1B: Changed phenotypes to: movement disorder, MONDO:0005395, intellectual disability, MONDO:0001071
18 Jul 2025	Intellectual disability v9.38	PDE1B	Achchuthan Shanmugasundram Publications for gene: PDE1B were set to PMID: 40492975
18 Jul 2025	Intellectual disability v9.37	PDE1B	Achchuthan Shanmugasundram reviewed gene: PDE1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 40492975; Phenotypes: movement disorder, MONDO:0005395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
18 Jul 2025	Retinal disorders v8.9	RP1L1	Chris Campbell reviewed gene: RP1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
18 Jul 2025	Paediatric disorders - additional genes v7.1	CACHD1	Achchuthan Shanmugasundram changed review comment from: PMID:38158856 reported six affected individuals from four unrelated families with biallelic (either homozygous or compound heterozygous) CACHD1 variants (3 splice, 2 frameshift and 1 nonsense variant). Excluding the two fatal cases from the fourth family, all others were affected by syndromic neurodevelopmental abnormalities, multiple organ systems featuring global impairment of psychomotor development, dysmorphic facial features, genitourinary abnormalities, oculo-auricular and congenital malformation. Cognitive impairment was reported to be mild in three cases from three different families, while the fourth case had no cognitive impairment. Psychomotor delay was reported in two unrelated cases and seizure was reported in one. Functional evidence from human stem cell-derived neural models and zebrafish mutants are also available in support of the disease association. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature; to: PMID:38158856 reported six affected individuals from four unrelated families with biallelic (either homozygous or compound heterozygous) CACHD1 variants (3 splice, 2 frameshift and 1 nonsense variant). Excluding the two fetal cases from the fourth family, all others were affected by syndromic neurodevelopmental abnormalities, multiple organ systems featuring global impairment of psychomotor development, dysmorphic facial features, genitourinary abnormalities, oculo-auricular and congenital malformation. Cognitive impairment was reported to be mild in three cases from three different families, while the fourth case had no cognitive impairment. Psychomotor delay was reported in two unrelated cases and seizure was reported in one. Functional evidence from human stem cell-derived neural models and zebrafish mutants are also available in support of the disease association. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature
18 Jul 2025	Structural eye disease v4.16	NR6A1	Achchuthan Shanmugasundram Classified gene: NR6A1 as Amber List (moderate evidence)
18 Jul 2025	Structural eye disease v4.16	NR6A1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
18 Jul 2025	Structural eye disease v4.16	NR6A1	Achchuthan Shanmugasundram Gene: nr6a1 has been classified as Amber List (Moderate Evidence).
18 Jul 2025	Structural eye disease v4.15	NR6A1	Achchuthan Shanmugasundram Phenotypes for gene: NR6A1 were changed from microphthalmia, coloboma to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129
18 Jul 2025	Structural eye disease v4.14	NR6A1	Achchuthan Shanmugasundram Publications for gene: NR6A1 were set to PMID: 40610405
18 Jul 2025	Structural eye disease v4.13	NR6A1	Achchuthan Shanmugasundram Mode of inheritance for gene: NR6A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
18 Jul 2025	Structural eye disease v4.12	NR6A1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NR6A1. Tag Q3_25_NHS_review tag was added to gene: NR6A1.
18 Jul 2025	Structural eye disease v4.12	NR6A1	Achchuthan Shanmugasundram reviewed gene: NR6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40610405; Phenotypes: coloboma, MONDO:0001476, microphthalmia, MONDO:0021129; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
18 Jul 2025	Structural eye disease v4.12	EFEMP1	Achchuthan Shanmugasundram Classified gene: EFEMP1 as Amber List (moderate evidence)
18 Jul 2025	Structural eye disease v4.12	EFEMP1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic EFEMP1 variants with glaucoma, which fits into the scope of this panel. Hence, this gene can be promoted to green rating in the next GMS update.
18 Jul 2025	Structural eye disease v4.12	EFEMP1	Achchuthan Shanmugasundram Gene: efemp1 has been classified as Amber List (Moderate Evidence).
18 Jul 2025	Structural eye disease v4.11	EFEMP1	Achchuthan Shanmugasundram Phenotypes for gene: EFEMP1 were changed from Doyne honeycomb degeneration of retina, 126600; Eye Disorders to Glaucoma 1, open angle, H, OMIM:611276
18 Jul 2025	Structural eye disease v4.10	EFEMP1	Achchuthan Shanmugasundram Publications for gene: EFEMP1 were set to
18 Jul 2025	Structural eye disease v4.9	EFEMP1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: EFEMP1.
18 Jul 2025	Structural eye disease v4.9	EFEMP1	Achchuthan Shanmugasundram reviewed gene: EFEMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glaucoma 1, open angle, H, OMIM:611276; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	CFAP74	Achchuthan Shanmugasundram commented on gene: CFAP74: The ClinGen Motile Ciliopathy expert panel has updated the classification for the association of CFAP74 gene to ciliary dyskinesia, primary, 49, without situs inversus (MONDO:0859353) from 'Limited' to 'Moderate' on 18/06/2025. The reason for classification change is summarised in ClinGen (https://search.clinicalgenome.org/CCID:004429) as follows: "Recurated and changed classification from Limited to Moderate. Additional proband from a ClinVar submission, and additional immunofluorescence data from patients previously reported."
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	TEKT1	Achchuthan Shanmugasundram Tag disputed tag was added to gene: TEKT1.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	MNS1	Achchuthan Shanmugasundram Tag disputed tag was added to gene: MNS1.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	DNAH14	Achchuthan Shanmugasundram Tag disputed was removed from gene: DNAH14.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	DNAH14	Achchuthan Shanmugasundram Tag disputed tag was added to gene: DNAH14.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	DNAH8	Achchuthan Shanmugasundram Tag disputed tag was added to gene: DNAH8.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	DNAH6	Achchuthan Shanmugasundram Tag disputed tag was added to gene: DNAH6.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	CFAP43	Achchuthan Shanmugasundram Tag disputed tag was added to gene: CFAP43.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	AK7	Achchuthan Shanmugasundram Tag disputed tag was added to gene: AK7.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	BRWD1	Achchuthan Shanmugasundram Classified gene: BRWD1 as Red List (low evidence)
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.44	BRWD1	Achchuthan Shanmugasundram Gene: brwd1 has been classified as Red List (Low Evidence).
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.43	BRWD1	Achchuthan Shanmugasundram Tag disputed tag was added to gene: BRWD1.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.43	BRWD1	Achchuthan Shanmugasundram changed review comment from: As reviewed by Ivone Leong below, biallelic BRWD1 variants have been reported in three unrelated patients displaying PCD-like phenotype recurring airway infections, bronchiectasis and rhinosinusitis. This gene is now associated with relevant phenotype in OMIM (MIM #620438). However, the association of BRWD1 gene with primary ciliary dyskinesia (MONDO:0016575) has been classified as 'Disputed' by the Motile Ciliopathy expert panel in ClinGen. Detailed information on this classification can be found in https://search.clinicalgenome.org/CCID:004289. The reason for their classification is as follows: "Individuals with variants in BRWD1 and clinical features of PCD are reported in the literature. However, no functional data support the pathogenicity of the variants and their association with PCD. No valid experimental evidence remains to support this curation."; to: As reviewed by Ivone Leong below, biallelic BRWD1 variants have been reported in three unrelated patients displaying PCD-like phenotype including recurring airway infections, bronchiectasis and rhinosinusitis. This gene is now associated with relevant phenotype in OMIM (MIM #620438). However, the association of BRWD1 gene with primary ciliary dyskinesia (MONDO:0016575) has been classified as 'Disputed' by the Motile Ciliopathy expert panel in ClinGen. Detailed information on this classification can be found in https://search.clinicalgenome.org/CCID:004289. The reason for their classification is as follows: "Individuals with variants in BRWD1 and clinical features of PCD are reported in the literature. However, no functional data support the pathogenicity of the variants and their association with PCD. No valid experimental evidence remains to support this curation."
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.43	DAW1	Achchuthan Shanmugasundram Classified gene: DAW1 as Green List (high evidence)
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.43	DAW1	Achchuthan Shanmugasundram Added comment: Comment on list classification: The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient. Expert review is being sought from Genomic Laboratory Hubs on demotion of this gene from green to red.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.43	DAW1	Achchuthan Shanmugasundram Gene: daw1 has been classified as Green List (High Evidence).
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	DAW1	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has updated the classification for the association of DAW1 gene to ciliary dyskinesia, primary, 52 (MONDO:0957922) from 'Moderate' to 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008408. ClinGen has provided the following summary as the reason(s) for change: "The DAW1-PCD gene-disease relationship was changed to LIMITED pending more information on the respiratory and ultrastructural axoneme phenotypes of three sister patients carrying the p.Asn143Asp DAW1 variant OR the reporting of additional patients carrying biallelic DAW1 variants with laterality AND respiratory symptoms. The genetic evidence in this curation warranted scoring and the curation included strong experimental evidence from non-human model organisms, but the Motile Ciliopathy GCEP decided that this curation did not reach the level of a MODERATE classification." Below is the summary of previously published cases: PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients. PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported. The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient.; to: The ClinGen Motile Ciliopathy expert panel has updated the classification for the association of DAW1 gene to ciliary dyskinesia, primary, 52 (MONDO:0957922) from 'Moderate' to 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008408. ClinGen has provided the following summary as the reason(s) for change: "The DAW1-PCD gene-disease relationship was changed to LIMITED pending more information on the respiratory and ultrastructural axoneme phenotypes of three sister patients carrying the p.Asn143Asp DAW1 variant OR the reporting of additional patients carrying biallelic DAW1 variants with laterality AND respiratory symptoms. The genetic evidence in this curation warranted scoring and the curation included strong experimental evidence from non-human model organisms, but the Motile Ciliopathy GCEP decided that this curation did not reach the level of a MODERATE classification." Below is the summary of previously published cases: PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients. PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	DAW1	Achchuthan Shanmugasundram changed review comment from: DAW1 has the gene-disease validity rating of 'Limited' in ClinGen. ClinGen has rated this gene with 'Limited' rating as there are no reported respiratory symptoms in the cases. PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients. PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported. The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient.; to: The ClinGen Motile Ciliopathy expert panel has updated the classification for the association of DAW1 gene to ciliary dyskinesia, primary, 52 (MONDO:0957922) from 'Moderate' to 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008408. ClinGen has provided the following summary as the reason(s) for change: "The DAW1-PCD gene-disease relationship was changed to LIMITED pending more information on the respiratory and ultrastructural axoneme phenotypes of three sister patients carrying the p.Asn143Asp DAW1 variant OR the reporting of additional patients carrying biallelic DAW1 variants with laterality AND respiratory symptoms. The genetic evidence in this curation warranted scoring and the curation included strong experimental evidence from non-human model organisms, but the Motile Ciliopathy GCEP decided that this curation did not reach the level of a MODERATE classification." Below is the summary of previously published cases: PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients. PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported. The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	STK36	Achchuthan Shanmugasundram changed review comment from: STK36 has the gene-disease validity rating of 'Moderate' in ClinGen, based on evidence from a single reported human case and experiment evidence from both non-human models and patient cell line. Hence, the evidence is only sufficient for an amber rating.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of STK36 gene to ciliary dyskinesia, primary, 46 (MONDO:0030332) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008521. However, this 'moderate' rating in ClinGen was based on evidence from a single reported human case and experiment evidence from both non-human models and patient cell line. This evidence is only sufficient for an amber rating, as per rating criteria used by PanelApp.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	GAS2L2	Achchuthan Shanmugasundram commented on gene: GAS2L2: The ClinGen Motile Ciliopathy expert panel has classified the association of GAS2L2 gene to ciliary dyskinesia, primary, 41 (MONDO:0032757) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:004922.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	DNAJB13	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877. There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877. There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	DNAJB13	Achchuthan Shanmugasundram changed review comment from: DNAJB13 has the gene-disease validity rating of 'Moderate' in ClinGen. There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877. There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	CFAP46	Achchuthan Shanmugasundram changed review comment from: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene. PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus. In addition, this gene-disease association is supported by Chlamydomonas reinhardtii null mutant model (PMID:22573824) and gene expression data (PMID:23715323). In addition, immunofluorescence microscopy analyses of respiratory epithelial cells show that CFAP46 localises along the entire ciliary axoneme in healthy individuals but is lost in the respiratory cells of a CFAP46-PCD patient (PMID:39362668). This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.; to: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene. As reviewed by Zornitza Stark below, the authors speculate that LEFTY1 variant might be responsible for the phenotype. PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus. In addition, this gene-disease association is supported by Chlamydomonas reinhardtii null mutant model (PMID:22573824) and gene expression data (PMID:23715323). In addition, immunofluorescence microscopy analyses of respiratory epithelial cells show that CFAP46 localises along the entire ciliary axoneme in healthy individuals but is lost in the respiratory cells of a CFAP46-PCD patient (PMID:39362668). This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	CFAP46	Achchuthan Shanmugasundram Classified gene: CFAP46 as Red List (low evidence)
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	CFAP46	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case reported with biallelic CFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. However, these are high frequency variants with homozygotes in gnomAD. Hence, this gene is rated red with the current evidence.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.42	CFAP46	Achchuthan Shanmugasundram Gene: cfap46 has been classified as Red List (Low Evidence).
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	CFAP46	Achchuthan Shanmugasundram Deleted their comment
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	CFAP46	Achchuthan Shanmugasundram edited their review of gene: CFAP46: Changed rating: RED
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	CFAP221	Achchuthan Shanmugasundram changed review comment from: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen. There are additional cases reported with primary ciliary dyskinesia now. PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants. PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss. This gene has also been associated with relevant phenotypes in OMIM (MIM #279000).; to: The ClinGen Motile Ciliopathy expert panel has classified the association of CFAP221 gene to primary ciliary dyskinesia (MONDO:0016575) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:004421. There are additional cases reported with primary ciliary dyskinesia now. PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants. PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss. This gene has also been associated with relevant phenotypes in OMIM (MIM #279000).
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	TP73	Achchuthan Shanmugasundram changed review comment from: TP73 has the gene-disease validity rating of 'Strong' in ClinGen. PMID:34077761 - Five different homozygous loss-of-function variants in TP73 gene have been reported in seven individuals from five unrelated families. They presented with a chronic airway disease, and brain malformation consistent with lissencephaly. Respiratory distress syndrome and recurrent respiratory infections have been reported in five and six patients respectively. There is also some experimental evidence available. This gene has been associated with relevant phenotypes in both OMIM (MIM #619466) and Gene2Phenotype (with 'strong' rating on the DD panel). Sources: Literature; to: The ClinGen Motile Ciliopathy expert panel has classified the association of TP73 gene to ciliary dyskinesia, primary, 47, and lissencephaly (MONDO:0030346) as 'Strong'. More information can be found in https://search.clinicalgenome.org/CCID:006420. PMID:34077761 - Five different homozygous loss-of-function variants in TP73 gene have been reported in seven individuals from five unrelated families. They presented with a chronic airway disease, and brain malformation consistent with lissencephaly. Respiratory distress syndrome and recurrent respiratory infections have been reported in five and six patients respectively. There is also some experimental evidence available. This gene has been associated with relevant phenotypes in both OMIM (MIM #619466) and Gene2Phenotype (with 'strong' rating on the DD panel). Sources: Literature
17 Jul 2025	Amelogenesis imperfecta v4.5	TP63	Claire Smith reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:not listed; Phenotypes: ectodermal dysplasia, split hand/foot malformation, orofacial defect, dry skin, wiry hair, fewer teeth, malformed teeth, amelogenesis imperfecta, dystrophic nails, reduced sweat glands, mammary gland and nipple hypoplasia, lacrimal duct defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	NEK10	Achchuthan Shanmugasundram changed review comment from: NEK10 has the gene-disease validity rating of 'Strong' in ClinGen. Additional cases reported with ciliopathy now. PMID:32414360 - Two siblings were reported with a classical primary ciliary dyskinesia and were identified with a homozygous truncating variant (p.Tyr1134Ter) in the NEK10 gene. They both presented with bronchiectasis and chronic cough. PMID:35728977 - Using the genetic data from severe bronchiectasis patients recruited to the Genomics England 100k Genomes Project, one patient was identified with compound heterozugous variants (c.1A>G & c.1028+1G>T). This gene has been associated with relevant phenotypes in OMIM (MIM #618781).; to: The ClinGen Motile Ciliopathy expert panel has classified the association of NEK10 gene to ciliary dyskinesia, primary, 44 (MONDO:0032914) as 'Strong'. More information can be found in https://search.clinicalgenome.org/CCID:005617. Additional cases reported with ciliopathy now. PMID:32414360 - Two siblings were reported with a classical primary ciliary dyskinesia and were identified with a homozygous truncating variant (p.Tyr1134Ter) in the NEK10 gene. They both presented with bronchiectasis and chronic cough. PMID:35728977 - Using the genetic data from severe bronchiectasis patients recruited to the Genomics England 100k Genomes Project, one patient was identified with compound heterozugous variants (c.1A>G & c.1028+1G>T). This gene has been associated with relevant phenotypes in OMIM (MIM #618781).
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	EFCAB1	Achchuthan Shanmugasundram changed review comment from: EFCAB1 has the gene-disease validity rating of 'Strong' in ClinGen. PMID:36727596 - Three individuals from three unrelated families were identified with three different homozygous variants in EFCAB1 gene (p.Arg98Ter, p.Glu123Ter & p.Glu40Trpfs16). All three patients presented with situs inversus/ situs ambiguous, while chronic rhino-sinusitis was reported in one, and recurrent pneumonia and respiratory insufficiency were reported in another patient. There is also some functional evidence available. This gene has also been associated with relevant phenotype in OMIM (MIM #620642). Sources: Literature; to: The ClinGen Motile Ciliopathy expert panel has classified the association of EFCAB1 gene to ciliary dyskinesia, primary, 53 (MONDO:0957991) as 'Strong'. More information can be found in https://search.clinicalgenome.org/CCID:008800. PMID:36727596 - Three individuals from three unrelated families were identified with three different homozygous variants in EFCAB1 gene (p.Arg98Ter, p.Glu123Ter & p.Glu40Trpfs16). All three patients presented with situs inversus/ situs ambiguous, while chronic rhino-sinusitis was reported in one, and recurrent pneumonia and respiratory insufficiency were reported in another patient. There is also some functional evidence available. This gene has also been associated with relevant phenotype in OMIM (MIM #620642). Sources: Literature
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	TUBB4B	Achchuthan Shanmugasundram commented on gene: TUBB4B: The ClinGen Motile Ciliopathy expert panel has classified the association of TUBB4B gene to TUBB4B-related ciliopathy (MONDO:1060115) as 'Definitive'. More information can be found in https://search.clinicalgenome.org/CCID:006481.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	TTC12	Achchuthan Shanmugasundram changed review comment from: TTC12 has the gene-disease validity rating of 'Definitive' in ClinGen. PMID:36273201 - Five unrelated families with multisystem ciliopathy syndromes were studies, of which three were identified with biallelic variants in TTC12 gene. Two of them had respiratory phenotype. PMID:37325566 - Three unrelated male patients from a large cohort of infertile Chinese males with asthenoteratozoospermia were identified with homozygous TTC12 variants. They also had a mild PCD-related nasosinusitis phenotype, which is a respiratory cilia impairment. However, they declined to undergo further investigation. PMID:38992144 - A novel homozygous missense TTC12 variant was identified in an infertile Pakistani male with severe oligoasthenoteratozoospermia and primary ciliary dyskinesia. The patient also presented with sinusitis.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of TTC12 gene to ciliary dyskinesia, primary, 45 (MONDO:0032924) as 'Definitive'. More information can be found in https://search.clinicalgenome.org/CCID:008762. PMID:36273201 - Five unrelated families with multisystem ciliopathy syndromes were studies, of which three were identified with biallelic variants in TTC12 gene. Two of them had respiratory phenotype. PMID:37325566 - Three unrelated male patients from a large cohort of infertile Chinese males with asthenoteratozoospermia were identified with homozygous TTC12 variants. They also had a mild PCD-related nasosinusitis phenotype, which is a respiratory cilia impairment. However, they declined to undergo further investigation. PMID:38992144 - A novel homozygous missense TTC12 variant was identified in an infertile Pakistani male with severe oligoasthenoteratozoospermia and primary ciliary dyskinesia. The patient also presented with sinusitis.
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	CEP164	Achchuthan Shanmugasundram changed review comment from: CEP164 has the gene-disease validity rating of 'Definitive' in ClinGen. As per ClinGen curation, seven different variants have been reported in 6 probands in four publications (PMIDs: 22863007, 34132027, 27708425, 36273371), of which 3 probands have been associated with non-CF bronchiectasis. Two of them also had cough, pneumonia, rhinitis and/ or recurrent infections. PMID:22863007 - This study reported four different patients with biallelic CEP164 variants, of which one patient with homozygous variant (p.Arg576Ter) had cerebeller vermis hypoplasia, facial dysmorphism, obesity, bronchiectasis and polydactyly in addition to nephronophthisis. PMID:34556108 - 21 probands from the PCD cohort and 52 probands from non-CF bronchiectasis cohort were recruited in Wessex Genome Medicine Centre (GMC) and their genomes sequenced as part of Genomics England 100k genomes project. Compound heterozygous variants in CEP164 (p.Gln1410Ter/ p.Arg576Ter) were reported in one of these probands from non-CF bronchiectasis cohort. PMID:36273371 - A patient with bronchiectasis was reported with atypical motile ciliopathy phenotype and the same compound heterozygous CEP164 variants as above. Sources: Literature; to: The ClinGen Kidney Cystic and Ciliopathy Disorders expert panel has classified the association of CEP164 gene to ciliopathy (MONDO:0005308) as 'Definitive'. More information can be found in https://search.clinicalgenome.org/CCID:004416. As per ClinGen curation, seven different variants have been reported in 6 probands in four publications (PMIDs: 22863007, 34132027, 27708425, 36273371), of which 3 probands have been associated with non-CF bronchiectasis. Two of them also had cough, pneumonia, rhinitis and/ or recurrent infections. PMID:22863007 - This study reported four different patients with biallelic CEP164 variants, of which one patient with homozygous variant (p.Arg576Ter) had cerebeller vermis hypoplasia, facial dysmorphism, obesity, bronchiectasis and polydactyly in addition to nephronophthisis. PMID:34556108 - 21 probands from the PCD cohort and 52 probands from non-CF bronchiectasis cohort were recruited in Wessex Genome Medicine Centre (GMC) and their genomes sequenced as part of Genomics England 100k genomes project. Compound heterozygous variants in CEP164 (p.Gln1410Ter/ p.Arg576Ter) were reported in one of these probands from non-CF bronchiectasis cohort. PMID:36273371 - A patient with bronchiectasis was reported with atypical motile ciliopathy phenotype and the same compound heterozygous CEP164 variants as above. Sources: Literature
17 Jul 2025	Amelogenesis imperfecta v4.5	SMARCD2	Claire Smith reviewed gene: SMARCD2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33279574, 28369036, 33025377, 36135322; Phenotypes: many including Amelogenesis imperfecta; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
17 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	CFAP54	Achchuthan Shanmugasundram commented on gene: CFAP54: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive CFAP54 variants to ciliary dyskinesia, primary, 54 (MONDO:0100607) as 'Strong'. More information can be found in https://search.clinicalgenome.org/
16 Jul 2025	Amelogenesis imperfecta v4.5	NECTIN4	Claire Smith gene: NECTIN4 was added gene: NECTIN4 was added to Amelogenesis imperfecta. Sources: Literature Mode of inheritance for gene: NECTIN4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NECTIN4 were set to PMID: 34067522; 37183149 Phenotypes for gene: NECTIN4 were set to syndactyly of the toes and fingers; hair abnormalities; variable dental genesis; enamel hypoplasia (amelogenesis imperfecta?); variable nail dystrophy; variable palmoplantar keratoderma, hyperkeratosis, reduced sweating Penetrance for gene: NECTIN4 were set to Complete Review for gene: NECTIN4 was set to GREEN Added comment: Evidence from literature is that loss of function variants in NECTIN4 lead to a syndromic phenotype which includes "enamel hypoplasia" a term often used when amelogenesis imperfecta occurs with other symptoms. PMID:34067522 describes ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4. Nine other EDSS1 cases have been described prior to this report. 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in NECTIN4. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2–3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1. PMID 37183149 reported a large Pakistani consanguineous family, the affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. NECTIN4 novel nonsense variant [c.163C>T; p.(Arg55*)]. Most likely Nectin-4 function will be lost. Sources: Literature
16 Jul 2025	Congenital myopathy v6.34	SRPK3	Anna Sarkozy reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 38429495, PMID: 39667923; Phenotypes: congenital myopathy; Mode of inheritance: Other
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	CFAP46	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is only one case reported with biallelic CFFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. Hence, this gene can be rated amber with the current evidence.; to: Comment on list classification: There is only one case reported with biallelic CFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. Hence, this gene can be rated amber with the current evidence.
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.41	DNAH8	Achchuthan Shanmugasundram Phenotypes for gene: DNAH8 were changed from Ciliopathies to Spermatogenic failure 46, OMIM:619095; primary ciliary dyskinesia, MONDO:0016575
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.40	DNAH8	Achchuthan Shanmugasundram Classified gene: DNAH8 as Red List (low evidence)
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.40	DNAH8	Achchuthan Shanmugasundram Gene: dnah8 has been classified as Red List (Low Evidence).
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.39	DNAH8	Achchuthan Shanmugasundram Tag watchlist was removed from gene: DNAH8.
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.39	DNAH8	Achchuthan Shanmugasundram reviewed gene: DNAH8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 46, OMIM:619095, primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.39	DNAH6	Achchuthan Shanmugasundram Phenotypes for gene: DNAH6 were changed from to primary ciliary dyskinesia, MONDO:0016575
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.38	DNAH6	Achchuthan Shanmugasundram Mode of inheritance for gene: DNAH6 was changed from to BIALLELIC, autosomal or pseudoautosomal
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.37	DNAH6	Achchuthan Shanmugasundram Classified gene: DNAH6 as Red List (low evidence)
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.37	DNAH6	Achchuthan Shanmugasundram Gene: dnah6 has been classified as Red List (Low Evidence).
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.36	DNAH6	Achchuthan Shanmugasundram reviewed gene: DNAH6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.36	TEKT1	Achchuthan Shanmugasundram Phenotypes for gene: TEKT1 were changed from to primary ciliary dyskinesia, MONDO:0016575
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.35	TEKT1	Achchuthan Shanmugasundram edited their review of gene: TEKT1: Changed phenotypes to: primary ciliary dyskinesia, MONDO:0016575
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.35	TEKT1	Achchuthan Shanmugasundram gene: TEKT1 was added gene: TEKT1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen Mode of inheritance for gene: TEKT1 was set to BIALLELIC, autosomal or pseudoautosomal Review for gene: TEKT1 was set to RED Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive TEKT1 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:008874. Sources: ClinGen
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.34	MNS1	Achchuthan Shanmugasundram gene: MNS1 was added gene: MNS1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen Mode of inheritance for gene: MNS1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MNS1 were set to Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM:618948 Review for gene: MNS1 was set to RED Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive MNS1 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:005401. Sources: ClinGen
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.33	DNAH14	Achchuthan Shanmugasundram gene: DNAH14 was added gene: DNAH14 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DNAH14 were set to primary ciliary dyskinesia, MONDO:0016575 Review for gene: DNAH14 was set to RED Added comment: The ClinGen Motile Ciliopathy expert panel is currently reviewing the evidence for the association of DNAH14 gene to primary ciliary dyskinesia (MONDO:0016575). More information can be found in https://search.clinicalgenome.org/kb/genes/HGNC:2945. Sources: ClinGen
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.32	CFAP43	Achchuthan Shanmugasundram Source Literature was removed from CFAP43. Source ClinGen was added to CFAP43.
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.31	CFAP43	Achchuthan Shanmugasundram gene: CFAP43 was added gene: CFAP43 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature Mode of inheritance for gene: CFAP43 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CFAP43 were set to Spermatogenic failure 19, OMIM:617592; primary ciliary dyskinesia, MONDO:0016575 Review for gene: CFAP43 was set to RED Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive CFAP43 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:004425. Sources: Literature
15 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.30	BRWD1	Achchuthan Shanmugasundram changed review comment from: As reviewed by Ivone Leong below, biallelic BRWD1 variants have been reported in three unrelated patients displaying PCD-like phenotype recurring airway infections, bronchiectasis and rhinosinusitis. This gene is now associated with relevant phenotype in OMIM (MIM #620438). However, the association of BRWD1 gene with primary ciliary dyskinesia (MONDO:0016575) has been classified as 'Disputed' by the Motile Ciliopathy expert panel in ClinGen. Detailed information on this classification can be found in https://search.clinicalgenome.org/CCID:004289.; to: As reviewed by Ivone Leong below, biallelic BRWD1 variants have been reported in three unrelated patients displaying PCD-like phenotype recurring airway infections, bronchiectasis and rhinosinusitis. This gene is now associated with relevant phenotype in OMIM (MIM #620438). However, the association of BRWD1 gene with primary ciliary dyskinesia (MONDO:0016575) has been classified as 'Disputed' by the Motile Ciliopathy expert panel in ClinGen. Detailed information on this classification can be found in https://search.clinicalgenome.org/CCID:004289. The reason for their classification is as follows: "Individuals with variants in BRWD1 and clinical features of PCD are reported in the literature. However, no functional data support the pathogenicity of the variants and their association with PCD. No valid experimental evidence remains to support this curation."
14 Jul 2025	Skeletal dysplasia v8.6	FGF4	Eleanor Williams Classified gene: FGF4 as Amber List (moderate evidence)
14 Jul 2025	Skeletal dysplasia v8.6	FGF4	Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation of green rating following GMS review. 2 unrelated cases plus a supportive mouse model.
14 Jul 2025	Skeletal dysplasia v8.6	FGF4	Eleanor Williams Gene: fgf4 has been classified as Amber List (Moderate Evidence).
14 Jul 2025	Skeletal dysplasia v8.5	FGF4	Eleanor Williams gene: FGF4 was added gene: FGF4 was added to Skeletal dysplasia. Sources: Literature Q3_25_promote_green tags were added to gene: FGF4. Mode of inheritance for gene: FGF4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FGF4 were set to 40259859; 33210601 Phenotypes for gene: FGF4 were set to Short-rib thoracic dysplasia 22 without polydactyly, OMIM:621260; Jeune syndrome, MONDO:0018770 Review for gene: FGF4 was set to GREEN Added comment: Associated with Short-rib thoracic dysplasia 22 without polydactyly, OMIM:621260 (AR) PMID: 40259859 - Watts et al 2025 report 2 unrelated families (1 in the 100,000 Genomes project) with a clinical diagnosis of thoracic dystrophy with associated respiratory insufficiency. Family 1 - 2 affected boys clinically suspected to have Jeune syndrome, and 3 unaffected children born to healthy consanguineous 2nd cousin parents. Both affected individuals had narrow/small thorax and short ribs (11 pairs). 2nd child died at 3 months from respiratory infection. Both affected children were homozygous for a missense variant in FGF4 (c.256C>T p.(Leu86Phe)). Parents are confirmed carriers and 2 of the 3 unaffected siblings do not carry the variant. Family 2 - 1 male with a chest shape suggesting thoracic dystrophy and a clinical suspicion of Jeune syndrome. A biallelic missense variant in FGF4 NM_002007.4:c.611C>A p.(Pro204His) was identified. Parents were both heterozygous carriers. The variants are absent from gnomAD and UK Biobank and are predicted to be damaging by multiple in silico tools. PMID: 33210601 - Anderson et al 2020 - Mouse mutants lacking Fgf4 Fgf4 show a variety of segmentation defects in the cervical and thoracic vertebrae with 100% penetrance. Sources: Literature
14 Jul 2025	Fetal anomalies v6.9	GPKOW	Eleanor Williams reviewed gene: GPKOW: Rating: GREEN; Mode of pathogenicity: None; Publications: 28612833, 40221893; Phenotypes: syndromic disease, MONDO:0002254; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
14 Jul 2025	Childhood onset hereditary spastic paraplegia v8.6	FLVCR1	Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
14 Jul 2025	Childhood onset hereditary spastic paraplegia v8.6	FLVCR1	Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
14 Jul 2025	Childhood onset hereditary spastic paraplegia v8.6	FLVCR1	Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
14 Jul 2025	Limb disorders v7.10	FLVCR1	Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
14 Jul 2025	Limb disorders v7.10	FLVCR1	Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
14 Jul 2025	Limb disorders v7.10	FLVCR1	Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
14 Jul 2025	Severe microcephaly v8.7	FLVCR1	Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
14 Jul 2025	Severe microcephaly v8.7	FLVCR1	Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
14 Jul 2025	Severe microcephaly v8.7	FLVCR1	Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
14 Jul 2025	Limb disorders v7.9	FLVCR1	Eleanor Williams gene: FLVCR1 was added gene: FLVCR1 was added to Limb disorders. Sources: Literature Q3_25_promote_green tags were added to gene: FLVCR1. Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FLVCR1 were set to 39306721 Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126 Review for gene: FLVCR1 was set to GREEN Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060. Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033 PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region. 13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals. All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1. There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel. Sources: Literature
14 Jul 2025	Childhood onset hereditary spastic paraplegia v8.5	FLVCR1	Eleanor Williams gene: FLVCR1 was added gene: FLVCR1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature Q3_25_promote_green tags were added to gene: FLVCR1. Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FLVCR1 were set to 39306721 Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126 Review for gene: FLVCR1 was set to GREEN Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060. Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033 PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region. 13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals. All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1. There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel. Sources: Literature
14 Jul 2025	Early onset or syndromic epilepsy v8.10	FLVCR1	Eleanor Williams gene: FLVCR1 was added gene: FLVCR1 was added to Early onset or syndromic epilepsy. Sources: Literature Q3_25_promote_green tags were added to gene: FLVCR1. Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FLVCR1 were set to 39306721 Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126 Review for gene: FLVCR1 was set to GREEN Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060. Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033 PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region. 13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals. All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1. There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel. Sources: Literature
14 Jul 2025	Severe microcephaly v8.6	FLVCR1	Eleanor Williams gene: FLVCR1 was added gene: FLVCR1 was added to Severe microcephaly. Sources: Literature Q3_25_promote_green tags were added to gene: FLVCR1. Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FLVCR1 were set to 39306721 Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126 Review for gene: FLVCR1 was set to GREEN Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060. Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033 PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region. 13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals. All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1. There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel. Sources: Literature
14 Jul 2025	Fetal anomalies v6.9	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from ATAXIA, POSTERIOR COLUMN, WITH RETINITIS PIGMENTOSA to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
14 Jul 2025	Fetal anomalies v6.8	FLVCR1	Eleanor Williams Publications for gene: FLVCR1 were set to
14 Jul 2025	Fetal anomalies v6.7	FLVCR1	Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
14 Jul 2025	Fetal anomalies v6.7	FLVCR1	Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
14 Jul 2025	Fetal anomalies v6.7	FLVCR1	Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
14 Jul 2025	Fetal anomalies v6.6	FLVCR1	Eleanor Williams Tag Q3_25_promote_green tag was added to gene: FLVCR1.
14 Jul 2025	Fetal anomalies v6.6	FLVCR1	Eleanor Williams reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39306721; Phenotypes: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060, neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
14 Jul 2025	Intellectual disability v9.37	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126 to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
14 Jul 2025	Intellectual disability v9.36	FLVCR1	Eleanor Williams Publications for gene: FLVCR1 were set to 30656474; 22279524; 21267618; 21070897; 9409377; 30444160; 39306721
14 Jul 2025	Intellectual disability v9.36	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from ATAXIA, POSTERIOR COLUMN, WITH RETINITIS PIGMENTOSA to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
14 Jul 2025	Intellectual disability v9.35	FLVCR1	Eleanor Williams Publications for gene: FLVCR1 were set to 21267618; 9409377; 21070897
14 Jul 2025	Intellectual disability v9.35	FLVCR1	Eleanor Williams Classified gene: FLVCR1 as Amber List (moderate evidence)
14 Jul 2025	Intellectual disability v9.35	FLVCR1	Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
14 Jul 2025	Intellectual disability v9.35	FLVCR1	Eleanor Williams Gene: flvcr1 has been classified as Amber List (Moderate Evidence).
14 Jul 2025	Intellectual disability v9.34	FLVCR1	Eleanor Williams Tag Q3_25_promote_green tag was added to gene: FLVCR1.
14 Jul 2025	Intellectual disability v9.34	FLVCR1	Eleanor Williams edited their review of gene: FLVCR1: Changed rating: GREEN
14 Jul 2025	Intellectual disability v9.34	FLVCR1	Eleanor Williams edited their review of gene: FLVCR1: Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060. Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033 PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region. 13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals. All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1. There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.; Changed publications to: 30656474, 22279524, 21267618, 21070897, 9409377, 30444160, 39306721; Changed phenotypes to: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060, neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.30	BRWD1	Achchuthan Shanmugasundram reviewed gene: BRWD1: Rating: RED; Mode of pathogenicity: None; Publications: 33389130; Phenotypes: Ciliary dyskinesia, primary, 51, OMIM:620438; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.30	AK7	Achchuthan Shanmugasundram gene: AK7 was added gene: AK7 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen Mode of inheritance for gene: AK7 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AK7 were set to ?Spermatogenic failure 27, OMIM:617965; primary ciliary dyskinesia, MONDO:0016575 Review for gene: AK7 was set to RED Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive AK7 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Disputed'. More information can be found in https://search.clinicalgenome.org/CCID:004087. Sources: ClinGen
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.29	IFT74	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive IFT74 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008711.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive IFT74 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008711.
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.29	IFT74	Achchuthan Shanmugasundram Phenotypes for gene: IFT74 were changed from ciliary dyskinesia, MONDO:0016575 to primary ciliary dyskinesia, MONDO:0016575
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.28	DNAH10	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008793. Sources: ClinGen; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to primary ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008793. Sources: ClinGen
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.28	IFT74	Achchuthan Shanmugasundram reviewed gene: IFT74: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.28	IFT74	Achchuthan Shanmugasundram Phenotypes for gene: IFT74 were changed from ciliary dyskinesia, MONDO:0016575) to ciliary dyskinesia, MONDO:0016575
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.27	IFT74	Achchuthan Shanmugasundram gene: IFT74 was added gene: IFT74 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IFT74 were set to ciliary dyskinesia, MONDO:0016575)
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.26	DNAH1	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified this association as 'Limited' for ciliary dyskinesia, primary, 37 (MONDO:0033204). As per ClinGen, three unrelated patients have been reported with DNAH1 variants and bronchiectasis and other respiratory phenotypes including cough and respiratory distress. However, one of these patients has been reported with heterozygous variants. PMID:25927852 - Two affected sisters with PCD were identified with homozygous missense p.Lys1154Gln variant. The variant segregated with the phenotypes and was not found in unaffected members of the family. The proband had a history of chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis. She also showed situs inversus and bronchiectasis, in addition to infertility. PMID:31765523 - In a cohort of 265 patients with PCD, one patient was reported with heterozygous missense DNAH1 variant (p.Ala2599Ser). PMID:34210339 - In a cohort of 26 individuals with PCD, one patient was reported with homozygous DNAH1 variant (p.P3909Rfs33). The patient was infertile and presented with bronchiectasis, cough and sinusitis. As per ClinGen, this variant is recurrent in patients with isolated infertility and hence the association with PCD is doubtful. Hence, this gene should be rated red with the current evidence.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH1 variants to ciliary dyskinesia, primary, 37 (MONDO:0033204) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:004667. As per ClinGen, three unrelated patients have been reported with DNAH1 variants and bronchiectasis and other respiratory phenotypes including cough and respiratory distress. However, one of these patients has been reported with heterozygous variants. PMID:25927852 - Two affected sisters with PCD were identified with homozygous missense p.Lys1154Gln variant. The variant segregated with the phenotypes and was not found in unaffected members of the family. The proband had a history of chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis. She also showed situs inversus and bronchiectasis, in addition to infertility. PMID:31765523 - In a cohort of 265 patients with PCD, one patient was reported with heterozygous missense DNAH1 variant (p.Ala2599Ser). PMID:34210339 - In a cohort of 26 individuals with PCD, one patient was reported with homozygous DNAH1 variant (p.P3909Rfs33). The patient was infertile and presented with bronchiectasis, cough and sinusitis. As per ClinGen, this variant is recurrent in patients with isolated infertility and hence the association with PCD is doubtful. Hence, this gene should be rated red with the current evidence.
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.26	DNAH7	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH7 variants to ciliary dyskinesia, primary, 50 (MONDO:0957252) as 'Limited'. Please see https://search.clinicalgenome.org/CCID:008791 for more information. Sources: ClinGen; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH7 variants to ciliary dyskinesia, primary, 50 (MONDO:0957252) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008791. Sources: ClinGen
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.26	DNAH10	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. Please see https://search.clinicalgenome.org/CCID:008793 for more information. Sources: ClinGen; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. More information can be found in https://search.clinicalgenome.org/CCID:008793. Sources: ClinGen
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.26	DNAH7	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified this association as 'Limited' for ciliary dyskinesia, primary, 50 (MONDO:0957252). Sources: ClinGen; to: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH7 variants to ciliary dyskinesia, primary, 50 (MONDO:0957252) as 'Limited'. Please see https://search.clinicalgenome.org/CCID:008791 for more information. Sources: ClinGen
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.26	DNAH10	Achchuthan Shanmugasundram gene: DNAH10 was added gene: DNAH10 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen Mode of inheritance for gene: DNAH10 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DNAH10 were set to Spermatogenic failure 56, OMIM:619515; primary ciliary dyskinesia, MONDO:0016575 Review for gene: DNAH10 was set to RED Added comment: The ClinGen Motile Ciliopathy expert panel has classified the association of autosomal recessive DNAH10 variants to ciliary dyskinesia (MONDO:0016575) as 'Limited'. Please see https://search.clinicalgenome.org/CCID:008793 for more information. Sources: ClinGen
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.25	DNAH7	Achchuthan Shanmugasundram gene: DNAH7 was added gene: DNAH7 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: ClinGen Mode of inheritance for gene: DNAH7 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DNAH7 were set to Ciliary dyskinesia, primary, 50, OMIM:620356; ciliary dyskinesia, primary, 50, MONDO:0957252 Review for gene: DNAH7 was set to RED Added comment: The ClinGen Motile Ciliopathy expert panel has classified this association as 'Limited' for ciliary dyskinesia, primary, 50 (MONDO:0957252). Sources: ClinGen
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.24	DNAH1	Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel have classified this association as 'Limited' for ciliary dyskinesia, primary, 37 (MONDO:0033204). As per ClinGen, three unrelated patients have been reported with DNAH1 variants and bronchiectasis and other respiratory phenotypes including cough and respiratory distress. However, one of these patients has been reported with heterozygous variants. PMID:25927852 - Two affected sisters with PCD were identified with homozygous missense p.Lys1154Gln variant. The variant segregated with the phenotypes and was not found in unaffected members of the family. The proband had a history of chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis. She also showed situs inversus and bronchiectasis, in addition to infertility. PMID:31765523 - In a cohort of 265 patients with PCD, one patient was reported with heterozygous missense DNAH1 variant (p.Ala2599Ser). PMID:34210339 - In a cohort of 26 individuals with PCD, one patient was reported with homozygous DNAH1 variant (p.P3909Rfs33). The patient was infertile and presented with bronchiectasis, cough and sinusitis. As per ClinGen, this variant is recurrent in patients with isolated infertility and hence the association with PCD is doubtful. Hence, this gene should be rated red with the current evidence.; to: The ClinGen Motile Ciliopathy expert panel has classified this association as 'Limited' for ciliary dyskinesia, primary, 37 (MONDO:0033204). As per ClinGen, three unrelated patients have been reported with DNAH1 variants and bronchiectasis and other respiratory phenotypes including cough and respiratory distress. However, one of these patients has been reported with heterozygous variants. PMID:25927852 - Two affected sisters with PCD were identified with homozygous missense p.Lys1154Gln variant. The variant segregated with the phenotypes and was not found in unaffected members of the family. The proband had a history of chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis. She also showed situs inversus and bronchiectasis, in addition to infertility. PMID:31765523 - In a cohort of 265 patients with PCD, one patient was reported with heterozygous missense DNAH1 variant (p.Ala2599Ser). PMID:34210339 - In a cohort of 26 individuals with PCD, one patient was reported with homozygous DNAH1 variant (p.P3909Rfs33). The patient was infertile and presented with bronchiectasis, cough and sinusitis. As per ClinGen, this variant is recurrent in patients with isolated infertility and hence the association with PCD is doubtful. Hence, this gene should be rated red with the current evidence.
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.24	DNAH1	Achchuthan Shanmugasundram Phenotypes for gene: DNAH1 were changed from Too new - not yet linked to the PCD mutations publication to Ciliary dyskinesia, primary, 37, OMIM:617577; ciliary dyskinesia, primary, 37, MONDO:0033204
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.23	DNAH1	Achchuthan Shanmugasundram Publications for gene: DNAH1 were set to
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.22	DNAH1	Achchuthan Shanmugasundram Classified gene: DNAH1 as Red List (low evidence)
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.22	DNAH1	Achchuthan Shanmugasundram Gene: dnah1 has been classified as Red List (Low Evidence).
14 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.21	DNAH1	Achchuthan Shanmugasundram reviewed gene: DNAH1: Rating: RED; Mode of pathogenicity: None; Publications: 25927852, 31765523, 34210339; Phenotypes: Ciliary dyskinesia, primary, 37, OMIM:617577, ciliary dyskinesia, primary, 37, MONDO:0033204; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
14 Jul 2025	Amelogenesis imperfecta v4.5	AIRE	Claire Smith changed review comment from: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668). Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F. Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3 years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation. This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1. Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins. Sources: Literature; to: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668). Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F. Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3 years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation. This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1. Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins. Sources: Literature Edit: I didn't add Amelogenesis imperfecta to the phenotype list. Can you please add this! I can't seem to add it in retrospect!
14 Jul 2025	Amelogenesis imperfecta v4.5	AIRE	Claire Smith gene: AIRE was added gene: AIRE was added to Amelogenesis imperfecta. Sources: Literature Mode of inheritance for gene: AIRE was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: AIRE were set to PMID: 37993717; 19393987; 27253668 Phenotypes for gene: AIRE were set to Addison disease; hypoparathyroidism; chronic mucocutaneous candidiasis Penetrance for gene: AIRE were set to unknown Review for gene: AIRE was set to GREEN Added comment: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668). Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F. Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3 years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation. This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1. Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins. Sources: Literature
14 Jul 2025	Amelogenesis imperfecta v4.5	TUFT1	Claire Smith reviewed gene: TUFT1: Rating: RED; Mode of pathogenicity: None; Publications: 36689522; Phenotypes: woolly hair, skin fragility, keratosis pilaris; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
14 Jul 2025	Amelogenesis imperfecta v4.5	CLDN16	Claire Smith reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 32710267; Phenotypes: amelogenesis imperfecta, hyperparathyroidism, short stature, nephrocalcinosis, polyuria, polydipsia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
14 Jul 2025	Distal myopathies v6.8	NEB	Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of monoallelic intragenic deletions in NEB gene with a milder distal myopathy phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.
14 Jul 2025	Distal myopathies v6.8	NEB	Achchuthan Shanmugasundram Mode of inheritance for gene: NEB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
14 Jul 2025	Distal myopathies v6.7	NEB	Achchuthan Shanmugasundram Phenotypes for gene: NEB were changed from Nemaline myopathy 2, 256030 to Nemaline myopathy 2, OMIM:256030; distal myopathy, MONDO:0018949
14 Jul 2025	Distal myopathies v6.6	NEB	Achchuthan Shanmugasundram Publications for gene: NEB were set to 12207937; 30679003; 39474605
14 Jul 2025	Distal myopathies v6.5	NEB	Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: NEB.
14 Jul 2025	Distal myopathies v6.5	NEB	Achchuthan Shanmugasundram reviewed gene: NEB: Rating: GREEN; Mode of pathogenicity: None; Publications: 40517164; Phenotypes: distal myopathy, MONDO:0018949; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
14 Jul 2025	Paediatric pseudo-obstruction syndrome v2.1	KIF26A	Anna Rybak changed review comment from: New patient with neurological impairment and paediatric intestinal pseudo-obstruction, has been found to be a carrier of KIF26A homozygous c.5111-2A>G LP variant. Genetic diagnosis explains Abdullah's history of developmental delay, brain abnormalities, hypertonia, and bowel issues. AR inheritance, both parents confirmed to be carriers. Consanguineous parents. Another three patients published in 2024: Nosrati MSS, Doustmohammadi A, Severino M, Romano F, Zafari M, Nemati AH, Velmans C, Netzer C, Breuer J, Broekaert IJ, Joachim A, Almasri N, Kruer MC, Skidmore P, Bisarad P, Hoque J, Bakhtiari S, Torella A, Nigro V, Buffelli F, Fulcheri E, Müller A, Zara F, Capra V, Scala M. Novel KIF26A variants associated with pediatric intestinal pseudo-obstruction (PIPO) and brain developmental defects. Clin Genet. 2025 Jan;107(1):83-90. doi: 10.1111/cge.14621.; to: New patient with neurological impairment and paediatric intestinal pseudo-obstruction, has been found to be a carrier of KIF26A homozygous c.5111-2A>G LP variant. Genetic diagnosis explains patient's history of developmental delay, brain abnormalities, hypertonia, and bowel issues. AR inheritance, both parents confirmed to be carriers. Consanguineous parents. Another three patients published in 2024: Nosrati MSS, Doustmohammadi A, Severino M, Romano F, Zafari M, Nemati AH, Velmans C, Netzer C, Breuer J, Broekaert IJ, Joachim A, Almasri N, Kruer MC, Skidmore P, Bisarad P, Hoque J, Bakhtiari S, Torella A, Nigro V, Buffelli F, Fulcheri E, Müller A, Zara F, Capra V, Scala M. Novel KIF26A variants associated with pediatric intestinal pseudo-obstruction (PIPO) and brain developmental defects. Clin Genet. 2025 Jan;107(1):83-90. doi: 10.1111/cge.14621.
14 Jul 2025	Paediatric pseudo-obstruction syndrome v2.1	KIF26A	Anna Rybak reviewed gene: KIF26A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: KIF26A homozygous c.5111-2A>G LP varian; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
14 Jul 2025	Dilated and arrhythmogenic cardiomyopathy v3.1	MYLK3	Matthew Edwards Deleted their comment
14 Jul 2025	Dilated and arrhythmogenic cardiomyopathy v3.1	MYLK3	Matthew Edwards edited their review of gene: MYLK3: Added comment: Several mouse models (and a zebrafish), one of which is heterozygous KO which recapitulates DCM (31244672). Good expression/protein interaction evidence 17885681, 18202317) Rare cases in literature - PMID: 29235529 has two families: Family A - two early onset sibs and their affected mother (later onset) had heterozygous MYLK3 LOF variant - sibs also had a FLNC LOF variant (from unaffected father), likely explaining early onset. Family B two later onset sibs with heterozygous MYLK3 LOF variant. functional studies of both showed reduced protein expression. PMID: 30690923: has proband with heterozygous LOF variant. 3 consanguineous families with hom LOf (2 families) and hom missense (1 family). We've seen 10 LOF variants in DCM patients (with 3 detected in control set of non-DCM cases ~5000 samples - one possibly too young for phenotype, 2 with variant in only one of two isforms expressed in heart), but currently classify as VUS due to limited haploinsufficiency evidence. (Clin~Gen curation still pending); Changed rating: GREEN
09 Jul 2025	Retinal disorders v8.9	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177 to Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
09 Jul 2025	Retinal disorders v8.8	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033 posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177 to Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
09 Jul 2025	Hereditary ataxia with onset in adulthood v8.6	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Posterior Column Ataxia with Retinitis Pigmentosa; Posterior column ataxia with retinitis pigmentosa, 609033; Ataxia, posterior column, with retinitis pigmentosa, to Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
09 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.9	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177 to Retinopathy-sensory neuropathy syndrome, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
09 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.8	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033 posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177 to Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033; posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
09 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.7	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Posterior Column Ataxia with Retinitis Pigmentosa; Ataxia, posterior column, with retinitis pigmentosa, to Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033 posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
09 Jul 2025	Retinal disorders v8.7	FLVCR1	Eleanor Williams Phenotypes for gene: FLVCR1 were changed from Eye Disorders; Posterior Column Ataxia with Retinitis Pigmentosa; Ataxia, posterior column, with retinitis pigmentosa, 609033; Retinitis pigmentosa to Ataxia, posterior column, with retinitis pigmentosa, OMIM:609033 posterior column ataxia-retinitis pigmentosa syndrome, MONDO:0012177
09 Jul 2025	Severe microcephaly v8.5	WARS	Eleanor Williams changed review comment from: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review as there are 4 families with intellectual disability.; to: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review as there are 4 families with progressive microcephaly in the severe range.
09 Jul 2025	Severe microcephaly v8.5	WARS	Eleanor Williams Entity copied from Intellectual disability v9.34
09 Jul 2025	Severe microcephaly v8.5	WARS	Eleanor Williams gene: WARS was added gene: WARS was added to Severe microcephaly. Sources: Expert Review Amber,Literature Q3_25_promote_green tags were added to gene: WARS. Mode of inheritance for gene: WARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WARS were set to 34585293; 35790048; 35815345 Phenotypes for gene: WARS were set to Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, OMIM:620317; neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, MONDO:0957218
09 Jul 2025	Intellectual disability v9.34	WARS	Eleanor Williams Classified gene: WARS as Amber List (moderate evidence)
09 Jul 2025	Intellectual disability v9.34	WARS	Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review as there are 4 families with intellectual disability.
09 Jul 2025	Intellectual disability v9.34	WARS	Eleanor Williams Gene: wars has been classified as Amber List (Moderate Evidence).
09 Jul 2025	Intellectual disability v9.33	WARS	Eleanor Williams Tag Q3_25_promote_green tag was added to gene: WARS.
09 Jul 2025	Intellectual disability v9.33	WARS	Eleanor Williams changed review comment from: Sources: Literature; to: Associated with Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities OMIM:620317 (AR). Also associated with Neuronopathy, distal hereditary motor, autosomal dominant 9, OMIM:617721 (AD). 5 families reported with biallelic variants in WARS1 and phenotype of intellectual disability and progressive severe microcephaly in 4 families. Variable other phenotypes were also present such as hearing loss, skeletal and brain abnormalities and seizures. PMID: 34585293 - Okamoto et al 2022 - 4 year old female Japanese proband with compound het variants in WARS1 (p.Arg448Trp and p.Ala333Thr). Parents were heterozygous. Variants are rare. She presented with hypotonia, developmental delay, delayed myelination in the cerebral white matter. She had a seizure age 2. Severe intellectual disability at age 4, did not walk independently. Head circumference was -0.4 SD at birth and -3.4 SD by age 4. PMID: 35815345 - Lin et al 2022 - 3 probands from 2 consanguineous Pakistani families. In family 1, one proband at age 20 had developmental delay, mild ID, mild microcephaly, mild sensorineural hearing loss. The second proband at age 16 had severe delayed developmental milestones/intellectual disability, hypotonia, severe microcephaly (-7.8 SD), severe hearing impairment and skeletal abnormalities of the legs. In family 2, the 5 year male had global developmental delay, complex partial epilepsy, a history of central adrenal insufficiency, cortical blindness, and multiple brain abnormalities. He has a history of seizures. A homozygous, rare, start loss variant (c.1A>G, p.Met1?) in exon 2 of WARS1 was identified in family 1 with parents as carriers. A homozygous c.1255G>A, p.(Asp419Asn) variant was identified in WARS1 in family 2, with parents as carriers. This variant is present in population databases with a MAF ~ 0.003 but not in the homozygous state. Zebrafish wars1 knockout displayed microcephaly, hearing loss, and musculoskeletal abnormalities, and the homozygous animals do not survive past Day 10 PMID: 35790048 - Bögershausen et al 2022 - 4 individuals from 2 families all with the same missense variant in WARS1 (c.397C>T, p.(R133C)). All 4 had progressive microcephaly with OFC at (-4.2, -4.3, -3.8 and −3.5) at assessment at ages 5, 13, 8 and 7 years. the proband from family 1 had mild ID, the three from family 2 had severe ID and two from family 2 had hypotonia. No seizures or hearing loss was reported. The WARS1 variant negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model.
09 Jul 2025	Intellectual disability v9.33	WARS	Eleanor Williams gene: WARS was added gene: WARS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: WARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WARS were set to 34585293; 35790048; 35815345 Phenotypes for gene: WARS were set to Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, OMIM:620317; neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, MONDO:0957218 Review for gene: WARS was set to GREEN Added comment: Sources: Literature
09 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.6	CRNKL1	Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
09 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.6	CRNKL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are nine unrelated patients reported with pontocerebellar hypoplasia, this gene can be promoted to green rating in the next GMS update.
09 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.6	CRNKL1	Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
09 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.5	CRNKL1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
09 Jul 2025	Severe microcephaly v8.4	CRNKL1	Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
09 Jul 2025	Severe microcephaly v8.4	CRNKL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
09 Jul 2025	Severe microcephaly v8.4	CRNKL1	Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
09 Jul 2025	Severe microcephaly v8.3	CRNKL1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
09 Jul 2025	Early onset or syndromic epilepsy v8.9	CRNKL1	Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
09 Jul 2025	Early onset or syndromic epilepsy v8.9	CRNKL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
09 Jul 2025	Early onset or syndromic epilepsy v8.9	CRNKL1	Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
09 Jul 2025	Early onset or syndromic epilepsy v8.8	CRNKL1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
09 Jul 2025	Intellectual disability v9.32	CRNKL1	Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
09 Jul 2025	Intellectual disability v9.32	CRNKL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
09 Jul 2025	Intellectual disability v9.32	CRNKL1	Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
09 Jul 2025	Intellectual disability v9.31	CRNKL1	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
09 Jul 2025	Severe microcephaly v8.3	CRNKL1	Achchuthan Shanmugasundram gene: CRNKL1 was added gene: CRNKL1 was added to Severe microcephaly. Sources: Literature Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013 Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: CRNKL1 was set to GREEN Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients). Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes. This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype. Sources: Literature
09 Jul 2025	Ataxia and cerebellar anomalies - narrow panel v8.5	CRNKL1	Achchuthan Shanmugasundram gene: CRNKL1 was added gene: CRNKL1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013 Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: CRNKL1 was set to GREEN Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients). Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes. This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype. Sources: Literature
09 Jul 2025	Early onset or syndromic epilepsy v8.8	CRNKL1	Achchuthan Shanmugasundram gene: CRNKL1 was added gene: CRNKL1 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013 Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: CRNKL1 was set to GREEN Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients). Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes. This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype. Sources: Literature
09 Jul 2025	Intellectual disability v9.31	CRNKL1	Achchuthan Shanmugasundram gene: CRNKL1 was added gene: CRNKL1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013 Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: CRNKL1 was set to GREEN Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients). Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes. This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype. Sources: Literature
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.21	CFAP46	Achchuthan Shanmugasundram Classified gene: CFAP46 as Amber List (moderate evidence)
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.21	CFAP46	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case reported with biallelic CFFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. Hence, this gene can be rated amber with the current evidence.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.21	CFAP46	Achchuthan Shanmugasundram Gene: cfap46 has been classified as Amber List (Moderate Evidence).
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.20	CFAP46	Achchuthan Shanmugasundram Publications for gene: CFAP46 were set to 29843777; 39362668
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	CFAP46	Achchuthan Shanmugasundram edited their review of gene: CFAP46: Changed rating: AMBER; Changed publications to: 22573824, 23715323, 29843777, 39362668
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	CFAP46	Achchuthan Shanmugasundram changed review comment from: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene. PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus. This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.; to: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene. PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus. In addition, this gene-disease association is supported by Chlamydomonas reinhardtii null mutant model (PMID:22573824) and gene expression data (PMID:23715323). In addition, immunofluorescence microscopy analyses of respiratory epithelial cells show that CFAP46 localises along the entire ciliary axoneme in healthy individuals but is lost in the respiratory cells of a CFAP46-PCD patient (PMID:39362668). This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	CFAP46	Achchuthan Shanmugasundram edited their review of gene: CFAP46: Changed publications to: 22573824, 29843777, 39362668
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	DAW1	Achchuthan Shanmugasundram edited their review of gene: DAW1: Changed rating: RED; Changed publications to: 28991257, 36074124; Changed phenotypes to: Ciliary dyskinesia, primary, 52, OMIM:620570
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	DAW1	Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: DAW1.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	DAW1	Achchuthan Shanmugasundram Tag Q2_25_ demote_red tag was added to gene: DAW1.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	DAW1	Achchuthan Shanmugasundram changed review comment from: DAW1 has the gene-disease validity rating of 'Limited' in ClinGen. There are no reported respiratory symptoms in the cases, and only had situs inversus.; to: DAW1 has the gene-disease validity rating of 'Limited' in ClinGen. ClinGen has rated this gene with 'Limited' rating as there are no reported respiratory symptoms in the cases. PMID:28991257 - Two patients reported with biallelic DAW1 variants - Both of them presented with cardiac phenotypes including heterotaxy. One of them had Situs ambiguous and abdominal Situs Inversus. However, respiratory symptoms were not recorded in these patients. PMID:36074124 - Four individuals from two different families were reported with biallelic DAW1 variants. Three individuals from the first family were reported with features suggestive of mild primary ciliary dyskinesia. One individual had situs inversus (SI) without otosinopulmonary symptoms, another had SI and had a history of recurrent otitis media in childhood and the third had normal situs but is reported with lower respiratory tract infections, chronic wet cough and recurrent episodes of otitis media in early life. An unrelated Palestinian boy was reported with congenital heart disease including heterotaxy, and Situs ambiguous, however no respiratory symptoms or Otitis media were reported. The evidence available is not sufficient for the association of this gene with green rating on this panel as respiratory phenotype was present only in one patient.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	DAW1	Achchuthan Shanmugasundram edited their review of gene: DAW1: Added comment: DAW1 has the gene-disease validity rating of 'Limited' in ClinGen. There are no reported respiratory symptoms in the cases, and only had situs inversus.; Changed rating: AMBER
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	STK36	Achchuthan Shanmugasundram reviewed gene: STK36: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Ciliary dyskinesia, primary, 41, OMIM:618449; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	GAS2L2	Achchuthan Shanmugasundram Tag watchlist was removed from gene: GAS2L2.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	DNAJB13	Achchuthan Shanmugasundram Classified gene: DNAJB13 as Amber List (moderate evidence)
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	DNAJB13	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases from two different publications) for the promotion of this gene to green rating in the next GMS update.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.19	DNAJB13	Achchuthan Shanmugasundram Gene: dnajb13 has been classified as Amber List (Moderate Evidence).
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.18	DNAJB13	Achchuthan Shanmugasundram Tag watchlist was removed from gene: DNAJB13. Tag Q2_25_ promote_green tag was added to gene: DNAJB13.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.18	DNAJB13	Achchuthan Shanmugasundram Publications for gene: DNAJB13 were set to 27486783
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.17	DNAJB13	Achchuthan Shanmugasundram reviewed gene: DNAJB13: Rating: GREEN; Mode of pathogenicity: None; Publications: 35166991; Phenotypes: Ciliary dyskinesia, primary, 34, OMIM:617091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.17	CFAP221	Achchuthan Shanmugasundram Classified gene: CFAP221 as Amber List (moderate evidence)
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.17	CFAP221	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available now for the promotion of this gene to green rating in the next GMS update.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.17	CFAP221	Achchuthan Shanmugasundram Gene: cfap221 has been classified as Amber List (Moderate Evidence).
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.16	CFAP221	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: CFAP221.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.16	CFAP221	Achchuthan Shanmugasundram changed review comment from: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen. There are additional cases reported with primary ciliary dyskinesia now. PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants. PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss.; to: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen. There are additional cases reported with primary ciliary dyskinesia now. PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants. PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss. This gene has also been associated with relevant phenotypes in OMIM (MIM #279000).
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.16	CFAP221	Achchuthan Shanmugasundram Phenotypes for gene: CFAP221 were changed from Primary ciliary dyskinesia, MONDO:0016575 to Ciliary dyskinesia, primary, 55, OMIM:279000
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.15	CFAP221	Achchuthan Shanmugasundram Publications for gene: CFAP221 were set to 31636325; 39362668
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.14	CFAP221	Achchuthan Shanmugasundram changed review comment from: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen. There are additional cases reported with primary ciliary dyskinesia now. PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.; to: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen. There are additional cases reported with primary ciliary dyskinesia now. PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants. PMID:40250778 - A Polish male patient with PCD was identified with a novel homozygous protein-truncating variant in CFAP221 gene (p.Asp146His). The patient was reported with neonatal respiratory distress, admission to neonatal unit, congenital heart defect, chronic cough, otitis media, and sinusitis, glue ear and conductive hearing loss.
07 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.14	CFAP221	Achchuthan Shanmugasundram edited their review of gene: CFAP221: Changed publications to: 31636325, 38960684, 39362668, 40250778
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.14	CFAP221	Achchuthan Shanmugasundram edited their review of gene: CFAP221: Added comment: CFAP221 has the gene-disease validity rating of 'Moderate' in ClinGen. There are additional cases reported with primary ciliary dyskinesia now. PMID:38960684 - A 42-year-old male patient with bronchiectasis, sinusitis and a history of infertility treatment for obstructive azoospermia were identified with compound heterozygous deletion variants.; Changed rating: GREEN; Changed publications to: 31636325, 38960684, 39362668; Changed phenotypes to: Ciliary dyskinesia, primary, 55, OMIM:279000
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.14	CFAP221	Achchuthan Shanmugasundram Deleted their comment
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.14	TP73	Achchuthan Shanmugasundram Classified gene: TP73 as Amber List (moderate evidence)
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.14	TP73	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.14	TP73	Achchuthan Shanmugasundram Gene: tp73 has been classified as Amber List (Moderate Evidence).
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.13	TP73	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: TP73.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.13	TP73	Achchuthan Shanmugasundram gene: TP73 was added gene: TP73 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature Mode of inheritance for gene: TP73 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TP73 were set to 34077761 Phenotypes for gene: TP73 were set to Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466 Review for gene: TP73 was set to GREEN Added comment: TP73 has the gene-disease validity rating of 'Strong' in ClinGen. PMID:34077761 - Five different homozygous loss-of-function variants in TP73 gene have been reported in seven individuals from five unrelated families. They presented with a chronic airway disease, and brain malformation consistent with lissencephaly. Respiratory distress syndrome and recurrent respiratory infections have been reported in five and six patients respectively. There is also some experimental evidence available. This gene has been associated with relevant phenotypes in both OMIM (MIM #619466) and Gene2Phenotype (with 'strong' rating on the DD panel). Sources: Literature
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.12	NEK10	Achchuthan Shanmugasundram Classified gene: NEK10 as Amber List (moderate evidence)
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.12	NEK10	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available now from three different studies for the association of biallelic variants in NEK10 gene with this panel. Hence, this gene can be promoted to green rating in the next GMS update.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.12	NEK10	Achchuthan Shanmugasundram Gene: nek10 has been classified as Amber List (Moderate Evidence).
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.11	NEK10	Achchuthan Shanmugasundram Publications for gene: NEK10 were set to 31959991; 32414360
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.10	NEK10	Achchuthan Shanmugasundram Tag watchlist was removed from gene: NEK10. Tag Q2_25_ promote_green tag was added to gene: NEK10.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.10	NEK10	Achchuthan Shanmugasundram reviewed gene: NEK10: Rating: GREEN; Mode of pathogenicity: None; Publications: 32414360, 35728977; Phenotypes: Ciliary dyskinesia, primary, 44, OMIM:618781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.10	EFCAB1	Achchuthan Shanmugasundram Classified gene: EFCAB1 as Amber List (moderate evidence)
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.10	EFCAB1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases and some experimental evidence) for the promotion of this gene to green rating in the next GMS update.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.10	EFCAB1	Achchuthan Shanmugasundram Gene: efcab1 has been classified as Amber List (Moderate Evidence).
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.9	EFCAB1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: EFCAB1.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.9	EFCAB1	Achchuthan Shanmugasundram commented on gene: EFCAB1: The 'new-gene-name' tag has been added as the official HGNC gene symbol for EFCAB1 is CLXN.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.9	EFCAB1	Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: EFCAB1.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.9	EFCAB1	Achchuthan Shanmugasundram gene: EFCAB1 was added gene: EFCAB1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EFCAB1 were set to 36727596 Phenotypes for gene: EFCAB1 were set to Ciliary dyskinesia, primary, 53, OMIM:620642 Review for gene: EFCAB1 was set to GREEN Added comment: EFCAB1 has the gene-disease validity rating of 'Strong' in ClinGen. PMID:36727596 - Three individuals from three unrelated families were identified with three different homozygous variants in EFCAB1 gene (p.Arg98Ter, p.Glu123Ter & p.Glu40Trpfs*16). All three patients presented with situs inversus/ situs ambiguous, while chronic rhino-sinusitis was reported in one, and recurrent pneumonia and respiratory insufficiency were reported in another patient. There is also some functional evidence available. This gene has also been associated with relevant phenotype in OMIM (MIM #620642). Sources: Literature
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.8	TTC12	Achchuthan Shanmugasundram Classified gene: TTC12 as Amber List (moderate evidence)
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.8	TTC12	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (10 unrelated cases) for the association of biallelic TTC12 patients with respiratory ciliopathy. Hence, this gene can be promoted to green rating in the next GMS update.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.8	TTC12	Achchuthan Shanmugasundram Gene: ttc12 has been classified as Amber List (Moderate Evidence).
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.7	TTC12	Achchuthan Shanmugasundram Tag watchlist was removed from gene: TTC12. Tag Q2_25_ promote_green tag was added to gene: TTC12.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.7	TTC12	Achchuthan Shanmugasundram Publications for gene: TTC12 were set to 31978331
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.6	TTC12	Achchuthan Shanmugasundram reviewed gene: TTC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 36273201, 37325566, 38992144; Phenotypes: Ciliary dyskinesia, primary, 45, OMIM:618801; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.6	CEP164	Achchuthan Shanmugasundram Classified gene: CEP164 as Amber List (moderate evidence)
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.6	CEP164	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated probands reported with biallelic CEP164 variants and non-CF bronchiectasis. Hence, this gene can be promoted to green rating in the next GMS update.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.6	CEP164	Achchuthan Shanmugasundram Gene: cep164 has been classified as Amber List (Moderate Evidence).
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.5	CEP164	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: CEP164.
04 Jul 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.5	CEP164	Achchuthan Shanmugasundram gene: CEP164 was added gene: CEP164 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature Mode of inheritance for gene: CEP164 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP164 were set to 22863007; 34556108; 36273371 Phenotypes for gene: CEP164 were set to Nephronophthisis 15, OMIM:614845; Bronchiectasis, HP:0002110 Review for gene: CEP164 was set to GREEN Added comment: CEP164 has the gene-disease validity rating of 'Definitive' in ClinGen. As per ClinGen curation, seven different variants have been reported in 6 probands in four publications (PMIDs: 22863007, 34132027, 27708425, 36273371), of which 3 probands have been associated with non-CF bronchiectasis. Two of them also had cough, pneumonia, rhinitis and/ or recurrent infections. PMID:22863007 - This study reported four different patients with biallelic CEP164 variants, of which one patient with homozygous variant (p.Arg576Ter) had cerebeller vermis hypoplasia, facial dysmorphism, obesity, bronchiectasis and polydactyly in addition to nephronophthisis. PMID:34556108 - 21 probands from the PCD cohort and 52 probands from non-CF bronchiectasis cohort were recruited in Wessex Genome Medicine Centre (GMC) and their genomes sequenced as part of Genomics England 100k genomes project. Compound heterozygous variants in CEP164 (p.Gln1410Ter/ p.Arg576Ter) were reported in one of these probands from non-CF bronchiectasis cohort. PMID:36273371 - A patient with bronchiectasis was reported with atypical motile ciliopathy phenotype and the same compound heterozygous CEP164 variants as above. Sources: Literature
04 Jul 2025	Structural eye disease v4.9	NR6A1	Siying Lin gene: NR6A1 was added gene: NR6A1 was added to Structural eye disease. Sources: Literature Mode of inheritance for gene: NR6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NR6A1 were set to PMID: 40610405 Phenotypes for gene: NR6A1 were set to microphthalmia, coloboma Penetrance for gene: NR6A1 were set to Incomplete Mode of pathogenicity for gene: NR6A1 was set to Other Review for gene: NR6A1 was set to GREEN Added comment: PMID 40610405: 6 unrelated families with autosomal dominant syndromic form of colobomatous microphthalmia and missing vertebrae with or without congenital kidney abnormalities Sources: Literature
02 Jul 2025	Cerebral vascular malformations v4.5	ANO1	Eleanor Williams Tag Q2_25_expert_review tag was added to gene: ANO1.
02 Jul 2025	Monogenic hearing loss v5.22	MRPL49	Arina Puzriakova Tag Q2_25_expert_review was removed from gene: MRPL49.
02 Jul 2025	Thrombocythaemia v1.6	SH2B3	Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: SH2B3.
02 Jul 2025	Thrombocythaemia v1.6	SH2B3	Arina Puzriakova commented on gene: SH2B3: Tagging for GMS expert review to determine whether this gene should be included and the MOI that should be set on this panel. Both germline and somatic variants have been reported - MOI currently set to Other to capture somatic origin. Terri McVeigh states that this gene should be included on the panel, although thrombocythaemia typically presents alongside myeloproliferative neoplasm. Testing criteria for this panel states that secondary causes such as myeloproliferative neoplasm should be excluded.
02 Jul 2025	Hereditary Erythrocytosis v2.13	SH2B3	Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: SH2B3.
02 Jul 2025	Hereditary Erythrocytosis v2.13	SH2B3	Arina Puzriakova edited their review of gene: SH2B3: Added comment: Tagging for GMS expert review to determine whether this gene should be included and the MOI that should be set on this panel. Erythrocytosis is thought to be caused by somatic variants (for somatic variants MOI is set to Other) and testing criteria for this panel states that secondary causes such as myeloproliferative neoplasm should be excluded. However, Terri McVeigh states that germline variants should be included, although these are typically linked to myeloproliferative neoplasms. Cases of erythrocytosis due to germline variants are rare, and most studies reporting SH2B3 variants have not determined germline or somatic status (PMID: 20843259; 23812944; 27651169; 34349782). In the literature, there is only one report of idiopathic erythrocytosis, without signs of myeloproliferative neoplasms, associated with a confirmed germline heterozygous SH2B3 variant. The mother was also a carrier but had no signs of erythrocytosis (PMID: 38024597).; Changed publications to: 20843259, 23812944, 27651169, 34349782, 38024597
02 Jul 2025	Acute intermittent porphyria v1.3	HMBS	Arina Puzriakova Tag Q2_25_expert_review was removed from gene: HMBS.
02 Jul 2025	Non-acute porphyrias v1.26	HMBS	Arina Puzriakova commented on gene: HMBS
02 Jul 2025	Retinal disorders v8.6	POC5	Siying Lin reviewed gene: POC5: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 29272404, 40590205; Phenotypes: Retinal dystrophy, diabetes mellitus, lipodystrophy, renal failure, abnormal muscle physiology; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 Jul 2025	Adult onset leukodystrophy v6.4	NOTCH3	Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic cysteine-involving missense variants of NOTCH3 gene with early-adult-onset leukodystrophy. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
01 Jul 2025	Adult onset leukodystrophy v6.4	NOTCH3	Achchuthan Shanmugasundram Mode of inheritance for gene: NOTCH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
01 Jul 2025	Adult onset leukodystrophy v6.3	NOTCH3	Achchuthan Shanmugasundram Publications for gene: NOTCH3 were set to 27159321; 25527826; 28334938; 20301621; 24357685
01 Jul 2025	Adult onset leukodystrophy v6.2	NOTCH3	Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310 to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310; neurodevelopmental disorder, MONDO:0700092; leukodystrophy, MONDO:0019046
01 Jul 2025	Adult onset leukodystrophy v6.1	NOTCH3	Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: NOTCH3.
01 Jul 2025	Adult onset leukodystrophy v6.1	NOTCH3	Achchuthan Shanmugasundram edited their review of gene: NOTCH3: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, leukodystrophy, MONDO:0019046
01 Jul 2025	Adult onset leukodystrophy v6.1	NOTCH3	Achchuthan Shanmugasundram reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
01 Jul 2025	Childhood onset hereditary spastic paraplegia v8.4	NOTCH3	Achchuthan Shanmugasundram changed review comment from: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families. Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. 19 of these patients from 11 different families were reported with spasticity. Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Spasticity and ataxia were reported in three and four patients respectively. Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.; to: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families. Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. 19 of these patients from 11 different families were reported with spasticity. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old. Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Spasticity and ataxia were reported in three and four patients respectively. Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
01 Jul 2025	Childhood onset hereditary spastic paraplegia v8.4	NOTCH3	Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
01 Jul 2025	Childhood onset hereditary spastic paraplegia v8.4	NOTCH3	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available for the association of biallelic LoF variants from NOTCH3 gene with childhood-onset spastic paraplegia. Hence, this gene can be promoted to green rating in the next GMS update.
01 Jul 2025	Childhood onset hereditary spastic paraplegia v8.4	NOTCH3	Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
01 Jul 2025	Childhood onset hereditary spastic paraplegia v8.3	NOTCH3	Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Spasticity, stroke, periatrial white matter volume loss to neurodevelopmental disorder, MONDO:0700092
01 Jul 2025	Childhood onset hereditary spastic paraplegia v8.2	NOTCH3	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NOTCH3. Tag Q3_25_NHS_review tag was added to gene: NOTCH3.
01 Jul 2025	Childhood onset hereditary spastic paraplegia v8.2	NOTCH3	Achchuthan Shanmugasundram reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 Jul 2025	White matter disorders and cerebral calcification - narrow panel v7.8	NOTCH3	Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
01 Jul 2025	White matter disorders and cerebral calcification - narrow panel v7.8	NOTCH3	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available for the association of biallelic LoF variants from NOTCH3 gene with childhood-onset leukoencephalopathy. Hence, this gene can be promoted to green rating in the next GMS update.
01 Jul 2025	White matter disorders and cerebral calcification - narrow panel v7.8	NOTCH3	Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
01 Jul 2025	White matter disorders and cerebral calcification - narrow panel v7.7	NOTCH3	Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310 to neurodevelopmental disorder, MONDO:0700092; leukodystrophy, MONDO:0019046
01 Jul 2025	White matter disorders and cerebral calcification - narrow panel v7.6	NOTCH3	Achchuthan Shanmugasundram Publications for gene: NOTCH3 were set to
01 Jul 2025	White matter disorders and cerebral calcification - narrow panel v7.5	NOTCH3	Achchuthan Shanmugasundram Mode of inheritance for gene: NOTCH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
01 Jul 2025	White matter disorders and cerebral calcification - narrow panel v7.4	NOTCH3	Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NOTCH3. Tag Q3_25_NHS_review tag was added to gene: NOTCH3.
01 Jul 2025	White matter disorders and cerebral calcification - narrow panel v7.4	NOTCH3	Achchuthan Shanmugasundram reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: neurodevelopmental disorder, MONDO:0700092, leukodystrophy, MONDO:0019046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 Jul 2025	Autosomal recessive primary hypertrophic osteoarthropathy v1.14	SLCO2A1	Arina Puzriakova Tag Q2_25_expert_review was removed from gene: SLCO2A1.
01 Jul 2025	Early onset or syndromic epilepsy v8.7	NOTCH3	Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
01 Jul 2025	Early onset or syndromic epilepsy v8.7	NOTCH3	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic LoF variants in NOTCH3 gene with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
01 Jul 2025	Early onset or syndromic epilepsy v8.7	NOTCH3	Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
01 Jul 2025	Early onset or syndromic epilepsy v8.6	NOTCH3	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: NOTCH3. Tag Q3_25_promote_green tag was added to gene: NOTCH3.
01 Jul 2025	Intellectual disability v9.30	NOTCH3	Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
01 Jul 2025	Intellectual disability v9.30	NOTCH3	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic LoF variants in NOTCH3 gene with intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
01 Jul 2025	Intellectual disability v9.30	NOTCH3	Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
01 Jul 2025	Intellectual disability v9.29	NOTCH3	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: NOTCH3. Tag Q3_25_promote_green tag was added to gene: NOTCH3.
01 Jul 2025	Early onset or syndromic epilepsy v8.6	NOTCH3	Achchuthan Shanmugasundram gene: NOTCH3 was added gene: NOTCH3 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NOTCH3 were set to 39191170 Phenotypes for gene: NOTCH3 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: NOTCH3 was set to GREEN Added comment: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families. Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Of these 24 patients from 15 families had developmental delay, ranging from mild or only motor delay in 7 patients to global developmental impairment in 17 patients. 21 patents from 13 families had predominantly severe intellectual disability, of which five had mild ID. Seizures were reported in 10 patients from seven different families. Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype. Sources: Literature
01 Jul 2025	Intellectual disability v9.29	NOTCH3	Achchuthan Shanmugasundram gene: NOTCH3 was added gene: NOTCH3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NOTCH3 were set to 39191170 Phenotypes for gene: NOTCH3 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: NOTCH3 was set to GREEN Added comment: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families. Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Of these 24 patients from 15 families had developmental delay, ranging from mild or only motor delay in 7 patients to global developmental impairment in 17 patients. 21 patents from 13 families had predominantly severe intellectual disability, of which five had mild ID. Seizures were reported in 10 patients from seven different families. Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype. Sources: Literature
01 Jul 2025	Hereditary Erythrocytosis v2.13	JAK2	Arina Puzriakova Tag Q1_25_ MOI was removed from gene: JAK2.
01 Jul 2025	Thrombocythaemia v1.6	SH2B3	Arina Puzriakova Tag Q2_25_ MOI was removed from gene: SH2B3.
01 Jul 2025	Haematological malignancies cancer susceptibility v4.25	SH2B3	Arina Puzriakova Tag Q2_25_ MOI was removed from gene: SH2B3.
01 Jul 2025	Hereditary Erythrocytosis v2.13	SH2B3	Achchuthan Shanmugasundram Tag Q2_25_ MOI was removed from gene: SH2B3.
30 Jun 2025	Intellectual disability v9.28	KDM5B	Arina Puzriakova commented on gene: KDM5B
30 Jun 2025	Intellectual disability v9.28	KDM5B	Arina Puzriakova Tag Q2_25_ demote_red was removed from gene: KDM5B. Tag Q2_25_ MOI tag was added to gene: KDM5B.
30 Jun 2025	Intellectual disability v9.28	KDM5B	Arina Puzriakova Tag Q2_25_ demote_amber was removed from gene: KDM5B. Tag Q2_25_ demote_red tag was added to gene: KDM5B.
30 Jun 2025	Intellectual disability v9.28	KDM5B	Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: KDM5B. Tag Q2_25_ demote_amber tag was added to gene: KDM5B. Tag Q2_25_ NHS_review tag was added to gene: KDM5B.
30 Jun 2025	Dilated and arrhythmogenic cardiomyopathy v3.1	MYLK3	Arina Puzriakova commented on gene: MYLK3: Tagged for GMS review to determine whether this gene should remain Amber or be promoted to Green. As stated by Matthew Edwards, the evidence is borderline - several unrelated cases and supportive mouse model but MOI varies, one family also had variants in another DCM gene and there are unaffected carriers. MYLK3 is green on the R135 Paediatric or syndromic cardiomyopathy panel based on the same evidence.
30 Jun 2025	Monogenic hearing loss v5.22	PLCG1	Arina Puzriakova Tag watchlist tag was added to gene: PLCG1.
30 Jun 2025	Dilated and arrhythmogenic cardiomyopathy v3.1	MYLK3	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MYLK3. Tag Q2_25_expert_review tag was added to gene: MYLK3. Tag Q2_25_ NHS_review tag was added to gene: MYLK3.
29 Jun 2025	Congenital myopathy v6.34	MT-TP	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TP.
29 Jun 2025	Congenital myopathy v6.34	MT-TE	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TE.
29 Jun 2025	Congenital myopathy v6.34	MT-TG	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TG.
29 Jun 2025	Congenital myopathy v6.34	MT-TN	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TN.
29 Jun 2025	Congenital myopathy v6.34	MT-TA	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TA.
29 Jun 2025	Congenital myopathy v6.34	MT-TW	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TW.
29 Jun 2025	Paediatric or syndromic cardiomyopathy v7.6	MT-TV	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TV.
29 Jun 2025	Hypertrophic cardiomyopathy v5.12	MT-TV	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TV.
29 Jun 2025	Monogenic hearing loss v5.22	MT-TK	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TK.
29 Jun 2025	Congenital myopathy v6.34	MT-TK	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TK.
29 Jun 2025	Optic neuropathy v5.23	MT-TK	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TK.
29 Jun 2025	Monogenic hearing loss v5.22	MT-TS2	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TS2.
29 Jun 2025	Optic neuropathy v5.23	MT-TS2	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TS2.
29 Jun 2025	Congenital myopathy v6.34	MT-TP	Achchuthan Shanmugasundram Classified gene: MT-TP as Amber List (moderate evidence)
29 Jun 2025	Congenital myopathy v6.34	MT-TP	Achchuthan Shanmugasundram Gene: mt-tp has been classified as Amber List (Moderate Evidence).
29 Jun 2025	Congenital myopathy v6.33	MT-TP	Achchuthan Shanmugasundram Phenotypes for gene: MT-TP were changed from to inborn mitochondrial myopathy, MONDO:0009637
29 Jun 2025	Congenital myopathy v6.32	MT-TP	Achchuthan Shanmugasundram Publications for gene: MT-TP were set to
29 Jun 2025	Congenital myopathy v6.31	MT-TP	Achchuthan Shanmugasundram edited their review of gene: MT-TP: Changed phenotypes to: inborn mitochondrial myopathy, MONDO:0009637
29 Jun 2025	Congenital myopathy v6.31	MT-TP	Achchuthan Shanmugasundram reviewed gene: MT-TP: Rating: AMBER; Mode of pathogenicity: None; Publications: 7689388, 32305257; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
29 Jun 2025	Congenital myopathy v6.31	MT-TA	Achchuthan Shanmugasundram changed review comment from: PMID:17825557 - One family reported with predominantly proximal myopathy, with the onset of symptoms around five years, six years and 53 years in three affected individuals. They were identified with m.5650G>A pathogenic variant in MT-TA gene. MitoPhen (https://www.mitophen.org) also reported patients from PMID:11715067 and PMID:14569122 with myopathy. PMID:11715067 - A 53 year old patient was reported with CADASIL and myopathy. He was identified with a NOTCH3 variant, responsible for CADASIL. He was also identified with m.5650G>A variant. This variant was also present to a lower extent in the unaffected sister of the patient. PMID:14569122 - A 38-year-old patient was first reported with weakness during regular exercise at 14 years of age, and then with slowly progressive proximal muscle weakness and atrophy of the lower limbs. He was also identified with the same m.5650G>A variant.; to: PMID:17825557 - One family reported with predominantly proximal myopathy, with the onset of symptoms around five years, six years and 53 years in three affected individuals. They were identified with m.5650G>A pathogenic variant in MT-TA gene. MitoPhen (https://www.mitophen.org) also reported patients from PMID:11715067 and PMID:14569122 with myopathy. PMID:11715067 - A 53 year old patient was reported with CADASIL and myopathy. He was identified with a NOTCH3 variant, responsible for CADASIL. He was also identified with m.5650G>A variant. This variant was also present to a lower extent in the unaffected sister of the patient. PMID:14569122 - A 38-year-old patient was first reported with weakness during regular exercise at 14 years of age, and then with slowly progressive proximal muscle weakness and atrophy of the lower limbs. He was also identified with the same m.5650G>A variant. In summary, there are no cases reported with onset of myopathy in infancy. However, it appears that there is one family with myopathy since early childhood. The other reported cases developed myopathy later in life.
29 Jun 2025	Congenital myopathy v6.31	MT-TA	Achchuthan Shanmugasundram Classified gene: MT-TA as Amber List (moderate evidence)
29 Jun 2025	Congenital myopathy v6.31	MT-TA	Achchuthan Shanmugasundram Gene: mt-ta has been classified as Amber List (Moderate Evidence).
29 Jun 2025	Congenital myopathy v6.30	MT-TA	Achchuthan Shanmugasundram Phenotypes for gene: MT-TA were changed from to inborn mitochondrial myopathy, MONDO:0009637
29 Jun 2025	Congenital myopathy v6.29	MT-TA	Achchuthan Shanmugasundram Publications for gene: MT-TA were set to
29 Jun 2025	Congenital myopathy v6.28	MT-TA	Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TA. Tag Q2_25_expert_review was removed from gene: MT-TA. Tag Q2_25_ NHS_review was removed from gene: MT-TA.
29 Jun 2025	Congenital myopathy v6.28	MT-TA	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TA. Tag Q2_25_expert_review tag was added to gene: MT-TA. Tag Q2_25_ NHS_review tag was added to gene: MT-TA.
29 Jun 2025	Congenital myopathy v6.28	MT-TA	Achchuthan Shanmugasundram edited their review of gene: MT-TA: Changed publications to: 11715067, 14569122, 17825557
29 Jun 2025	Congenital myopathy v6.28	MT-TA	Achchuthan Shanmugasundram changed review comment from: PMID:17825557 - One family reported with predominantly proximal myopathy, with the onset of symptoms around five years, six years and 53 years in three affected individuals. They were identified with m.5650G>A pathogenic variant in MT-TA gene. MitoPhen (https://www.mitophen.org) also reported patients from PMID:11715067 and PMID:14569122 with myopathy. PMID:11715067 - A 53 year old patient was reported with CADASIL and myopathy. He was identified with a NOTCH3 variant, responsible for CADASIL. He was also identified with m.5650G>A variant. PMID:14569122 - A 38-year-old patient was first reported with weakness during regular exercise at 14 years of age, and then with slowly progressive proximal muscle weakness and atrophy of the lower limbs. He was also identified with the same m.5650G>A variant.; to: PMID:17825557 - One family reported with predominantly proximal myopathy, with the onset of symptoms around five years, six years and 53 years in three affected individuals. They were identified with m.5650G>A pathogenic variant in MT-TA gene. MitoPhen (https://www.mitophen.org) also reported patients from PMID:11715067 and PMID:14569122 with myopathy. PMID:11715067 - A 53 year old patient was reported with CADASIL and myopathy. He was identified with a NOTCH3 variant, responsible for CADASIL. He was also identified with m.5650G>A variant. This variant was also present to a lower extent in the unaffected sister of the patient. PMID:14569122 - A 38-year-old patient was first reported with weakness during regular exercise at 14 years of age, and then with slowly progressive proximal muscle weakness and atrophy of the lower limbs. He was also identified with the same m.5650G>A variant.
29 Jun 2025	Congenital myopathy v6.28	MT-TA	Achchuthan Shanmugasundram reviewed gene: MT-TA: Rating: AMBER; Mode of pathogenicity: None; Publications: 17825557; Phenotypes: inborn mitochondrial myopathy, MONDO:0009637; Mode of inheritance: MITOCHONDRIAL
28 Jun 2025	Optic neuropathy v5.23	MT-TS2	Achchuthan Shanmugasundram Classified gene: MT-TS2 as Amber List (moderate evidence)
28 Jun 2025	Optic neuropathy v5.23	MT-TS2	Achchuthan Shanmugasundram Added comment: Comment on list classification: Katherine Schon has reviewed this gene green on this panel. However, the ophthalmological phenotypes reported in the families identified with m.12258C>A variant are retinitis pigmentosa and cataracts. Hence, expert review is sought from the Genomic Medicine Service on the rating of MT-TS2 gene on this panel.
28 Jun 2025	Optic neuropathy v5.23	MT-TS2	Achchuthan Shanmugasundram Gene: mt-ts2 has been classified as Amber List (Moderate Evidence).
28 Jun 2025	Optic neuropathy v5.22	MT-TS2	Achchuthan Shanmugasundram changed review comment from: PMIDs: 8432539;9135384;10090882 - A large Irish kindred was reported with progressive sensorineural hearing loss and retinitis pigmentosa. The patient also had optic disc pallor and progressive visual loss. They were identified with pathogenic m.12258C>A variant in MT-TS2 gene. PMID:9792552 - A 61-year-old mother and 30-year old daughter were reported with maternally inherited syndrome consisting of cerebellar ataxia, cataracts, deafness and diabetes. They were identified with m.12258C>A variant. PMID:12086967 - This study reported 28 patients that had maternally inherited diabetes with or without one or more additional features of mitochondrial disease, including bilateral sensorineural deafness and neuromuscular disease. One of these patients with additional features (cerebellar ataxia, bilateral nerve deafness and cataracts) harboured m.12258C>A variant.; to: PMIDs: 8432539;9135384;10090882 - A large Irish kindred was reported with progressive sensorineural hearing loss and retinitis pigmentosa. The patients also had optic disc pallor and progressive visual loss. They were identified with pathogenic m.12258C>A variant in MT-TS2 gene. PMID:9792552 - A 61-year-old mother and 30-year old daughter were reported with maternally inherited syndrome consisting of cerebellar ataxia, cataracts, deafness and diabetes. They were identified with m.12258C>A variant. PMID:12086967 - This study reported 28 patients that had maternally inherited diabetes with or without one or more additional features of mitochondrial disease, including bilateral sensorineural deafness and neuromuscular disease. One of these patients with additional features (cerebellar ataxia, bilateral nerve deafness and cataracts) harboured m.12258C>A variant.
28 Jun 2025	Optic neuropathy v5.22	MT-TS2	Achchuthan Shanmugasundram Publications for gene: MT-TS2 were set to
28 Jun 2025	Optic neuropathy v5.21	MT-TS2	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TS2. Tag Q2_25_expert_review tag was added to gene: MT-TS2. Tag Q2_25_ NHS_review tag was added to gene: MT-TS2.
28 Jun 2025	Optic neuropathy v5.21	MT-TS2	Achchuthan Shanmugasundram reviewed gene: MT-TS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 8432539, 9135384, 9792552, 10090882, 12086967; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
28 Jun 2025	Monogenic hearing loss v5.22	MT-TS2	Achchuthan Shanmugasundram Classified gene: MT-TS2 as Amber List (moderate evidence)
28 Jun 2025	Monogenic hearing loss v5.22	MT-TS2	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available (three unrelated families) for the association of m.12258C>A variant in MT-TS2 gene with sensorineural hearing loss. Hence, this gene can be promoted to green rating in the next GMS update.
28 Jun 2025	Monogenic hearing loss v5.22	MT-TS2	Achchuthan Shanmugasundram Gene: mt-ts2 has been classified as Amber List (Moderate Evidence).
28 Jun 2025	Monogenic hearing loss v5.21	MT-TS2	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TS2. Tag Q2_25_expert_review tag was added to gene: MT-TS2. Tag Q2_25_ NHS_review tag was added to gene: MT-TS2.
28 Jun 2025	Monogenic hearing loss v5.21	MT-TS2	Achchuthan Shanmugasundram Phenotypes for gene: MT-TS2 were changed from to Sensorineural hearing impairment, HP:0000407
28 Jun 2025	Monogenic hearing loss v5.20	MT-TS2	Achchuthan Shanmugasundram Publications for gene: MT-TS2 were set to
28 Jun 2025	Monogenic hearing loss v5.19	MT-TS2	Achchuthan Shanmugasundram edited their review of gene: MT-TS2: Changed phenotypes to: Sensorineural hearing impairment, HP:0000407
28 Jun 2025	Monogenic hearing loss v5.19	MT-TS2	Achchuthan Shanmugasundram reviewed gene: MT-TS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9792552, 10090882, 12086967; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
28 Jun 2025	Congenital myopathy v6.28	MT-TE	Achchuthan Shanmugasundram edited their review of gene: MT-TE: Changed rating: GREEN
28 Jun 2025	Congenital myopathy v6.28	MT-TE	Achchuthan Shanmugasundram Classified gene: MT-TE as Amber List (moderate evidence)
28 Jun 2025	Congenital myopathy v6.28	MT-TE	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed below, patients with MT-TE variants are reported with either congenital myopathy or adult-onset myopathy. As there are >3 unrelated cases with congenital myopathy, this gene can be considered for promotion to green rating in the next GMS update.
28 Jun 2025	Congenital myopathy v6.28	MT-TE	Achchuthan Shanmugasundram Gene: mt-te has been classified as Amber List (Moderate Evidence).
28 Jun 2025	Congenital myopathy v6.27	MT-TE	Achchuthan Shanmugasundram Phenotypes for gene: MT-TE were changed from to inborn mitochondrial myopathy, MONDO:0009637; congenital myopathy, MONDO:0019952
28 Jun 2025	Congenital myopathy v6.26	MT-TE	Achchuthan Shanmugasundram Publications for gene: MT-TE were set to
28 Jun 2025	Congenital myopathy v6.25	MT-TE	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TE. Tag Q2_25_expert_review tag was added to gene: MT-TE. Tag Q2_25_ NHS_review tag was added to gene: MT-TE.
28 Jun 2025	Congenital myopathy v6.25	MT-TE	Achchuthan Shanmugasundram edited their review of gene: MT-TE: Changed phenotypes to: inborn mitochondrial myopathy, MONDO:0009637, congenital myopathy, MONDO:0019952
28 Jun 2025	Congenital myopathy v6.25	MT-TE	Achchuthan Shanmugasundram reviewed gene: MT-TE: Rating: AMBER; Mode of pathogenicity: None; Publications: 7726155, 10392369, 15607216, 21194154; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
27 Jun 2025	Pigmentary skin disorders v4.4	BLM	Eleanor Williams Tag Q2_25_ promote_green tag was added to gene: BLM.
27 Jun 2025	Pigmentary skin disorders v4.4	BLM	Eleanor Williams Classified gene: BLM as Amber List (moderate evidence)
27 Jun 2025	Pigmentary skin disorders v4.4	BLM	Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for a green rating following NHS GMS review. After consultation with the Genomics England clinical team, their recommendation is for green as there are management implications (including avoiding exposures / ionising radiation) so the view is that is reasonable to include on this panel.
27 Jun 2025	Pigmentary skin disorders v4.4	BLM	Eleanor Williams Gene: blm has been classified as Amber List (Moderate Evidence).
27 Jun 2025	Congenital myopathy v6.25	MT-TG	Achchuthan Shanmugasundram Classified gene: MT-TG as Amber List (moderate evidence)
27 Jun 2025	Congenital myopathy v6.25	MT-TG	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients reported with m.10010T>C variant and with myopathy as part of the presenting phenotype. Hence, this gene is rated amber.
27 Jun 2025	Congenital myopathy v6.25	MT-TG	Achchuthan Shanmugasundram Gene: mt-tg has been classified as Amber List (Moderate Evidence).
27 Jun 2025	Congenital myopathy v6.24	MT-TG	Achchuthan Shanmugasundram Phenotypes for gene: MT-TG were changed from to mitochondrial encephalomyopathy, MONDO:0004675
27 Jun 2025	Congenital myopathy v6.23	MT-TG	Achchuthan Shanmugasundram Publications for gene: MT-TG were set to
27 Jun 2025	Congenital myopathy v6.22	MT-TG	Achchuthan Shanmugasundram reviewed gene: MT-TG: Rating: AMBER; Mode of pathogenicity: None; Publications: 11971101, 16120360; Phenotypes: mitochondrial encephalomyopathy, MONDO:0004675; Mode of inheritance: MITOCHONDRIAL
27 Jun 2025	Congenital myopathy v6.22	MT-TN	Achchuthan Shanmugasundram Classified gene: MT-TN as Amber List (moderate evidence)
27 Jun 2025	Congenital myopathy v6.22	MT-TN	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, pathogenic variants in MT-TN have been reported to cause mitochondrial myopathy. However, there is no clear evidence to suggest that the reported patients had onset of myopathy during infancy/ early childhood. Hence, expert review is sought on whether this gene can be promoted to green rating in the next GMS update.
27 Jun 2025	Congenital myopathy v6.22	MT-TN	Achchuthan Shanmugasundram Gene: mt-tn has been classified as Amber List (Moderate Evidence).
27 Jun 2025	Congenital myopathy v6.21	MT-TN	Achchuthan Shanmugasundram Phenotypes for gene: MT-TN were changed from to inborn mitochondrial myopathy, MONDO:0009637
27 Jun 2025	Congenital myopathy v6.20	MT-TN	Achchuthan Shanmugasundram Publications for gene: MT-TN were set to
27 Jun 2025	Congenital myopathy v6.19	MT-TN	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TN. Tag Q2_25_expert_review tag was added to gene: MT-TN. Tag Q2_25_ NHS_review tag was added to gene: MT-TN.
27 Jun 2025	Congenital myopathy v6.19	MT-TN	Achchuthan Shanmugasundram edited their review of gene: MT-TN: Changed publications to: 8254046, 16908752, 23696415, 31026515
27 Jun 2025	Congenital myopathy v6.19	MT-TN	Achchuthan Shanmugasundram changed review comment from: PMID:8254046 - Two patients were reported with identification of pathogenic variants in two different mitochondrial tRNA genes. One of them had m.5703G>A variant in MT-TN gene and it was associated with isolated ophthalmoplegia. Electromyography tests taken at 27 years of age were compatible with myopathy. However, the actual age of onset of myopathy was not reported. PMID:16908752 - A 13-year-old male patient with multi organ failure was identified with m.5728C>T variant in MT-TN gene. The patient had initial symptoms since 2 years of age and muscle weakness was first reported at 10 years. PMID:23696415 - This study identified nine different mt-tRNA variants in nine families, of which one was m.5690A>G variant from MT-TN gene. The patient had the onset of disease at 13 years and presented with chronic progressive external ophthalmoplegia (CPEO), ptosis and proximal myopathy. PMID:31026515 - A nine-year old female was identified with m.5728C>T variant and has a milder clinical phenotype with isolated ptosis and ophthalmoplegia. She She was reported to have the onset of ptosis at around 8 years of age.; to: PMID:8254046 - Two patients were reported with identification of pathogenic variants in two different mitochondrial tRNA genes. One of them had m.5703G>A variant in MT-TN gene and it was associated with isolated ophthalmoplegia. Electromyography tests taken at 27 years of age were compatible with myopathy. However, the actual age of onset of myopathy was not reported. PMID:16908752 - A 13-year-old male patient with multi organ failure was identified with m.5728C>T variant in MT-TN gene. The patient had initial symptoms since 2 years of age and muscle weakness was first reported at 10 years. PMID:23696415 - This study identified nine different mt-tRNA variants in nine families, of which one was m.5690A>G variant from MT-TN gene. The patient had the onset of disease at 13 years and presented with chronic progressive external ophthalmoplegia (CPEO), ptosis and proximal myopathy. PMID:31026515 - A nine-year old female was identified with m.5728C>T variant and has a milder clinical phenotype with isolated ptosis and ophthalmoplegia. She was reported to have the onset of ptosis at around 8 years of age.
27 Jun 2025	Congenital myopathy v6.19	MT-TN	Achchuthan Shanmugasundram reviewed gene: MT-TN: Rating: GREEN; Mode of pathogenicity: None; Publications: 8254046, 16908752, 23696415; Phenotypes: inborn mitochondrial myopathy, MONDO:0009637; Mode of inheritance: MITOCHONDRIAL
27 Jun 2025	Congenital myopathy v6.19	MT-TW	Achchuthan Shanmugasundram Classified gene: MT-TW as Amber List (moderate evidence)
27 Jun 2025	Congenital myopathy v6.19	MT-TW	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, myopathy has been reported in patients with m.5521G>A variant in MT-TW. However, there is no clear evidence for the onset of myopathy in infancy or early childhood. Hence, expert review is being sought on whether to promote this gene to green rating on this panel.
27 Jun 2025	Congenital myopathy v6.19	MT-TW	Achchuthan Shanmugasundram Gene: mt-tw has been classified as Amber List (Moderate Evidence).
27 Jun 2025	Congenital myopathy v6.18	MT-TW	Achchuthan Shanmugasundram Phenotypes for gene: MT-TW were changed from to inborn mitochondrial myopathy, MONDO:0009637
27 Jun 2025	Congenital myopathy v6.17	MT-TW	Achchuthan Shanmugasundram Publications for gene: MT-TW were set to
27 Jun 2025	Congenital myopathy v6.16	MT-TW	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TW. Tag Q2_25_expert_review tag was added to gene: MT-TW. Tag Q2_25_ NHS_review tag was added to gene: MT-TW.
27 Jun 2025	Congenital myopathy v6.16	MT-TW	Achchuthan Shanmugasundram edited their review of gene: MT-TW: Changed publications to: 9673981, 20360171, 23841600; Changed phenotypes to: inborn mitochondrial myopathy, MONDO:0009637
27 Jun 2025	Congenital myopathy v6.16	MT-TW	Achchuthan Shanmugasundram changed review comment from: PMID:9673981 - The m.5521G>A variant in MT-TW gene was identified in a patient with late-onset mitochondrial myopathy. PMID:23841600 - Three Tunisian patients were reported with mitochondrial myopathy. One of these patients was detected with m.5521G>A variant in MT-TW and with m.8682A>G variant in MT-ATP6 gene.; to: PMID:9673981 - The m.5521G>A variant in MT-TW gene was identified in a patient with late-onset mitochondrial myopathy. PMID:20360171 - A female patient was reported with m.5521G>A variant, who initially developed sensorineural hearing loss at 24 years of age. She was diagnosed with overlapped MERRF/ MELAS phenotype. PMID:23841600 - Three Tunisian patients were reported with mitochondrial myopathy. One of these patients was detected with m.5521G>A variant in MT-TW and with m.8682A>G variant in MT-ATP6 gene. This patient had the onset of the disorder at 11 months of age with neurodevelopmental and psychomotor delay, mental retardation, axial hypotonia, paraplegia, seizures and lactic acidosis. It is not clear when this patient started showing myopathic features.
27 Jun 2025	Congenital myopathy v6.16	MT-TW	Achchuthan Shanmugasundram reviewed gene: MT-TW: Rating: AMBER; Mode of pathogenicity: None; Publications: 9673981, 23841600; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
27 Jun 2025	Monogenic hearing loss v5.19	MT-CO1	Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: MT-CO1. Tag Q2_25_ NHS_review tag was added to gene: MT-CO1.
27 Jun 2025	Monogenic hearing loss v5.19	MT-CO1	Achchuthan Shanmugasundram Classified gene: MT-CO1 as Amber List (moderate evidence)
27 Jun 2025	Monogenic hearing loss v5.19	MT-CO1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon and Sarah Leigh, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
27 Jun 2025	Monogenic hearing loss v5.19	MT-CO1	Achchuthan Shanmugasundram Gene: mt-co1 has been classified as Amber List (Moderate Evidence).
27 Jun 2025	Monogenic hearing loss v5.18	MT-CO1	Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: MT-CO1.
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.6	MT-TV	Achchuthan Shanmugasundram Classified gene: MT-TV as Amber List (moderate evidence)
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.6	MT-TV	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in at least three unrelated patients with variants in MT-TV gene. This gene can therefore be promoted to green rating on the next GMS update.
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.6	MT-TV	Achchuthan Shanmugasundram Gene: mt-tv has been classified as Amber List (Moderate Evidence).
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.5	MT-TV	Achchuthan Shanmugasundram Deleted their comment
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.5	MT-TV	Achchuthan Shanmugasundram edited their review of gene: MT-TV: Changed rating: GREEN
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.5	MT-TV	Achchuthan Shanmugasundram Tag Q2_25_ NHS_review was removed from gene: MT-TV.
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.5	MT-TV	Achchuthan Shanmugasundram Tag Q2_25_expert_review was removed from gene: MT-TV.
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.5	MT-TV	Achchuthan Shanmugasundram Entity copied from Hypertrophic cardiomyopathy v5.12
27 Jun 2025	Paediatric or syndromic cardiomyopathy v7.5	MT-TV	Achchuthan Shanmugasundram gene: MT-TV was added gene: MT-TV was added to Paediatric or syndromic cardiomyopathy. Sources: Literature,Expert Review Amber Q2_25_ promote_green, Q2_25_expert_review, Q2_25_ NHS_review tags were added to gene: MT-TV. Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL Publications for gene: MT-TV were set to 15320572; 21986556; 34298071 Phenotypes for gene: MT-TV were set to MELAS syndrome, MONDO:0010789; hypertrophic cardiomyopathy, MONDO:000504 Mode of pathogenicity for gene: MT-TV was set to Other
27 Jun 2025	Hypertrophic cardiomyopathy v5.12	MT-TV	Achchuthan Shanmugasundram Classified gene: MT-TV as Amber List (moderate evidence)
27 Jun 2025	Hypertrophic cardiomyopathy v5.12	MT-TV	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least three unrelated cases reported with MT-TV variants and with hypertrophic cardiomyopathy. However, HCM is part of a syndromic phenotype. R131 is only intended for genes associated with isolated HCM and not for syndromic genes. Hence, expert review is sought on whether this gene can be promoted to green rating on this panel. This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
27 Jun 2025	Hypertrophic cardiomyopathy v5.12	MT-TV	Achchuthan Shanmugasundram Gene: mt-tv has been classified as Amber List (Moderate Evidence).
27 Jun 2025	Hypertrophic cardiomyopathy v5.11	MT-TV	Achchuthan Shanmugasundram Phenotypes for gene: MT-TV were changed from to MELAS syndrome, MONDO:0010789; hypertrophic cardiomyopathy, MONDO:000504
27 Jun 2025	Hypertrophic cardiomyopathy v5.10	MT-TV	Achchuthan Shanmugasundram Publications for gene: MT-TV were set to
27 Jun 2025	Hypertrophic cardiomyopathy v5.9	MT-TV	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TV. Tag Q2_25_expert_review tag was added to gene: MT-TV. Tag Q2_25_ NHS_review tag was added to gene: MT-TV.
27 Jun 2025	Hypertrophic cardiomyopathy v5.9	MT-TV	Achchuthan Shanmugasundram reviewed gene: MT-TV: Rating: AMBER; Mode of pathogenicity: None; Publications: 15320572, 21986556, 34298071; Phenotypes: MELAS syndrome, MONDO:0010789, hypertrophic cardiomyopathy, MONDO:0005045; Mode of inheritance: MITOCHONDRIAL
27 Jun 2025	Congenital myopathy v6.16	MT-TK	Achchuthan Shanmugasundram Classified gene: MT-TK as Amber List (moderate evidence)
27 Jun 2025	Congenital myopathy v6.16	MT-TK	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, myopathy is one of the clinical presentations of MERFF syndrome caused by m.8344A>G variant in MT-TK gene. However, it should be noted that the onset of myopathic features is not during infancy or first few years of life in the reported patients. Hence, expert review is sought from the Genomic Medicine Service on upgrading this gene to green rating on this panel.
27 Jun 2025	Congenital myopathy v6.16	MT-TK	Achchuthan Shanmugasundram Gene: mt-tk has been classified as Amber List (Moderate Evidence).
27 Jun 2025	Rare genetic inflammatory skin disorders v4.1	FLG	Ronnie Wright reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:16444271; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
27 Jun 2025	Congenital myopathy v6.15	MT-TK	Achchuthan Shanmugasundram Publications for gene: MT-TK were set to
27 Jun 2025	Congenital myopathy v6.14	MT-TK	Achchuthan Shanmugasundram Phenotypes for gene: MT-TK were changed from to MERRF syndrome, MONDO:0010790; inborn mitochondrial myopathy, MONDO:0009637
27 Jun 2025	Congenital myopathy v6.13	MT-TK	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TK. Tag Q2_25_expert_review tag was added to gene: MT-TK. Tag Q2_25_ NHS_review tag was added to gene: MT-TK.
27 Jun 2025	Congenital myopathy v6.13	MT-TK	Achchuthan Shanmugasundram reviewed gene: MT-TK: Rating: AMBER; Mode of pathogenicity: None; Publications: 1463006, 8228033; Phenotypes: MERRF syndrome, MONDO:0010790, inborn mitochondrial myopathy, MONDO:0009637; Mode of inheritance: MITOCHONDRIAL
26 Jun 2025	Monogenic hearing loss v5.18	MT-TK	Achchuthan Shanmugasundram Classified gene: MT-TK as Amber List (moderate evidence)
26 Jun 2025	Monogenic hearing loss v5.18	MT-TK	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of variants in MT-TK gene with sensorineural hearing loss. Hence, this gene can be promoted to green rating in the next GMS update.
26 Jun 2025	Monogenic hearing loss v5.18	MT-TK	Achchuthan Shanmugasundram Gene: mt-tk has been classified as Amber List (Moderate Evidence).
26 Jun 2025	Monogenic hearing loss v5.17	MT-TK	Achchuthan Shanmugasundram Publications for gene: MT-TK were set to 8651277; 1899320; 23224446
26 Jun 2025	Monogenic hearing loss v5.16	MT-TK	Achchuthan Shanmugasundram Phenotypes for gene: MT-TK were changed from to MERRF syndrome, MONDO:0010790; Sensorineural hearing impairment, HP:0000407
26 Jun 2025	Monogenic hearing loss v5.16	MT-TK	Achchuthan Shanmugasundram Publications for gene: MT-TK were set to
26 Jun 2025	Monogenic hearing loss v5.15	MT-TK	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TK. Tag Q2_25_expert_review tag was added to gene: MT-TK. Tag Q2_25_ NHS_review tag was added to gene: MT-TK.
26 Jun 2025	Monogenic hearing loss v5.15	MT-TK	Achchuthan Shanmugasundram edited their review of gene: MT-TK: Changed phenotypes to: MERRF syndrome, MONDO:0010790, Sensorineural hearing impairment, HP:0000407
26 Jun 2025	Monogenic hearing loss v5.15	MT-TK	Achchuthan Shanmugasundram reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8651277, 1899320, 23224446; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
26 Jun 2025	Optic neuropathy v5.21	MT-TK	Achchuthan Shanmugasundram Classified gene: MT-TK as Amber List (moderate evidence)
26 Jun 2025	Optic neuropathy v5.21	MT-TK	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.8344A>G variant in MT-TK gene with optic atrophy. Hence, this gene can be promoted to green rating in the next GMS update.
26 Jun 2025	Optic neuropathy v5.21	MT-TK	Achchuthan Shanmugasundram Gene: mt-tk has been classified as Amber List (Moderate Evidence).
26 Jun 2025	Optic neuropathy v5.20	MT-TK	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TK. Tag Q2_25_expert_review tag was added to gene: MT-TK. Tag Q2_25_ NHS_review tag was added to gene: MT-TK.
26 Jun 2025	Optic neuropathy v5.20	MT-TK	Achchuthan Shanmugasundram Phenotypes for gene: MT-TK were changed from to MERRF syndrome, MONDO:0010790; optic atrophy, MONDO:0003608
26 Jun 2025	Optic neuropathy v5.19	MT-TK	Achchuthan Shanmugasundram Publications for gene: MT-TK were set to
26 Jun 2025	Optic neuropathy v5.18	MT-TK	Achchuthan Shanmugasundram reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: None; Publications: 1463006, 8228033, 33766967; Phenotypes: MERRF syndrome, MONDO:0010790, optic atrophy, MONDO:0003608; Mode of inheritance: MITOCHONDRIAL
26 Jun 2025	Pulmonary fibrosis familial v1.7	MUC5B	Matthew Edwards reviewed gene: MUC5B: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Risk allele for Pulmonary Fibrosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.4	MT-ND5	Achchuthan Shanmugasundram Classified gene: MT-ND5 as Amber List (moderate evidence)
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.4	MT-ND5	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with variants in MT-ND5 gene. This gene can therefore be promoted to green rating on the next GMS update.
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.4	MT-ND5	Achchuthan Shanmugasundram Gene: mt-nd5 has been classified as Amber List (Moderate Evidence).
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.3	MT-ND5	Achchuthan Shanmugasundram Tag Q2_25_ NHS_review was removed from gene: MT-ND5.
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.3	MT-ND5	Achchuthan Shanmugasundram edited their review of gene: MT-ND5: Changed rating: GREEN
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.3	MT-ND5	Achchuthan Shanmugasundram Deleted their comment
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.3	MT-ND5	Achchuthan Shanmugasundram Tag Q2_25_expert_review was removed from gene: MT-ND5.
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.3	MT-ND5	Achchuthan Shanmugasundram Entity copied from Hypertrophic cardiomyopathy v5.9
25 Jun 2025	Paediatric or syndromic cardiomyopathy v7.3	MT-ND5	Achchuthan Shanmugasundram gene: MT-ND5 was added gene: MT-ND5 was added to Paediatric or syndromic cardiomyopathy. Sources: Expert Review Amber,Literature Q2_25_ promote_green, Q2_25_expert_review, Q2_25_ NHS_review tags were added to gene: MT-ND5. Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL Publications for gene: MT-ND5 were set to 14520659; 22759514; 23847141; 30587702 Phenotypes for gene: MT-ND5 were set to hypertrophic cardiomyopathy, MONDO:0005045
25 Jun 2025	Hypertrophic cardiomyopathy v5.9	MT-ND5	Achchuthan Shanmugasundram Classified gene: MT-ND5 as Amber List (moderate evidence)
25 Jun 2025	Hypertrophic cardiomyopathy v5.9	MT-ND5	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with variants in MT-ND5. The only case of isolated HCM was the family reported in PMID:22759514. However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, expert review from the NHS Genomic Medicine Service is sought with regard to rating this gene green on this panel. This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
25 Jun 2025	Hypertrophic cardiomyopathy v5.9	MT-ND5	Achchuthan Shanmugasundram Gene: mt-nd5 has been classified as Amber List (Moderate Evidence).
25 Jun 2025	Hypertrophic cardiomyopathy v5.8	MT-ND5	Achchuthan Shanmugasundram Phenotypes for gene: MT-ND5 were changed from to hypertrophic cardiomyopathy, MONDO:0005045
25 Jun 2025	Hypertrophic cardiomyopathy v5.7	MT-ND5	Achchuthan Shanmugasundram Publications for gene: MT-ND5 were set to
25 Jun 2025	Hypertrophic cardiomyopathy v5.6	MT-ND5	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND5. Tag Q2_25_expert_review tag was added to gene: MT-ND5. Tag Q2_25_ NHS_review tag was added to gene: MT-ND5.
25 Jun 2025	Hypertrophic cardiomyopathy v5.6	MT-ND5	Achchuthan Shanmugasundram edited their review of gene: MT-ND5: Changed rating: AMBER
25 Jun 2025	Hypertrophic cardiomyopathy v5.6	MT-ND5	Achchuthan Shanmugasundram reviewed gene: MT-ND5: Rating: GREEN; Mode of pathogenicity: None; Publications: 14520659, 22759514, 23847141, 30587702; Phenotypes: hypertrophic cardiomyopathy, MONDO:0005045; Mode of inheritance: MITOCHONDRIAL
25 Jun 2025	Optic neuropathy v5.18	MT-ND5	Achchuthan Shanmugasundram Classified gene: MT-ND5 as Amber List (moderate evidence)
25 Jun 2025	Optic neuropathy v5.18	MT-ND5	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of MT-ND5 gene with LHON. Hence, this gene can be promoted to green rating in the next GMS update.
25 Jun 2025	Optic neuropathy v5.18	MT-ND5	Achchuthan Shanmugasundram Gene: mt-nd5 has been classified as Amber List (Moderate Evidence).
25 Jun 2025	Optic neuropathy v5.17	MT-ND5	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND5. Tag Q2_25_expert_review tag was added to gene: MT-ND5. Tag Q2_25_ NHS_review tag was added to gene: MT-ND5.
25 Jun 2025	Optic neuropathy v5.17	MT-ND5	Achchuthan Shanmugasundram Phenotypes for gene: MT-ND5 were changed from to Leber hereditary optic neuropathy, MONDO:0010788
25 Jun 2025	Optic neuropathy v5.16	MT-ND5	Achchuthan Shanmugasundram Publications for gene: MT-ND5 were set to
25 Jun 2025	Optic neuropathy v5.15	MT-ND5	Achchuthan Shanmugasundram reviewed gene: MT-ND5: Rating: GREEN; Mode of pathogenicity: None; Publications: 12509858, 12736867, 27164671, 38357617; Phenotypes: Leber hereditary optic neuropathy, MONDO:0010788; Mode of inheritance: MITOCHONDRIAL
25 Jun 2025	Optic neuropathy v5.15	MT-ND4L	Achchuthan Shanmugasundram Classified gene: MT-ND4L as Amber List (moderate evidence)
25 Jun 2025	Optic neuropathy v5.15	MT-ND4L	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.10663T>C variant from MT-ND4L gene with LHON. Hence, this gene can be promoted to green rating in the next GMS update.
25 Jun 2025	Optic neuropathy v5.15	MT-ND4L	Achchuthan Shanmugasundram Gene: mt-nd4l has been classified as Amber List (Moderate Evidence).
25 Jun 2025	Optic neuropathy v5.14	MT-ND4L	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND4L. Tag Q2_25_expert_review tag was added to gene: MT-ND4L. Tag Q2_25_ NHS_review tag was added to gene: MT-ND4L.
25 Jun 2025	Optic neuropathy v5.14	MT-ND4L	Achchuthan Shanmugasundram Phenotypes for gene: MT-ND4L were changed from to Leber hereditary optic neuropathy, MONDO:0010788
25 Jun 2025	Optic neuropathy v5.13	MT-ND4L	Achchuthan Shanmugasundram Publications for gene: MT-ND4L were set to
25 Jun 2025	Optic neuropathy v5.12	MT-ND4L	Achchuthan Shanmugasundram edited their review of gene: MT-ND4L: Changed phenotypes to: Leber hereditary optic neuropathy, MONDO:0010788
25 Jun 2025	Optic neuropathy v5.12	MT-ND4L	Achchuthan Shanmugasundram reviewed gene: MT-ND4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 11935318, 22879922, 29210930, 36381806; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
25 Jun 2025	Optic neuropathy v5.12	MT-ND3	Achchuthan Shanmugasundram Classified gene: MT-ND3 as Amber List (moderate evidence)
25 Jun 2025	Optic neuropathy v5.12	MT-ND3	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.10197G>A variant from MT-ND3 gene with LHON/ LDYT. Hence, this gene can be promoted to green rating in the next GMS update.
25 Jun 2025	Optic neuropathy v5.12	MT-ND3	Achchuthan Shanmugasundram Gene: mt-nd3 has been classified as Amber List (Moderate Evidence).
25 Jun 2025	Optic neuropathy v5.11	MT-ND3	Achchuthan Shanmugasundram Phenotypes for gene: MT-ND3 were changed from to Leber hereditary optic neuropathy, MONDO:0010788; Leber optic atrophy and dystonia, MONDO:0010772
25 Jun 2025	Optic neuropathy v5.10	MT-ND3	Achchuthan Shanmugasundram edited their review of gene: MT-ND3: Changed phenotypes to: Leber hereditary optic neuropathy, MONDO:0010788, Leber optic atrophy and dystonia, MONDO:0010772
25 Jun 2025	Optic neuropathy v5.10	MT-ND2	Achchuthan Shanmugasundram Publications for gene: MT-ND2 were set to
25 Jun 2025	Optic neuropathy v5.9	MT-ND2	Achchuthan Shanmugasundram Phenotypes for gene: MT-ND2 were changed from to Leber hereditary optic neuropathy, MONDO:0010788
25 Jun 2025	Optic neuropathy v5.8	MT-ND3	Achchuthan Shanmugasundram Publications for gene: MT-ND3 were set to
25 Jun 2025	Optic neuropathy v5.7	MT-ND3	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND3. Tag Q2_25_expert_review tag was added to gene: MT-ND3. Tag Q2_25_ NHS_review tag was added to gene: MT-ND3.
25 Jun 2025	Optic neuropathy v5.7	MT-ND3	Achchuthan Shanmugasundram changed review comment from: PMID:19458970 - Leber hereditary optic neuropathy and dystonia (LDYT) was reported in 18 patients from a Chinese family. They were identified with m.10197G>A variant (p.Ala47Thr). PMID:30199507 - A mother and daughter were reported with Leber hereditary optic neuropathy (LHON) and were identified with m.10197G>A variant. PMID:39923090 - A patient was reported with adult-onset Leigh syndrome (LS) and Leber hereditary optic neuropathy and dystonia (LDYT) and was identified with m.10197G>A variant. His mother also developed vision disturbance, epilepsy, and abnormal gait in her second decade and harboured the same variant.; to: PMID:19458970 - Leber hereditary optic neuropathy and dystonia (LDYT) was reported in 18 patients from a Chinese family. They were identified with m.10197G>A variant (p.Ala47Thr). PMID:30199507 - A mother and daughter were reported with Leber hereditary optic neuropathy (LHON) and were identified with m.10197G>A variant. PMID:39923090 - A patient was reported with adult-onset Leigh syndrome (LS) and Leber hereditary optic neuropathy and dystonia (LDYT) and was identified with m.10197G>A variant. His mother also developed vision disturbance, epilepsy, and abnormal gait in her second decade and harboured the same variant. This publication also reviewed previously published cases, and reported a total of 84 participants (78 patients and 6 asymptomatic carriers) harbouring the m.10197G>A variant. LHON and LDYT were reported in 18 and six patients each.
25 Jun 2025	Optic neuropathy v5.7	MT-ND3	Achchuthan Shanmugasundram reviewed gene: MT-ND3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19458970, 30199507, 39923090; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
25 Jun 2025	Optic neuropathy v5.7	MT-ND2	Achchuthan Shanmugasundram Classified gene: MT-ND2 as Amber List (moderate evidence)
25 Jun 2025	Optic neuropathy v5.7	MT-ND2	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has been reviewed green by Katherine Schon on this panel. Expert review from the Genomic Medicine Service is being sought on the inclusion of this gene with green rating on this panel.
25 Jun 2025	Optic neuropathy v5.7	MT-ND2	Achchuthan Shanmugasundram Gene: mt-nd2 has been classified as Amber List (Moderate Evidence).
25 Jun 2025	Optic neuropathy v5.6	MT-ND2	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-ND2. Tag Q2_25_expert_review tag was added to gene: MT-ND2. Tag Q2_25_ NHS_review tag was added to gene: MT-ND2.
25 Jun 2025	Optic neuropathy v5.6	MT-ND2	Achchuthan Shanmugasundram reviewed gene: MT-ND2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8680405, 11479733, 21145289, 20454697; Phenotypes: Leber hereditary optic neuropathy, MONDO:0010788; Mode of inheritance: MITOCHONDRIAL
25 Jun 2025	Congenital myopathy v6.13	MT-TL1	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As the myopathy phenotype has predominantly been reported to be relatively late-onset, expert review is sought from the Genomic Medicine Service on promotion of this gene to green rating.; to: Comment on list classification: As the myopathy phenotype has predominantly been reported to be relatively late-onset, expert review is sought from the Genomic Medicine Service on promotion of this gene to green rating on this panel.
25 Jun 2025	Congenital myopathy v6.13	MT-TL1	Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
25 Jun 2025	Congenital myopathy v6.13	MT-TL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As the myopathy phenotype has predominantly been reported to be relatively late-onset, expert review is sought from the Genomic Medicine Service on promotion of this gene to green rating.
25 Jun 2025	Congenital myopathy v6.13	MT-TL1	Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
25 Jun 2025	Congenital myopathy v6.12	MT-TL1	Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from MELAS syndrome, MONDO:0010789 to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; inborn mitochondrial myopathy, MONDO:0009637
25 Jun 2025	Congenital myopathy v6.11	MT-TL1	Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
25 Jun 2025	Congenital myopathy v6.10	MT-TL1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1. Tag Q2_25_expert_review tag was added to gene: MT-TL1. Tag Q2_25_ NHS_review tag was added to gene: MT-TL1.
25 Jun 2025	Congenital myopathy v6.10	MT-TL1	Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 8122892, 8559168, 18391161; Phenotypes: MELAS syndrome caused by mutation in MTTL1, MONDO:0800032, inborn mitochondrial myopathy, MONDO:0009637; Mode of inheritance: MITOCHONDRIAL
25 Jun 2025	Hypertrophic cardiomyopathy v5.6	MT-TL1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1. Tag Q2_25_expert_review tag was added to gene: MT-TL1. Tag Q2_25_ NHS_review tag was added to gene: MT-TL1.
25 Jun 2025	Hypertrophic cardiomyopathy v5.6	MT-TL1	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant. However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, expert review from the NHS Genomic Medicine Service is sought with regard to rating this gene green on this panel. This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.; to: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant. However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, expert review from the NHS Genomic Medicine Service is sought with regard to rating this gene green on this panel. This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
25 Jun 2025	Hypertrophic cardiomyopathy v5.6	MT-TL1	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant. However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, the rating should remain amber on this panel. This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.; to: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant. However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, expert review from the NHS Genomic Medicine Service is sought with regard to rating this gene green on this panel. This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
24 Jun 2025	Monogenic hearing loss v5.15	MT-TL1	Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
24 Jun 2025	Monogenic hearing loss v5.15	MT-TL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.3243A>G variant with sensorineural hearing loss. Hence, this gene can be promoted to green rating in the next GMS update.
24 Jun 2025	Monogenic hearing loss v5.15	MT-TL1	Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
24 Jun 2025	Monogenic hearing loss v5.14	MT-TL1	Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; maternally-inherited diabetes and deafness, MONDO:0010785; Sensorineural hearing impairment, HP:0000407 to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; maternally-inherited diabetes and deafness, MONDO:0010785; Sensorineural hearing impairment, HP:0000407
24 Jun 2025	Monogenic hearing loss v5.13	MT-TL1	Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; maternally-inherited diabetes and deafness, MONDO:0010785; Sensorineural hearing impairment, HP:0000407
24 Jun 2025	Monogenic hearing loss v5.12	MT-TL1	Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
24 Jun 2025	Monogenic hearing loss v5.11	MT-TL1	Achchuthan Shanmugasundram Mode of inheritance for gene: MT-TL1 was changed from to MITOCHONDRIAL
24 Jun 2025	Monogenic hearing loss v5.10	MT-TL1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1. Tag Q2_25_expert_review tag was added to gene: MT-TL1. Tag Q2_25_ NHS_review tag was added to gene: MT-TL1.
24 Jun 2025	Monogenic hearing loss v5.10	MT-TL1	Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22403016, 23355809, 35455034; Phenotypes: MELAS syndrome caused by mutation in MTTL1, MONDO:0800032, maternally-inherited diabetes and deafness, MONDO:0010785, Sensorineural hearing impairment, HP:0000407; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Paediatric or syndromic cardiomyopathy v7.2	MT-TL1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1.
24 Jun 2025	Paediatric or syndromic cardiomyopathy v7.2	MT-TL1	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant. However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, the rating should remain amber on this panel. This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.; to: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant. This gene can therefore be promoted to green rating on the next GMS update.
24 Jun 2025	Paediatric or syndromic cardiomyopathy v7.2	MT-TL1	Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Changed rating: GREEN
24 Jun 2025	Paediatric or syndromic cardiomyopathy v7.2	MT-TL1	Achchuthan Shanmugasundram Entity copied from Hypertrophic cardiomyopathy v5.6
24 Jun 2025	Paediatric or syndromic cardiomyopathy v7.2	MT-TL1	Achchuthan Shanmugasundram gene: MT-TL1 was added gene: MT-TL1 was added to Paediatric or syndromic cardiomyopathy. Sources: South West GLH,Expert Review,Expert Review Amber locus-type-rna-transfer tags were added to gene: MT-TL1. Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL Publications for gene: MT-TL1 were set to 7473662; 8477849; 12874464; 14673589; 25639022; 30888501; 30133155 Phenotypes for gene: MT-TL1 were set to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; hypertrophic cardiomyopathy, MONDO:0005045
24 Jun 2025	Hypertrophic cardiomyopathy v5.6	MT-TL1	Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; hypertrophic cardiomyopathy, MONDO:0005045
24 Jun 2025	Hypertrophic cardiomyopathy v5.5	MT-TL1	Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
24 Jun 2025	Hypertrophic cardiomyopathy v5.4	MT-TL1	Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
24 Jun 2025	Hypertrophic cardiomyopathy v5.4	MT-TL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant. However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, the rating should remain amber on this panel. This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
24 Jun 2025	Hypertrophic cardiomyopathy v5.4	MT-TL1	Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
24 Jun 2025	Optic neuropathy v5.6	MT-TL1	Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TL1.
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TL1	Achchuthan Shanmugasundram changed review comment from: PMID:7473662 - The m.3243 A > G variant segregated with maternally inherited diabetes mellitus, sensorineural deafness, hypertrophic cardiomyopathy (HCM), or renal failure in a large pedigree of 35 affected members across four generations. PMID:8477849 - The m.3243 A > G variant was identified in a family suffering from a syndrome with diabetes, deafness and HCMN as main clinical features. PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had HCM as one of the clinical manifestations. PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM. PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations. PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each. PMID:30133155 - Nine unrelated patients were reported with m.3243 A > G variant, of which only three patients met the criteria for MELAS syndrome. HCM was reported in eight of these patients moderate to severe regurgitation of various valves. Electrocardiography (ECG) showed preexcitation pattern with short PR intervals and delta waves (Wolff‐Parkinson‐White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient. ; to: As per https://www.mitophen.org, there are more than ten different patients reported in peer-reviewed scientific literature with m.3243A>G variant and with hypertrophic cardiomyopathy (HCM) as one of the presenting phenotypes PMID:7473662 - The m.3243 A > G variant segregated with maternally inherited diabetes mellitus, sensorineural deafness, HCM, or renal failure in a large pedigree of 35 affected members across four generations. PMID:8477849 - The m.3243 A > G variant was identified in a family suffering from a syndrome with diabetes, deafness and HCMN as main clinical features. PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had HCM as one of the clinical manifestations. PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM. PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations. PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each. PMID:30133155 - Nine unrelated patients were reported with m.3243 A > G variant, of which only three patients met the criteria for MELAS syndrome. HCM was reported in eight of these patients moderate to severe regurgitation of various valves. Electrocardiography (ECG) showed preexcitation pattern with short PR intervals and delta waves (Wolff‐Parkinson‐White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient.
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TL1	Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Changed publications to: 7473662, 8477849, 12874464, 14673589, 25639022, 30888501, 30133155; Changed phenotypes to: MELAS syndrome caused by mutation in MTTL1, MONDO:0800032, hypertrophic cardiomyopathy, MONDO:0005045
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TL1	Achchuthan Shanmugasundram changed review comment from: PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had hypertrophic cardiomyopathy (HCM) as one of the clinical manifestations. PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM. PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations. PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each.; to: PMID:7473662 - The m.3243 A > G variant segregated with maternally inherited diabetes mellitus, sensorineural deafness, hypertrophic cardiomyopathy (HCM), or renal failure in a large pedigree of 35 affected members across four generations. PMID:8477849 - The m.3243 A > G variant was identified in a family suffering from a syndrome with diabetes, deafness and HCMN as main clinical features. PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had HCM as one of the clinical manifestations. PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM. PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations. PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each. PMID:30133155 - Nine unrelated patients were reported with m.3243 A > G variant, of which only three patients met the criteria for MELAS syndrome. HCM was reported in eight of these patients moderate to severe regurgitation of various valves. Electrocardiography (ECG) showed preexcitation pattern with short PR intervals and delta waves (Wolff‐Parkinson‐White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient.
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TL1	Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Changed publications to: 7473662, 12874464, 14673589, 25639022, 30888501
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TL1	Achchuthan Shanmugasundram changed review comment from: PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had hypertrophic cardiomyopathy as one of the clinical manifestations. PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and hypertrophic cardiomyopathy. PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with hypertrophic cardiomyopathy among several clinical manifestations.; to: PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had hypertrophic cardiomyopathy (HCM) as one of the clinical manifestations. PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM. PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations. PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each.
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TL1	Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Changed publications to: 12874464, 14673589, 25639022, 30888501
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TL1	Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 12874464, 14673589, 25639022; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Optic neuropathy v5.6	MT-TL1	Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
24 Jun 2025	Optic neuropathy v5.6	MT-TL1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.3243 A > G heteroplasmic variant from MT-TL1 with optic neuropathy/ optic atrophy. Hence, this gene can be promoted to green rating in the next GMS update.
24 Jun 2025	Optic neuropathy v5.6	MT-TL1	Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
24 Jun 2025	Optic neuropathy v5.5	MT-TL1	Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; optic atrophy, MONDO:0003608
24 Jun 2025	Optic neuropathy v5.4	MT-TL1	Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
24 Jun 2025	Optic neuropathy v5.3	MT-TL1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1. Tag Q2_25_expert_review tag was added to gene: MT-TL1. Tag Q2_25_ NHS_review tag was added to gene: MT-TL1.
24 Jun 2025	Optic neuropathy v5.3	MT-TL1	Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Added comment: As per https://www.mitophen.org, there are seven different patients reported in peer-reviewed scientific literature with m.3243A>G variant and with optic atrophy as one of the presenting phenotypes. Two additional patients were reported with optic disc pallor as one of the phenotypes. PMID:7599199 - 14 patients with heteroplasmic m.3243A>G variant, of which only six patients had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. One of them presented with optic atrophy. PMID:7600089 - 22 probands with heteroplasmic m.3243A>G variant, of which 10 had clinical features consistent with MELAS syndrome. One had optic atrophy. PMID:8363452 - A 15-year-old boy was reported with heteroplasmic m.3243A>G variant and with bilateral optic atrophy since 8 years of age. PMID:8676159 - An 18-year-old male patient was reported with myoclonic epilepsy with ragged red fibres (MERRF) syndrome and with heteroplasmic m.3243A>G variant. The patient had bialateral optic atrophy. PMID:9228247 - Two patients with MELAS syndrome and m.3243A>G variant were reported with optic neuropathy. PMID:9619647 - A 21 year-old male patient with overlapping MELAS (mitochondrial encephalomyopathy, lactic acidosis, and 'stroke-like' episodes) and Kearns-Sayre syndrome. The heteroplasmic m.3243A>G variant has been identified in muscle tissue (79%), fibroblasts (49%) and blood cells (37%). There was no variant identified in E1alpha gene. Optic atrophy reported. PMID:22249460 - The m.3243A>G variant was identified in half of 14 patients reported in this study, of which optic atrophy was present in two. PMID:37095452 - Ischemic optic neuropathy reported as the first presentation in a patient with m.3243 A > G variant responsible for MELAS syndrome.; Changed publications to: 7599199, 7600089, 8363452, 8676159, 9228247, 9619647, 22249460, 37095452
24 Jun 2025	Optic neuropathy v5.3	MT-TL1	Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: MELAS syndrome caused by mutation in MTTL1, MONDO:0800032, optic atrophy, MONDO:0003608; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.10	MT-TP	Katherine Schon reviewed gene: MT-TP: Rating: AMBER; Mode of pathogenicity: Other; Publications: 7689388, 32305257; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.10	MT-TE	Katherine Schon reviewed gene: MT-TE: Rating: GREEN; Mode of pathogenicity: Other; Publications: 7726155, 21931168, 33128823, 15607216; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.10	MT-TL1	Katherine Schon reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 23355809, 20458543, 33484420; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.10	MT-TG	Katherine Schon reviewed gene: MT-TG: Rating: GREEN; Mode of pathogenicity: Other; Publications: 16120360, 11971101; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.10	MT-TK	Katherine Schon reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.10	MT-TN	Katherine Schon reviewed gene: MT-TN: Rating: GREEN; Mode of pathogenicity: Other; Publications: 23696415, 31026515, 8254046; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.10	MT-TA	Katherine Schon reviewed gene: MT-TA: Rating: AMBER; Mode of pathogenicity: Other; Publications: 17825557; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.10	MT-TW	Katherine Schon reviewed gene: MT-TW: Rating: GREEN; Mode of pathogenicity: Other; Publications: 9673981, 23841600; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Congenital myopathy v6.9	MT-TP	Achchuthan Shanmugasundram gene: MT-TP was added gene: MT-TP was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene gene: MT-TP was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TP was set to Other
24 Jun 2025	Congenital myopathy v6.9	MT-TE	Achchuthan Shanmugasundram gene: MT-TE was added gene: MT-TE was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene gene: MT-TE was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TE was set to Other
24 Jun 2025	Congenital myopathy v6.9	MT-TG	Achchuthan Shanmugasundram gene: MT-TG was added gene: MT-TG was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene gene: MT-TG was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TG was set to Other
24 Jun 2025	Congenital myopathy v6.9	MT-TK	Achchuthan Shanmugasundram gene: MT-TK was added gene: MT-TK was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TK was set to Other
24 Jun 2025	Congenital myopathy v6.9	MT-TN	Achchuthan Shanmugasundram gene: MT-TN was added gene: MT-TN was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene gene: MT-TN was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TN was set to Other
24 Jun 2025	Congenital myopathy v6.9	MT-TA	Achchuthan Shanmugasundram gene: MT-TA was added gene: MT-TA was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene gene: MT-TA was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TA was set to Other
24 Jun 2025	Congenital myopathy v6.9	MT-TW	Achchuthan Shanmugasundram gene: MT-TW was added gene: MT-TW was added to Congenital myopathy. Sources: Literature Mode of inheritance for gene gene: MT-TW was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TW was set to Other
24 Jun 2025	Monogenic hearing loss v5.10	MT-TS2	Katherine Schon reviewed gene: MT-TS2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 10090882; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Monogenic hearing loss v5.10	MT-TK	Katherine Schon reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: Other; Publications: https://www.ncbi.nlm.nih.gov/books/NBK1520/ (further reference from Table 2), 8651277; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Monogenic hearing loss v5.10	MT-CO1	Katherine Schon reviewed gene: MT-CO1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29605341, 36524552; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Monogenic hearing loss v5.10	MT-TL1	Katherine Schon reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 22403016, 35455034, 23355809; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Monogenic hearing loss v5.9	MT-TS2	Achchuthan Shanmugasundram gene: MT-TS2 was added gene: MT-TS2 was added to Monogenic hearing loss. Sources: Literature Mode of inheritance for gene gene: MT-TS2 was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TS2 was set to Other
24 Jun 2025	Monogenic hearing loss v5.9	MT-TK	Achchuthan Shanmugasundram gene: MT-TK was added gene: MT-TK was added to Monogenic hearing loss. Sources: Literature Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TK was set to Other
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-ND5	Katherine Schon reviewed gene: MT-ND5: Rating: GREEN; Mode of pathogenicity: ; Publications: 22759514, 30587702; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TL1	Katherine Schon reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 22513320, 31403078, 23355809; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Hypertrophic cardiomyopathy v5.3	MT-TV	Katherine Schon reviewed gene: MT-TV: Rating: GREEN; Mode of pathogenicity: Other; Publications: 34298071, 15320572; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
24 Jun 2025	Hypertrophic cardiomyopathy v5.2	MT-ND5	Achchuthan Shanmugasundram gene: MT-ND5 was added gene: MT-ND5 was added to Hypertrophic cardiomyopathy. Sources: Literature Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL
24 Jun 2025	Hypertrophic cardiomyopathy v5.2	MT-TV	Achchuthan Shanmugasundram gene: MT-TV was added gene: MT-TV was added to Hypertrophic cardiomyopathy. Sources: Literature Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TV was set to Other
24 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.5	STX16	Achchuthan Shanmugasundram Phenotypes for gene: STX16 were changed from Pseudohypoparathyroidism, type IB OMIM:603233; pseudohypoparathyroidism type 1B:MONDO:0011301 to Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301
24 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.4	STX16	Achchuthan Shanmugasundram Classified gene: STX16 as Amber List (moderate evidence)
24 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.4	STX16	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of STX16 deletions with Pseudohypoparathyroidism Ib (MIM #603233). As reviewed by Treena Cranston on Familial hypoparathyroidism panel (please see her review below, which was copied from that panel), the pseudohypoparathyroidism phenotype should be covered by this panel (R293) rather than R153. Hence, this gene should be considered for promotion to green rating on this panel in the next GMS update.
24 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.4	STX16	Achchuthan Shanmugasundram Gene: stx16 has been classified as Amber List (Moderate Evidence).
24 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.3	STX16	Achchuthan Shanmugasundram edited their review of gene: STX16: Changed rating: GREEN; Changed phenotypes to: Pseudohypoparathyroidism Ib, OMIM:603233; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
24 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.3	STX16	Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: STX16 is not clearly an imprinted gene. As reported in publications, only maternally inherited deletions are associated with this phenotype. Deletions in this gene are thought to disrupt cis-acting regulation of GNAS expression.
24 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.3	STX16	Achchuthan Shanmugasundram Mode of inheritance for gene: STX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
24 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.2	STX16	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: STX16. Tag Q2_25_expert_review tag was added to gene: STX16.
24 Jun 2025	Severe early-onset obesity v5.18	STX16	Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: STX16 is not clearly an imprinted gene. As reported in publications, only maternally inherited deletions are associated with this phenotype. Deletions in this gene are thought to disrupt cis-acting regulation of GNAS expression.
24 Jun 2025	Severe early-onset obesity v5.18	STX16	Achchuthan Shanmugasundram Mode of inheritance for gene: STX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
24 Jun 2025	Severe early-onset obesity v5.17	STX16	Achchuthan Shanmugasundram edited their review of gene: STX16: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
23 Jun 2025	Severe early-onset obesity v5.17	STX16	Achchuthan Shanmugasundram Mode of inheritance for gene: STX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
23 Jun 2025	Severe early-onset obesity v5.16	STX16	Achchuthan Shanmugasundram edited their review of gene: STX16: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
23 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.2	STX16	Achchuthan Shanmugasundram Entity copied from Familial hypoparathyroidism v3.1
23 Jun 2025	Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.2	STX16	Achchuthan Shanmugasundram gene: STX16 was added gene: STX16 was added to Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis. Sources: NHS GMS,Expert Review Amber,Literature non-coding-known-pathogenic, cnv tags were added to gene: STX16. Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: STX16 were set to 14561710; 15579741; 15800843; 33320452; 32337648; 35119251 Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB OMIM:603233; pseudohypoparathyroidism type 1B:MONDO:0011301
23 Jun 2025	Severe early-onset obesity v5.16	STX16	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: STX16.
23 Jun 2025	Severe early-onset obesity v5.16	STX16	Achchuthan Shanmugasundram changed review comment from: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion. PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect. As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features. All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B. Clinical opinion is therefore sought in relation to promoting this gene to green rating on this panel.; to: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion. PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect. As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features. All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B.
23 Jun 2025	Cholestasis v3.7	RINT1	Achchuthan Shanmugasundram Tag Q2_25_ demote_amber was removed from gene: RINT1. Tag Q2_25_ demote_red tag was added to gene: RINT1.
23 Jun 2025	Cholestasis v3.7	RINT1	Achchuthan Shanmugasundram Tag Q2_25_ demote_red was removed from gene: RINT1. Tag Q2_25_ demote_amber tag was added to gene: RINT1.
23 Jun 2025	Cholestasis v3.7	RINT1	Achchuthan Shanmugasundram Tag Q2_25_ demote_red tag was added to gene: RINT1. Tag Q2_25_expert_review tag was added to gene: RINT1.
23 Jun 2025	Cholestasis v3.7	RINT1	Achchuthan Shanmugasundram changed review comment from: As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RINT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients. PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported. PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia. As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/), this panel includes both cholestasis and hyperbilirubinaemia. As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.; to: As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RINT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients. PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported. PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia. As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/), this panel includes neonatal conjugated hyperbilirubinaemia, unexplained cholestasis or cholestasis of pregnancy-onset. As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.
23 Jun 2025	Cholestasis v3.7	RINT1	Achchuthan Shanmugasundram changed review comment from: As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RNT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients. PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported. PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia. As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/), this panel should include both cholestasis and hyperbilirubinaemia. As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.; to: As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RINT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients. PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported. PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia. As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/), this panel includes both cholestasis and hyperbilirubinaemia. As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.
23 Jun 2025	Multi locus imprinting disorders v1.14	OOEP	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is rated red on this panel after seeking clinical opinion from Helen Brittain. This is a maternal effect gene with similar genotypes causing different phenotypes. In PMID:29574422, a homozygous variant in mother resulted in a phenotype suggestive of MLID in the offspring, who was heterozygous for the same variant. The current standard testing for this type of finding appears to be MLID methylation test in the proband. In addition, this family is from South East Asian descent and this ethnicity is under-represented in population cohorts raising the question whether the variant might not be responsible for the clinical presentation. In PMID:35946397, compound heterozygous variants (one of these variants is the same as the homozygous variant above) resulted in recurrent preimplantation embryonic arrest in the patient, which is a different phenotype from the one above. In addition, this phenotype does not clearly lead to inclusion in any current panels within the Genomic Medicine Service.; to: Comment on list classification: This gene is rated red on this panel after seeking clinical opinion from Helen Brittain. This is a maternal effect gene with similar genotypes causing different phenotypes. In PMID:29574422, a homozygous variant in mother resulted in a phenotype suggestive of MLID in the offspring, who was heterozygous for the same variant. The current standard testing for this type of finding appears to be MLID methylation test in the proband. In addition, this family is from South East Asian descent and this ethnicity is under-represented in population cohorts raising the question whether the variant might not be responsible for the clinical presentation. In PMID:35946397, compound heterozygous variants (one of these variants is the same as the homozygous variant above) resulted in recurrent preimplantation embryonic arrest in the patient, which is a different phenotype from the one above. In addition, this phenotype does not clearly lead to inclusion in any current panels within the Genomic Medicine Service.
23 Jun 2025	Multi locus imprinting disorders v1.14	OOEP	Achchuthan Shanmugasundram Classified gene: OOEP as Red List (low evidence)
23 Jun 2025	Multi locus imprinting disorders v1.14	OOEP	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is rated red on this panel after seeking clinical opinion from Helen Brittain. This is a maternal effect gene with similar genotypes causing different phenotypes. In PMID:29574422, a homozygous variant in mother resulted in a phenotype suggestive of MLID in the offspring, who was heterozygous for the same variant. The current standard testing for this type of finding appears to be MLID methylation test in the proband. In addition, this family is from South East Asian descent and this ethnicity is under-represented in population cohorts raising the question whether the variant might not be responsible for the clinical presentation. In PMID:35946397, compound heterozygous variants (one of these variants is the same as the homozygous variant above) resulted in recurrent preimplantation embryonic arrest in the patient, which is a different phenotype from the one above. In addition, this phenotype does not clearly lead to inclusion in any current panels within the Genomic Medicine Service.
23 Jun 2025	Multi locus imprinting disorders v1.14	OOEP	Achchuthan Shanmugasundram Gene: ooep has been classified as Red List (Low Evidence).
23 Jun 2025	Multi locus imprinting disorders v1.13	OOEP	Achchuthan Shanmugasundram Deleted their comment
23 Jun 2025	Multi locus imprinting disorders v1.13	OOEP	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This is a maternal effect gene with similar genotypes causing different phenotypes. The homozygous variant in mother caused MLID in the offspring (PMID:29574422), and compound heterozygous variants (one of these variants is the same as the homozygous variant) caused recurrent preimplantation embryonic arrest. Hence, clinical opinion is being sought on the rating for this gene.; to: Comment on list classification: This gene is rated red on this panel after seeking clinical opinion from Helen Brittain. This is a maternal effect gene with similar genotypes causing different phenotypes. In PMID:29574422, a homozygous variant in mother resulted in a phenotype suggestive of MLID in the offspring, who was heterozygous for the same variant. The current standard testing for this type of finding appears to be MLID methylation test in the proaband. In PMID:35946397, compound heterozygous variants (one of these variants is the same as the homozygous variant above) caused recurrent preimplantation embryonic arrest in the patient, which is a different phenotype from the one above. In addition, Hence, clinical opinion is being sought on the rating for this gene.
23 Jun 2025	Multi locus imprinting disorders v1.13	OOEP	Achchuthan Shanmugasundram Classified gene: OOEP as Red List (low evidence)
23 Jun 2025	Multi locus imprinting disorders v1.13	OOEP	Achchuthan Shanmugasundram Gene: ooep has been classified as Red List (Low Evidence).
23 Jun 2025	Multi locus imprinting disorders v1.12	OOEP	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases: one with homozygous, and another with compound heterozygous variants, where one of these is the same as the homozygous variant. There is also some functional evidence available. However, similar genotypes cause different phenotypes. Hence, seeking clinical opinion on this gene before making green. The 'watchlist' tag is therefore added to reflect this.; to: Comment on list classification: This is a maternal effect gene with similar genotypes causing different phenotypes. The homozygous variant in mother caused MLID in the offspring (PMID:29574422), and compound heterozygous variants (one of these variants is the same as the homozygous variant) caused recurrent preimplantation embryonic arrest. Hence, clinical opinion is being sought on the rating for this gene.
23 Jun 2025	Multi locus imprinting disorders v1.12	OOEP	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases: one with homozygous, and another with compound heterozygous variants, where one of these is the same as the homozygous variant. There is also some functional evidence available. However, similar genotypes cause different phenotypes. Hence, seeking clinical opinion on this gene before making green. The 'watchlist' tag is therefore added to reflect this.; to: Comment on list classification: There are two unrelated cases: one with homozygous, and another with compound heterozygous variants, where one of these is the same as the homozygous variant. There is also some functional evidence available. However, similar genotypes cause different phenotypes. Hence, seeking clinical opinion on this gene before making green. The 'watchlist' tag is therefore added to reflect this.
23 Jun 2025	Multi locus imprinting disorders v1.12	OOEP	Achchuthan Shanmugasundram Tag watchlist was removed from gene: OOEP.
23 Jun 2025	Optic neuropathy v5.3	MT-TK	Katherine Schon reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: Other; Publications: 23635963, 33766967; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.3	MT-ND5	Katherine Schon reviewed gene: MT-ND5: Rating: GREEN; Mode of pathogenicity: ; Publications: 27164671, 12736867, 38357617; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.3	MT-ND3	Katherine Schon reviewed gene: MT-ND3: Rating: GREEN; Mode of pathogenicity: ; Publications: 30199507, 19458970; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.3	MT-TS2	Katherine Schon reviewed gene: MT-TS2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 9135384, 10090882, 8432539; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.3	MT-ND4L	Katherine Schon reviewed gene: MT-ND4L: Rating: GREEN; Mode of pathogenicity: ; Publications: 29210930, 36381806; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.3	MT-TL1	Katherine Schon reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 9228247, 39423307, 37095452; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.3	MT-ND2	Katherine Schon reviewed gene: MT-ND2: Rating: GREEN; Mode of pathogenicity: ; Publications: 11479733, 21145289; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.2	MT-TK	Achchuthan Shanmugasundram gene: MT-TK was added gene: MT-TK was added to Optic neuropathy. Sources: Literature Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TK was set to Other
23 Jun 2025	Optic neuropathy v5.2	MT-ND5	Achchuthan Shanmugasundram gene: MT-ND5 was added gene: MT-ND5 was added to Optic neuropathy. Sources: Literature Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.2	MT-ND3	Achchuthan Shanmugasundram gene: MT-ND3 was added gene: MT-ND3 was added to Optic neuropathy. Sources: Literature Mode of inheritance for gene gene: MT-ND3 was set to MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.2	MT-TS2	Achchuthan Shanmugasundram gene: MT-TS2 was added gene: MT-TS2 was added to Optic neuropathy. Sources: Literature Mode of inheritance for gene gene: MT-TS2 was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TS2 was set to Other
23 Jun 2025	Optic neuropathy v5.2	MT-ND4L	Achchuthan Shanmugasundram gene: MT-ND4L was added gene: MT-ND4L was added to Optic neuropathy. Sources: Literature Mode of inheritance for gene gene: MT-ND4L was set to MITOCHONDRIAL
23 Jun 2025	Optic neuropathy v5.2	MT-TL1	Achchuthan Shanmugasundram gene: MT-TL1 was added gene: MT-TL1 was added to Optic neuropathy. Sources: Literature Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL Mode of pathogenicity for gene: MT-TL1 was set to Other
23 Jun 2025	Optic neuropathy v5.2	MT-ND2	Achchuthan Shanmugasundram gene: MT-ND2 was added gene: MT-ND2 was added to Optic neuropathy. Sources: Literature Mode of inheritance for gene gene: MT-ND2 was set to MITOCHONDRIAL
20 Jun 2025	Retinal disorders v8.6	TBC1D32	Achchuthan Shanmugasundram Classified gene: TBC1D32 as Amber List (moderate evidence)
20 Jun 2025	Retinal disorders v8.6	TBC1D32	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating on the retinal disorders panel in the next GMS update.
20 Jun 2025	Retinal disorders v8.6	TBC1D32	Achchuthan Shanmugasundram Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
20 Jun 2025	Retinal disorders v8.5	TBC1D32	Achchuthan Shanmugasundram gene: TBC1D32 was added gene: TBC1D32 was added to Retinal disorders. Sources: Literature dd_review, Q2_25_ promote_green tags were added to gene: TBC1D32. Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBC1D32 were set to 37768732 Phenotypes for gene: TBC1D32 were set to retinitis pigmentosa, MONDO:0019200 Review for gene: TBC1D32 was set to GREEN Added comment: PMID:37768732 reported the identification of biallelic variants in TBC1D32 gene in four individuals from three unrelated families with retinitis pigmentosa. In addition, data from Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models also support the disease association. This gene is not yet associated with any phenotypes in OMIM. Sources: Literature
20 Jun 2025	Early onset or syndromic epilepsy v8.5	CELF4	Achchuthan Shanmugasundram Classified gene: CELF4 as Amber List (moderate evidence)
20 Jun 2025	Early onset or syndromic epilepsy v8.5	CELF4	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (nine unrelated cases with seizures) for the promotion of this gene to green rating on this panel in the next GMS update.
20 Jun 2025	Early onset or syndromic epilepsy v8.5	CELF4	Achchuthan Shanmugasundram Gene: celf4 has been classified as Amber List (Moderate Evidence).
20 Jun 2025	Early onset or syndromic epilepsy v8.4	CELF4	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CELF4.
20 Jun 2025	Intellectual disability v9.28	CELF4	Achchuthan Shanmugasundram Classified gene: CELF4 as Amber List (moderate evidence)
20 Jun 2025	Intellectual disability v9.28	CELF4	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (12 unrelated cases with GDD/ ID) for the promotion of this gene to green rating in the next GMS update.
20 Jun 2025	Intellectual disability v9.28	CELF4	Achchuthan Shanmugasundram Gene: celf4 has been classified as Amber List (Moderate Evidence).
20 Jun 2025	Intellectual disability v9.27	CELF4	Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CELF4.
20 Jun 2025	Early onset or syndromic epilepsy v8.4	CELF4	Achchuthan Shanmugasundram gene: CELF4 was added gene: CELF4 was added to Early onset or syndromic epilepsy. Sources: Literature Q2_25_ promote_green tags were added to gene: CELF4. Mode of inheritance for gene: CELF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CELF4 were set to 40108438 Phenotypes for gene: CELF4 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: CELF4 was set to GREEN Added comment: PMID:40108438 reported 15 patients with heterozygous missense or loss-of-function variants clustering in the N-terminal of the CELF4 gene. Most patients presented with neurodevelopmental disorders including global developmental delay (12 patients), intellectual disability (8, of which moderate in 2, mild in 3, and severity not defined in 3), seizures (9) and overweight/obesity (10) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature
20 Jun 2025	Intellectual disability v9.27	CELF4	Achchuthan Shanmugasundram gene: CELF4 was added gene: CELF4 was added to Intellectual disability. Sources: Literature Q2_25_ promote_green tags were added to gene: CELF4. Mode of inheritance for gene: CELF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CELF4 were set to 40108438 Phenotypes for gene: CELF4 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: CELF4 was set to GREEN Added comment: PMID:40108438 reported 15 patients with heterozygous missense or loss-of-function variants clustering in the N-terminal of the CELF4 gene. Most patients presented with neurodevelopmental disorders including global developmental delay (12 patients), intellectual disability (8, of which moderate in 2, mild in 3, and severity not defined in 3), seizures (9) and overweight/obesity (10) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature
20 Jun 2025	Multi locus imprinting disorders v1.12	ZFP57	Achchuthan Shanmugasundram Classified gene: ZFP57 as Amber List (moderate evidence)
20 Jun 2025	Multi locus imprinting disorders v1.12	ZFP57	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
20 Jun 2025	Multi locus imprinting disorders v1.12	ZFP57	Achchuthan Shanmugasundram Gene: zfp57 has been classified as Amber List (Moderate Evidence).
20 Jun 2025	Multi locus imprinting disorders v1.11	ZFP57	Achchuthan Shanmugasundram Phenotypes for gene: ZFP57 were changed from MLID to {Diabetes mellitus, transient neonatal 1}, OMIM:601410; Multi-locus imprinting disturbance (MLID)
20 Jun 2025	Multi locus imprinting disorders v1.10	ZFP57	Achchuthan Shanmugasundram Publications for gene: ZFP57 were set to PMID: 39090763
20 Jun 2025	Multi locus imprinting disorders v1.9	ZFP57	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: ZFP57.
20 Jun 2025	Multi locus imprinting disorders v1.9	ZFP57	Achchuthan Shanmugasundram reviewed gene: ZFP57: Rating: GREEN; Mode of pathogenicity: None; Publications: 35296332, 39090763; Phenotypes: {Diabetes mellitus, transient neonatal 1}, OMIM:601410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
20 Jun 2025	Multi locus imprinting disorders v1.9	OOEP	Achchuthan Shanmugasundram Classified gene: OOEP as Amber List (moderate evidence)
20 Jun 2025	Multi locus imprinting disorders v1.9	OOEP	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases: one with homozygous, and another with compound heterozygous variants, where one of these is the same as the homozygous variant. There is also some functional evidence available. However, similar genotypes cause different phenotypes. Hence, seeking clinical opinion on this gene before making green. The 'watchlist' tag is therefore added to reflect this.
20 Jun 2025	Multi locus imprinting disorders v1.9	OOEP	Achchuthan Shanmugasundram Gene: ooep has been classified as Amber List (Moderate Evidence).
20 Jun 2025	Multi locus imprinting disorders v1.8	OOEP	Achchuthan Shanmugasundram Tag watchlist tag was added to gene: OOEP.
20 Jun 2025	Multi locus imprinting disorders v1.8	OOEP	Achchuthan Shanmugasundram Phenotypes for gene: OOEP were changed from MLID to Multi-locus imprinting disturbance (MLID)
20 Jun 2025	Multi locus imprinting disorders v1.7	OOEP	Achchuthan Shanmugasundram Publications for gene: OOEP were set to PMID: 39090763
20 Jun 2025	Multi locus imprinting disorders v1.6	OOEP	Achchuthan Shanmugasundram reviewed gene: OOEP: Rating: AMBER; Mode of pathogenicity: None; Publications: 29574422, 35946397, 39090763; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
20 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.4	CFAP74	Arina Puzriakova Tag watchlist was removed from gene: CFAP74.
20 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.4	CFAP74	Arina Puzriakova Tag Q1_25_ expert_review tag was added to gene: CFAP74.
20 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.4	CFAP74	Arina Puzriakova commented on gene: CFAP74
19 Jun 2025	Limb disorders v7.8	RPL26	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are five unrelated families reported with congenital anomalies (particularly radial ray anomalies) and monoallelic RPL26 variants. Hence, this gene can be promoted to green rating in the next GMSW update.; to: Comment on list classification: There are five unrelated families reported with congenital anomalies (particularly radial ray anomalies) and monoallelic RPL26 variants. Hence, this gene can be promoted to green rating in the next GMS update.
19 Jun 2025	Limb disorders v7.8	RPL26	Achchuthan Shanmugasundram Classified gene: RPL26 as Amber List (moderate evidence)
19 Jun 2025	Limb disorders v7.8	RPL26	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with congenital anomalies (particularly radial ray anomalies) and monoallelic RPL26 variants. Hence, this gene can be promoted to green rating in the next GMSW update.
19 Jun 2025	Limb disorders v7.8	RPL26	Achchuthan Shanmugasundram Gene: rpl26 has been classified as Amber List (Moderate Evidence).
19 Jun 2025	Limb disorders v7.7	RPL26	Achchuthan Shanmugasundram Phenotypes for gene: RPL26 were changed from Radial Ray abnormality to ?Diamond-Blackfan anemia 11, OMIM:614900
19 Jun 2025	Limb disorders v7.6	RPL26	Achchuthan Shanmugasundram Publications for gene: RPL26 were set to
19 Jun 2025	Limb disorders v7.5	RPL26	Achchuthan Shanmugasundram Mode of inheritance for gene: RPL26 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
19 Jun 2025	Limb disorders v7.4	RPL26	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: RPL26.
19 Jun 2025	Limb disorders v7.4	RPL26	Achchuthan Shanmugasundram reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: None; Publications: 39268718; Phenotypes: ?Diamond-Blackfan anemia 11, OMIM:614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.20	RPL26	Achchuthan Shanmugasundram Classified gene: RPL26 as Amber List (moderate evidence)
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.20	RPL26	Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are five unrelated families reported with monoallelic RPL26 variants in total (PMIDs: 22431104 & 39268718), only two unrelated individuals have been reported with cytopenia. Hence, this gene can only be rated amber with current evidence.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.20	RPL26	Achchuthan Shanmugasundram Gene: rpl26 has been classified as Amber List (Moderate Evidence).
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.19	RPL26	Achchuthan Shanmugasundram Phenotypes for gene: RPL26 were changed from ?Diamond-Blackfan anemia 11, 614900 to ?Diamond-Blackfan anemia 11, OMIM:614900
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.18	RPL26	Achchuthan Shanmugasundram Publications for gene: RPL26 were set to
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.17	RPL26	Achchuthan Shanmugasundram Mode of inheritance for gene: RPL26 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.16	RPL26	Achchuthan Shanmugasundram reviewed gene: RPL26: Rating: AMBER; Mode of pathogenicity: None; Publications: 39268718; Phenotypes: ?Diamond-Blackfan anemia 11, OMIM:614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
19 Jun 2025	Limb disorders v7.4	RPL17	Achchuthan Shanmugasundram Classified gene: RPL17 as Red List (low evidence)
19 Jun 2025	Limb disorders v7.4	RPL17	Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is only one family reported with skeletal abnormalities, this gene can only be rated red on this panel with the current evidence.
19 Jun 2025	Limb disorders v7.4	RPL17	Achchuthan Shanmugasundram Gene: rpl17 has been classified as Red List (Low Evidence).
19 Jun 2025	Limb disorders v7.3	RPL17	Achchuthan Shanmugasundram Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia to Diamond-Blackfan anemia, MONDO:0015253
19 Jun 2025	Limb disorders v7.2	RPL17	Achchuthan Shanmugasundram edited their review of gene: RPL17: Changed rating: RED
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.16	RPL17	Achchuthan Shanmugasundram Classified gene: RPL17 as Amber List (moderate evidence)
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.16	RPL17	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are two unrelated pedigrees and functional evidence available in support of the association of this gene to phenotype. Hence, this can be promoted to green rating in the next GMS update.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.16	RPL17	Achchuthan Shanmugasundram Gene: rpl17 has been classified as Amber List (Moderate Evidence).
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.15	RPL17	Achchuthan Shanmugasundram Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia to Diamond-Blackfan anemia, MONDO:0015253
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.14	RPL17	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: RPL17.
19 Jun 2025	Limb disorders v7.2	RPL17	Achchuthan Shanmugasundram Entity copied from Cytopenia - NOT Fanconi anaemia v4.14
19 Jun 2025	Limb disorders v7.2	RPL17	Achchuthan Shanmugasundram gene: RPL17 was added gene: RPL17 was added to Limb disorders. Sources: Literature Mode of inheritance for gene: RPL17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPL17 were set to 39088281 Phenotypes for gene: RPL17 were set to Diamond-Blackfan anemia Penetrance for gene: RPL17 were set to Incomplete
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.14	RPL17	Achchuthan Shanmugasundram reviewed gene: RPL17: Rating: GREEN; Mode of pathogenicity: None; Publications: 39088281; Phenotypes: Diamond-Blackfan anemia, MONDO:0015253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.14	CASP10	Achchuthan Shanmugasundram Classified gene: CASP10 as Amber List (moderate evidence)
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.14	CASP10	Achchuthan Shanmugasundram Added comment: Comment on list classification: Despite sufficient cases being reported with the phenotype, the presence of identified variants in healthy individuals, reduced segregation of variants with the disease, inconsistencies in the reported phenotypes across cases with the same variants, and normal FAS-mediated apoptosis with variants from affected individuals suggest that this gene should not be promoted to green rating.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.14	CASP10	Achchuthan Shanmugasundram Gene: casp10 has been classified as Amber List (Moderate Evidence).
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.13	CASP10	Achchuthan Shanmugasundram Classified gene: CASP10 as Amber List (moderate evidence)
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.13	CASP10	Achchuthan Shanmugasundram Gene: casp10 has been classified as Amber List (Moderate Evidence).
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.12	CASP10	Achchuthan Shanmugasundram Publications for gene: CASP10 were set to
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.11	CASP10	Achchuthan Shanmugasundram Phenotypes for gene: CASP10 were changed from ALPS to Autoimmune lymphoproliferative syndrome, type II, OMIM:603909
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.10	CASP10	Achchuthan Shanmugasundram Mode of inheritance for gene: CASP10 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.9	CASP10	Achchuthan Shanmugasundram commented on gene: CASP10: PMID:34329798 - Two patients were identified with heterozygous p.Ile406Leu variant and one was identified with p.Cys401LeufsTer15 variant. The p.Ile406Leu variant did not segregate with the disease, while the family of the patient with p.Cys401LeufsTer15 variant was not studied. The p.Ile406Leu variant, which was previously reported in several cases was found at an allele frequency of 2% in healthy individuals in certain ethnicities from the 1000 genomes database. In addition, functional assays did not show any impairment in one of these patients and five previously reported patients in comparison to healthy donors. Although p.Cys401LeufsTer15 variant was classified as likely pathogenic, it is also proposed that it is not per se causative of disease as the variant is present at higher than expected allele frequency in healthy individuals. There is also significant differences in the clinical presentations with the patient with this variant in this publication and a previously reported patient within the same variant. Another previously reported variant, p.Tyr446Cys was also present at an allele frequency of 4% in healthy individuals from 1000 genomes database, and p.Val410Ile was discarded as disease-causing by the same authors. PMID:38704374 aimed to assess the impact of CASP10 variants on ALPS pathogenesis. Using a large cohort dataset, the authors were able to confirm that the missense variants p.Val410Ile and p.Tyr446Cys, are present in the general population at a high frequency. Furthermore, these variants do not affect the CASP10 catalytic domain and no difference was observed in CASP10 protein expression or FAS-mediated apoptosis between healthy controls and subjects bearing these variants in both homozygous and heterozygous states. Two patient had the CASP10 variant p.Cys401LeufsTer15, which lies within QACQG catalytic site in the CASP10 catalytic domain. One of the two patients was homozygous for this variant, resulting in a lack of Caspase-10 RNA and protein. However, it was reported that FAS-mediated apoptosis was comparable to healthy controls in each of the tested cell lines suspected to have a role in ALPS. In the other patient, who was heterozygous p.Cys401LeufsTer15, the authors report that although the levels of CASP10 protein expression was reduced, there was normal FAS-mediated apoptosis compared to healthy controls. From these results, it was concluded that Caspase-10 is dispensable for FAS-mediated apoptosis and an undetectable CASP10 protein expression has no impact on lymphocyte apoptosis and on individuals’ clinical and laboratory phenotype. It is also commented that post-translational or epigenetic mechanisms may play a role and yet unidentified.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.9	CASP10	Achchuthan Shanmugasundram reviewed gene: CASP10: Rating: AMBER; Mode of pathogenicity: None; Publications: 34329798, 38704374; Phenotypes: Autoimmune lymphoproliferative syndrome, type II, OMIM:603909; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
19 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.11	SRPK3	Arina Puzriakova Phenotypes for gene: SRPK3 were changed from to Slowly progressive myopathy, digenic
19 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.10	SRPK3	Arina Puzriakova Publications for gene: SRPK3 were set to 38429495
19 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.9	SRPK3	Arina Puzriakova Mode of inheritance for gene: SRPK3 was changed from Other to X-LINKED: hemizygous mutation in males, biallelic mutations in females
19 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.8	SRPK3	Arina Puzriakova Classified gene: SRPK3 as Red List (low evidence)
19 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.8	SRPK3	Arina Puzriakova Added comment: Comment on list classification: There is no evidence that monogenic variants in this gene cause myopathy. Digenic inheritance is not currently accommodated in tiering. The TTN gene is already included on this panel as Green meaning cases could still be picked up if a TTN variant is present. As this is digenic, this gene has been made Red and tagged 'digenic'.
19 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.8	SRPK3	Arina Puzriakova Gene: srpk3 has been classified as Red List (Low Evidence).
19 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7	SRPK3	Arina Puzriakova Tag digenic tag was added to gene: SRPK3.
19 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7	SRPK3	Arina Puzriakova reviewed gene: SRPK3: Rating: ; Mode of pathogenicity: None; Publications: 16140986, 38429495, 39667923; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
19 Jun 2025	Congenital myopathy v6.8	SRPK3	Arina Puzriakova Classified gene: SRPK3 as Red List (low evidence)
19 Jun 2025	Congenital myopathy v6.8	SRPK3	Arina Puzriakova Added comment: Comment on list classification: There is no evidence that monogenic variants in this gene cause myopathy. Digenic inheritance is not currently accommodated in tiering. The TTN gene is already included on this panel as Green meaning cases could still be picked up if a TTN variant is present. As this is digenic, this gene has been made Red and tagged 'digenic'.
19 Jun 2025	Congenital myopathy v6.8	SRPK3	Arina Puzriakova Gene: srpk3 has been classified as Red List (Low Evidence).
19 Jun 2025	Congenital myopathy v6.7	SRPK3	Arina Puzriakova Phenotypes for gene: SRPK3 were changed from Slowly progressive myopathy to Slowly progressive myopathy, digenic
19 Jun 2025	Congenital myopathy v6.6	SRPK3	Arina Puzriakova Publications for gene: SRPK3 were set to 26799446
19 Jun 2025	Congenital myopathy v6.5	SRPK3	Arina Puzriakova Phenotypes for gene: SRPK3 were changed from Nemaline myopathy, MONDO:0018958 to Slowly progressive myopathy
19 Jun 2025	Congenital myopathy v6.4	SRPK3	Arina Puzriakova Tag digenic tag was added to gene: SRPK3.
19 Jun 2025	Congenital myopathy v6.4	SRPK3	Arina Puzriakova reviewed gene: SRPK3: Rating: ; Mode of pathogenicity: None; Publications: 16140986, 38429495, 39667923; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.9	FASLG	Achchuthan Shanmugasundram Classified gene: FASLG as Amber List (moderate evidence)
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.9	FASLG	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic FASLG variants with ALPS, which has cytopenia as presenting phenotype. Hence, this gene can be promoted to green rating in the next GMS update.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.9	FASLG	Achchuthan Shanmugasundram Gene: faslg has been classified as Amber List (Moderate Evidence).
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.8	FASLG	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: FASLG.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.8	FASLG	Achchuthan Shanmugasundram Phenotypes for gene: FASLG were changed from ALPS to Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.7	FASLG	Achchuthan Shanmugasundram Publications for gene: FASLG were set to
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.6	FASLG	Achchuthan Shanmugasundram Mode of inheritance for gene: FASLG was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.5	FASLG	Achchuthan Shanmugasundram reviewed gene: FASLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 8787672, 16627752, 17605793, 25451160, 26334989; Phenotypes: Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.5	FAS	Achchuthan Shanmugasundram changed review comment from: FAS has a well-established gene-disease association for autosomal dominant autoimmune lymphoproliferative syndrome (ALPS) in OMIM (MIM #601859) and Gene2Phenotype (with 'definitive' rating on 'Skin disorders' panel). OMIM also reported autoimmune hemolytic anemia, thrombocytopenia and neutropenia as clinical presentations of this disorder. This gene has also been associated with biallelic ALPS syndrome in Gene2Phenotype (with 'definitive' rating on 'Skin disorders' panel). PMID:34171534 reviewed evidence from previously published reports, which showed that there is sufficient evidence available for the association of both monoallelic and biallelic germline variants with ALPS syndrome. There is also sufficient evidence available for the presence of autoimmune cytopenias (hemolytic anemia, thrombocytopenia and neutropenia) in both patients with both monoallelic and biallelic variants.; to: FAS has a well-established gene-disease association for autoimmune lymphoproliferative syndrome (ALPS). Both germline and somatic variants have been reported to cause ALPS. FAS has been associated with autosomal dominant ALPS in OMIM (MIM #601859) and Gene2Phenotype (with 'definitive' rating on 'Skin disorders' panel). OMIM also reports autoimmune hemolytic anemia, thrombocytopenia and neutropenia as clinical presentations of this disorder. This gene has also been associated with autosomal recessive ALPS syndrome in Gene2Phenotype (with 'definitive' rating on 'Skin disorders' panel). PMID:34171534 reviewed evidence from previously published reports, which showed that there is sufficient evidence available for the association of both monoallelic and biallelic germline variants with ALPS syndrome. There is also sufficient evidence available for the presence of autoimmune cytopenias (hemolytic anemia, thrombocytopenia and neutropenia) in both patients with both monoallelic and biallelic variants.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.5	FAS	Achchuthan Shanmugasundram Classified gene: FAS as Amber List (moderate evidence)
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.5	FAS	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants with autoimmune cytopenia. Hence, this gene can be promoted to green rating in the next GMS update.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.5	FAS	Achchuthan Shanmugasundram Gene: fas has been classified as Amber List (Moderate Evidence).
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.4	FAS	Achchuthan Shanmugasundram Phenotypes for gene: FAS were changed from ALPS to Autoimmune lymphoproliferative syndrome, type IA, OMIM:601859
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.3	FAS	Achchuthan Shanmugasundram Publications for gene: FAS were set to
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.2	FAS	Achchuthan Shanmugasundram Mode of inheritance for gene: FAS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.1	FAS	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: FAS.
19 Jun 2025	Cytopenia - NOT Fanconi anaemia v4.1	FAS	Achchuthan Shanmugasundram reviewed gene: FAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 34171534; Phenotypes: Autoimmune lymphoproliferative syndrome, type IA, OMIM:601859; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
19 Jun 2025	Intellectual disability v9.26	SRPK3	Arina Puzriakova Phenotypes for gene: SRPK3 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, X-linked 114, OMIM:301134
18 Jun 2025	Cholestasis v3.7	RINT1	Achchuthan Shanmugasundram reviewed gene: RINT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31204009, 37463447, 39186236; Phenotypes: Infantile liver failure syndrome 3, OMIM:618641; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
18 Jun 2025	Congenital myopathy v6.4	TNNT1	Arina Puzriakova commented on gene: TNNT1: - PMID: 25430424 (2015) - 2 year old Hispanic male diagnosed with nemaline myopathy and a homozygous variant c.323C>G (p.S108X) in the TNNT1 gene. Patient had low muscle tone, global muscle weakness (proximal more than distal), hip and knee contractures and developmental delay. Muscle biopsy confirmed nemaline myopathy. - PMID: 12732643 (2003) - a lethal form of nemaline myopathy (known as ANM - Amish nemaline myopathy) found in family with a homozygous nonsense variant Glu180 in TNNT1 (previously known as TNT). ANM presents with tremors at birth, proximal contractures and hypotonia, and progressive weakness often leading to death from respiratory insufficiency.
18 Jun 2025	Congenital myopathy v6.4	TNNI1	Arina Puzriakova Phenotypes for gene: TNNI1 were changed from Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease to Hypocontractile muscle disease
18 Jun 2025	Congenital myopathy v6.3	TNNI1	Arina Puzriakova Mode of inheritance for gene: TNNI1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
18 Jun 2025	Congenital myopathy v6.2	TNNI1	Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. 3 families with biallelic LOF variants and 3 families with monoallelic GOF variants, presenting with a hypo- or hypercontractile phenotype, respectively.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. 3 families with biallelic LOF variants and 3 families with monoallelic GOF variants, presenting with a hypo- or hypercontractile phenotype, respectively. However, the biallelic phenotype is early onset and more severe, thus is the only MOI relevant to this panel as severe congenital cases are more likely to be tested under this clinical indication.
18 Jun 2025	Congenital myopathy v6.2	TNNI1	Arina Puzriakova edited their review of gene: TNNI1: Changed phenotypes to: Hypocontractile (AR LOF) muscle disease; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
18 Jun 2025	Congenital myopathy v6.2	TNNI1	Arina Puzriakova Entity copied from Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7
18 Jun 2025	Congenital myopathy v6.2	TNNI1	Arina Puzriakova gene: TNNI1 was added gene: TNNI1 was added to Congenital myopathy. Sources: Literature,Expert Review Amber Q2_25_ promote_green tags were added to gene: TNNI1. Mode of inheritance for gene: TNNI1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: TNNI1 were set to 38569017; 34934811 Phenotypes for gene: TNNI1 were set to Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7	TNNI1	Arina Puzriakova Classified gene: TNNI1 as Amber List (moderate evidence)
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7	TNNI1	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. 3 families with biallelic LOF variants and 3 families with monoallelic GOF variants, presenting with a hypo- or hypercontractile phenotype, respectively.
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7	TNNI1	Arina Puzriakova Gene: tnni1 has been classified as Amber List (Moderate Evidence).
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.6	TNNI1	Arina Puzriakova Mode of inheritance for gene: TNNI1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.5	TNNI1	Arina Puzriakova Phenotypes for gene: TNNI1 were changed from Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease to Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.4	TNNI1	Arina Puzriakova Phenotypes for gene: TNNI1 were changed from to Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.4	TNNI1	Arina Puzriakova Publications for gene: TNNI1 were set to PMID: 38569017
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3	TNNI1	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: TNNI1.
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3	TNNI1	Arina Puzriakova changed review comment from: - PMID: 38569017 (2024) - 9 individuals from 3 families with biallelic LOF variants in the TNNI1 gene, manifesting with early-onset myopathy with progressive muscle weakness (proximal more than distal) and rod formation on histology. 2 individuals from different families presented with severe infantile weakness with minimal attainment of motor milestones. 3 individuals from 2 families had mild/moderate contractures. Also another 2 families with heterozygous GOF variants, resulting in hypercontractile disease with a constellation of symptoms including muscle cramping, myalgias, stiffness, and rod formation. 4/5 patients reported normal muscle strength and there is no mention of contractures. Recognition of symptoms ranged from childhood to adulthood. Functional studies in zebrafish demonstrate variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype. - PMID: 34934811 (2021) - Japanese family with 3 affected individuals with proximal arthrogryposis and elevated CK, albeit without muscle weakness. A presumed GOF heterozygous c.523A>T, p.K175* TNNI1 variant was identified (2 genotyped). Muscle biopsy demonstrated a moth-eaten appearance and mild fibre size variation in type 1 fibres, and electron microscopic analysis revealed type 1 fibre Z disk streaming. No functional studies were done.; to: - PMID: 38569017 (2024) - 9 individuals from 3 families with biallelic LOF variants in the TNNI1 gene, manifesting with early-onset myopathy with progressive muscle weakness (proximal more than distal) and rod formation on histology. 2 individuals from different families presented with severe infantile weakness with minimal attainment of motor milestones. 3 individuals from 2 families had mild/moderate contractures. Also another 2 families with heterozygous GOF variants, resulting in hypercontractile disease with a constellation of symptoms including muscle cramping, myalgias, stiffness, and rod formation. 4/5 patients reported normal muscle strength and there is no mention of contractures. Recognition of symptoms ranged from childhood to adulthood. Functional studies in zebrafish demonstrate variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype. - PMID: 34934811 (2021) - Japanese family with 3 affected individuals with proximal arthrogryposis and elevated CK, albeit without muscle weakness. A presumed GOF heterozygous c.523A>T, p.K175* TNNI1 variant was identified (2 genotyped). Muscle biopsy demonstrated a moth-eaten appearance and mild fibre size variation in type 1 fibres, and electron microscopic analysis revealed type 1 fibre Z disk streaming. No functional studies were done.
18 Jun 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3	TNNI1	Arina Puzriakova reviewed gene: TNNI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38569017, 34934811; Phenotypes: Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
18 Jun 2025	Severe early-onset obesity v5.16	STX16	Achchuthan Shanmugasundram Classified gene: STX16 as Amber List (moderate evidence)
18 Jun 2025	Severe early-onset obesity v5.16	STX16	Achchuthan Shanmugasundram Gene: stx16 has been classified as Amber List (Moderate Evidence).
18 Jun 2025	Severe early-onset obesity v5.15	STX16	Achchuthan Shanmugasundram Publications for gene: STX16 were set to PMID: 27338644; 28453643
18 Jun 2025	Severe early-onset obesity v5.14	STX16	Achchuthan Shanmugasundram Phenotypes for gene: STX16 were changed from Obesity with pseudohypoparathyroidism type 1B to Pseudohypoparathyroidism, type IB OMIM:603233; Obesity, HP:0001513
18 Jun 2025	Severe early-onset obesity v5.13	STX16	Achchuthan Shanmugasundram Mode of inheritance for gene: STX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
18 Jun 2025	Severe early-onset obesity v5.12	STX16	Achchuthan Shanmugasundram edited their review of gene: STX16: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
18 Jun 2025	Severe early-onset obesity v5.12	STX16	Achchuthan Shanmugasundram changed review comment from: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion. PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect. As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features. All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B. Clinical opinion is therefore sought in relation to promoting this gene to green rating on this panel. ; to: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion. PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect. As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features. All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B. Clinical opinion is therefore sought in relation to promoting this gene to green rating on this panel.
18 Jun 2025	Severe early-onset obesity v5.12	STX16	Achchuthan Shanmugasundram changed review comment from: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.; to: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion. PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect. As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features. All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B. Clinical opinion is therefore sought in relation to promoting this gene to green rating on this panel.
18 Jun 2025	Likely inborn error of metabolism v8.55	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from X-linked adrenoleukodystrophy (Disorders of peroxisomal alpha-, beta and omega-oxidation); Adrenoleukodystrophy 300100 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
18 Jun 2025	Intellectual disability v9.25	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenoleukodystrophy, 300100; Adrenomyeloneuropathy, adult, 300100; ADRENOLEUKODYSTROPHY, X-LINKED to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
18 Jun 2025	Hereditary neuropathy or pain disorder v7.2	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenoleukodystrophy, OMIM:300100; Adrenomyeloneuropathy, adult, OMIM:300100; adrenoleukodystrophy, MONDO:0018544 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
18 Jun 2025	Undiagnosed metabolic disorders v1.630	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from X-linked adrenoleukodystrophy (Disorders of peroxisomal alpha-, beta and omega-oxidation); Adrenoleukodystrophy 300100 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
18 Jun 2025	Adult onset neurodegenerative disorder v8.2	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Hereditary spastic paraplegia, MONDO:0019064; adrenal failure; VLCFA accumulation; spastic paraparesis to Adrenoleukodystrophy, adult, OMIM:300100
18 Jun 2025	Adult onset hereditary spastic paraplegia v6.2	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from spastic paraparesis; Hereditary spastic paraplegia; adrenal failure; VLCFA accumulation; Adrenoleukodystrophy, 300100 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100; Adrenal failure; VLCFA accumulation; Spastic paraparesis
18 Jun 2025	Childhood onset hereditary spastic paraplegia v8.2	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from spastic paraparesis; VLCFA accumulation; adrenal failure; Hereditary spastic paraplegia to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100; Adrenal failure; VLCFA accumulation; Spastic paraparesis
18 Jun 2025	Hereditary spastic paraplegia v1.315	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Hereditary spastic paraplegia; adrenal failure; VLCFA accumulation; spastic paraparesis; Adrenoleukodystrophy, 300100 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100; Adrenal failure; VLCFA accumulation; Spastic paraparesis
18 Jun 2025	Inherited white matter disorders v1.185	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenoleukodystrophy, 300100; Adrenomyeloneuropathy, adult, 300100; X-Linked Adrenoleukodystrophy; Adrenoleukodystrophy, X-linked; Adrenoleukodystrophy to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
18 Jun 2025	White matter disorders and cerebral calcification - narrow panel v7.4	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenomyeloneuropathy, adult, 300100; Adrenoleukodystrophy, X-linked; Adrenoleukodystrophy; Adrenoleukodystrophy, 300100; X-Linked Adrenoleukodystrophy to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
18 Jun 2025	Congenital adrenal hypoplasia v4.5	ABCD1	Arina Puzriakova Phenotypes for gene: ABCD1 were changed from X-linked adrenoleukodystrophy to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
18 Jun 2025	Congenital adrenal hypoplasia v4.4	ABCD1	Arina Puzriakova Publications for gene: ABCD1 were set to
18 Jun 2025	Congenital adrenal hypoplasia v4.3	ABCD1	Arina Puzriakova Classified gene: ABCD1 as Amber List (moderate evidence)
18 Jun 2025	Congenital adrenal hypoplasia v4.3	ABCD1	Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update as its plausible that ABCD1-related adrenoleukodystrophy, which presents with adrenal insufficiency, could be tested under this panel.
18 Jun 2025	Congenital adrenal hypoplasia v4.3	ABCD1	Arina Puzriakova Gene: abcd1 has been classified as Amber List (Moderate Evidence).
18 Jun 2025	Congenital adrenal hypoplasia v4.2	ABCD1	Arina Puzriakova Mode of inheritance for gene: ABCD1 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)
18 Jun 2025	Congenital adrenal hypoplasia v4.1	ABCD1	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: ABCD1.
18 Jun 2025	Pulmonary arterial hypertension v4.4	CAPNS1	Arina Puzriakova Tag watchlist tag was added to gene: CAPNS1.
18 Jun 2025	Pulmonary arterial hypertension v4.4	CAPNS1	Arina Puzriakova Classified gene: CAPNS1 as Amber List (moderate evidence)
18 Jun 2025	Pulmonary arterial hypertension v4.4	CAPNS1	Arina Puzriakova Added comment: Comment on list classification: Rating Amber with watchlist tag - 2 unrelated cases (2 Tunisian sibs, 1 Dutch man) have been identified with homozygous variants in this gene and severe pulmonary arterial hypertension. RNA sequencing demonstrated aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. Additional case required before promotion to Green.
18 Jun 2025	Pulmonary arterial hypertension v4.4	CAPNS1	Arina Puzriakova Gene: capns1 has been classified as Amber List (Moderate Evidence).
18 Jun 2025	Pulmonary arterial hypertension v4.3	CAPNS1	Arina Puzriakova Publications for gene: CAPNS1 were set to PMID:38230350
18 Jun 2025	Pulmonary arterial hypertension v4.2	CAPNS1	Arina Puzriakova Phenotypes for gene: CAPNS1 were changed from pulmonary arterial hypertension to Pulmonary hypertension, primary, 6, OMIM:620777
18 Jun 2025	Inherited bleeding disorders v1.181	PLG	Arina Puzriakova Publications for gene: PLG were set to
18 Jun 2025	Inherited bleeding disorders v1.180	PLG	Arina Puzriakova Classified gene: PLG as Red List (low evidence)
18 Jun 2025	Inherited bleeding disorders v1.180	PLG	Arina Puzriakova Added comment: Comment on list classification: PLG deficiency causes hypoplasminogenemia characterised by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature. Predisposition to thrombosis was indicated in knockout mice which develop spontaneous, severe thromboses in multiple organs (PMID: 7705657). However, studies in humans have shown that severe PLG deficiency is rare and only weakly associated with thrombosis, largely in combination with other risk factors (PMID: 9684804; 12850227; 16849641; 27976734). Overall the evidence indicates that this gene should be demoted from Green to Amber/Red.
18 Jun 2025	Inherited bleeding disorders v1.180	PLG	Arina Puzriakova Gene: plg has been classified as Red List (Low Evidence).
18 Jun 2025	Thrombophilia with a likely monogenic cause v2.7	PLG	Arina Puzriakova changed review comment from: Comment on list classification: PLG deficiency causes hypoplasminogenemia characterised by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature. Predisposition to thrombosis was indicated in knockout mice which develop spontaneous, severe thromboses in multiple organs (PMID: 7705657). However, studies in humans have shown that severe PLG deficiency is rare and only weakly associated with thrombosis, largely in combination with other risk factors (PMID: 9684804; 12850227; 16849641; 27976734). Overall the evidence indicates that this gene should be demoted from Green to Amber/Red at the next GMS panel update.; to: Comment on list classification: PLG deficiency causes hypoplasminogenemia characterised by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature. Predisposition to thrombosis was indicated in knockout mice which develop spontaneous, severe thromboses in multiple organs (PMID: 7705657). However, studies in humans have shown that severe PLG deficiency is rare and only weakly associated with thrombosis, largely in combination with other risk factors (PMID: 9684804; 12850227; 16849641; 27976734). Overall the evidence indicates that this gene should be demoted from Green to Amber/Red at the next GMS panel update.
18 Jun 2025	Thrombophilia with a likely monogenic cause v2.7	PLG	Arina Puzriakova Publications for gene: PLG were set to
18 Jun 2025	Thrombophilia with a likely monogenic cause v2.6	PLG	Arina Puzriakova Classified gene: PLG as Green List (high evidence)
18 Jun 2025	Thrombophilia with a likely monogenic cause v2.6	PLG	Arina Puzriakova Added comment: Comment on list classification: PLG deficiency causes hypoplasminogenemia characterised by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature. Predisposition to thrombosis was indicated in knockout mice which develop spontaneous, severe thromboses in multiple organs (PMID: 7705657). However, studies in humans have shown that severe PLG deficiency is rare and only weakly associated with thrombosis, largely in combination with other risk factors (PMID: 9684804; 12850227; 16849641; 27976734). Overall the evidence indicates that this gene should be demoted from Green to Amber/Red at the next GMS panel update.
18 Jun 2025	Thrombophilia with a likely monogenic cause v2.6	PLG	Arina Puzriakova Gene: plg has been classified as Green List (High Evidence).
18 Jun 2025	Thrombophilia with a likely monogenic cause v2.5	PLG	Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: PLG. Tag Q2_25_ demote_amber tag was added to gene: PLG.
17 Jun 2025	Amelogenesis imperfecta v4.5	LAMC2	Eleanor Williams Classified gene: LAMC2 as Amber List (moderate evidence)
17 Jun 2025	Amelogenesis imperfecta v4.5	LAMC2	Eleanor Williams Added comment: Comment on list classification: Keeping the rating as amber. 1 reported case (PMID: 37228816) but with no phenotype for the mother who also carries the variant in LAMC2. Supportive mouse model in (PMID:26956061).
17 Jun 2025	Amelogenesis imperfecta v4.5	LAMC2	Eleanor Williams Gene: lamc2 has been classified as Amber List (Moderate Evidence).
17 Jun 2025	Amelogenesis imperfecta v4.4	LAMC2	Eleanor Williams Phenotypes for gene: LAMC2 were changed from Amelogenesis Imperfecta; Epidermolysis bullosa, junctional, Herlitz type, 226700; Epidermolysis bullosa, junctional, non-Herlitz type, 226650 to amelogenesis imperfecta, MONDO:0019507
17 Jun 2025	Amelogenesis imperfecta v4.3	LAMC2	Eleanor Williams Added comment: Comment on mode of inheritance: Updating the mode of inheritance to monoallelic since in the only reported case the proband was heterozygous for a variant in LAMC2.
17 Jun 2025	Amelogenesis imperfecta v4.3	LAMC2	Eleanor Williams Mode of inheritance for gene: LAMC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
17 Jun 2025	Amelogenesis imperfecta v4.2	LAMC2	Eleanor Williams Publications for gene: LAMC2 were set to 26956061
17 Jun 2025	Pigmentary skin disorders v4.3	SMARCB1	Eleanor Williams changed review comment from: Comment on list classification: Since cafe-au-lait or other pigmentary changes do not appear to be common in Schwannomatosis-1, or the presenting feature, this gene has been rated amber on this panel.; to: Comment on list classification: Since cafe-au-lait or other pigmentary changes do not appear to be common in Schwannomatosis-1, or the presenting feature, this gene has been rated red on this panel.
17 Jun 2025	Pigmentary skin disorders v4.3	SMARCB1	Eleanor Williams Classified gene: SMARCB1 as Red List (low evidence)
17 Jun 2025	Pigmentary skin disorders v4.3	SMARCB1	Eleanor Williams Gene: smarcb1 has been classified as Red List (Low Evidence).
17 Jun 2025	Pigmentary skin disorders v4.2	SMARCB1	Eleanor Williams Classified gene: SMARCB1 as Amber List (moderate evidence)
17 Jun 2025	Pigmentary skin disorders v4.2	SMARCB1	Eleanor Williams Added comment: Comment on list classification: Since cafe-au-lait or other pigmentary changes do not appear to be common in Schwannomatosis-1, or the presenting feature, this gene has been rated amber on this panel.
17 Jun 2025	Pigmentary skin disorders v4.2	SMARCB1	Eleanor Williams Gene: smarcb1 has been classified as Amber List (Moderate Evidence).
17 Jun 2025	Pigmentary skin disorders v4.1	SMARCB1	Eleanor Williams reviewed gene: SMARCB1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
17 Jun 2025	Pigmentary skin disorders v4.1	BLM	Eleanor Williams edited their review of gene: BLM: Changed publications to: 7485150
17 Jun 2025	Pigmentary skin disorders v4.1	BLM	Eleanor Williams reviewed gene: BLM: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
17 Jun 2025	Cerebral vascular malformations v4.5	CBS	Arina Puzriakova changed review comment from: Individuals with CBS variants are at higher of thromboembolic events such as peripheral vein thrombosis, pulmonary embolism, stroke, peripheral artery occlusion, and myocardial infarction. Cerebral sinovenous thrombosis can occur but could not find evidence of vascular malformations. Therefore this gene does not appear relevant to this panel and rating as Red.; to: Individuals with CBS variants are at higher risk of thromboembolic events such as peripheral vein thrombosis, pulmonary embolism, stroke, peripheral artery occlusion, and myocardial infarction. Cerebral sinovenous thrombosis can occur but could not find evidence of vascular malformations. Therefore this gene does not appear relevant to this panel and rating as Red.
17 Jun 2025	Cerebral vascular malformations v4.5	CBS	Arina Puzriakova Classified gene: CBS as Red List (low evidence)
17 Jun 2025	Cerebral vascular malformations v4.5	CBS	Arina Puzriakova Gene: cbs has been classified as Red List (Low Evidence).
17 Jun 2025	Cerebral vascular malformations v4.4	CBS	Arina Puzriakova commented on gene: CBS
17 Jun 2025	Primary lymphoedema v4.3	TIE1	Arina Puzriakova Classified gene: TIE1 as Amber List (moderate evidence)
17 Jun 2025	Primary lymphoedema v4.3	TIE1	Arina Puzriakova Added comment: Comment on list classification: At least 6 families have been reported in literature with heterozygous variants in this gene and lymphedema which support inclusion on this panel with a Green rating at the next GMS panel update.
17 Jun 2025	Primary lymphoedema v4.3	TIE1	Arina Puzriakova Gene: tie1 has been classified as Amber List (Moderate Evidence).
17 Jun 2025	Primary lymphoedema v4.2	TIE1	Arina Puzriakova Tag watchlist was removed from gene: TIE1. Tag Q2_25_ promote_green tag was added to gene: TIE1.
17 Jun 2025	Primary lymphoedema v4.2	TIE1	Arina Puzriakova commented on gene: TIE1
17 Jun 2025	Primary lymphoedema v4.2	TIE1	Arina Puzriakova Publications for gene: TIE1 were set to 32947856; 24764452
17 Jun 2025	Intellectual disability v9.24	PDE1B	Sarah Dixon gene: PDE1B was added gene: PDE1B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE1B were set to PMID: 40492975 Phenotypes for gene: PDE1B were set to hypotonia; ataxia; dystonia; developmental delay; intellectual disability Penetrance for gene: PDE1B were set to unknown Review for gene: PDE1B was set to GREEN Added comment: PMID: 40492975 Biallelic LOF variants in PDE1B identified in seven individuals from ﬁve different families Disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability Sources: Literature
17 Jun 2025	Ataxia and cerebellar anomalies - narrow panel v8.4	PDE1B	Sarah Dixon gene: PDE1B was added gene: PDE1B was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE1B were set to PMID: 40492975 Phenotypes for gene: PDE1B were set to hypotonia; ataxia; dystonia; developmental delay; intellectual disability Penetrance for gene: PDE1B were set to unknown Review for gene: PDE1B was set to GREEN Added comment: PMID: 40492975 Biallelic LOF variants in PDE1B identified in seven individuals from ﬁve different families Disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability Sources: Literature
17 Jun 2025	DDG2P v6.1	PDE1B	Sarah Dixon gene: PDE1B was added gene: PDE1B was added to DDG2P. Sources: Literature Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE1B were set to PMID: 40492975 Phenotypes for gene: PDE1B were set to hypotonia; ataxia; dystonia; developmental delay; intellectual disability Penetrance for gene: PDE1B were set to unknown Review for gene: PDE1B was set to GREEN Added comment: PMID: 40492975 Biallelic LOF variants in PDE1B identified in seven individuals from ﬁve different families Disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability Sources: Literature
17 Jun 2025	Severe early-onset obesity v5.12	STX16	Achchuthan Shanmugasundram commented on gene: STX16: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.
17 Jun 2025	Severe early-onset obesity v5.12	STX16	Achchuthan Shanmugasundram reviewed gene: STX16: Rating: GREEN; Mode of pathogenicity: None; Publications: 27338644, 28453643; Phenotypes: Pseudohypoparathyroidism, type IB OMIM:603233, Obesity, HP:0001513; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
17 Jun 2025	Severe early-onset obesity v5.12	MRAP2	Achchuthan Shanmugasundram Phenotypes for gene: MRAP2 were changed from obesity; {?Obesity, susceptibility to, BMIQ18}; Prader-Willi syndrome to {?Obesity, susceptibility to, BMIQ18}, OMIM:615457
17 Jun 2025	Severe early-onset obesity v5.11	MRAP2	Achchuthan Shanmugasundram Publications for gene: MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a 10-year old boy with overall obesity in combination with intellectual disability in a screen of Prader-Willi syndrome (PWS) patients. The clinically diagnosed PWS could not be confirmed molecularly with MS-MLPA and CNV analysis of the 6q14.1–q16.3 region also showed no deletions in this patient. No further family data were available to determine whether the variant segregates with obesity in this family. It was shown to be (probably) damaging by in silico analysis and found in only one European (non-Finnish) individual in the ExAC database (since this database cannot release phenotype information about the screened individuals, no conclusions regarding causality of this variant can be drawn).
17 Jun 2025	Severe early-onset obesity v5.10	MRAP2	Achchuthan Shanmugasundram reviewed gene: MRAP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 23869016, 26795956, 27474872, 31700171; Phenotypes: {?Obesity, susceptibility to, BMIQ18}, OMIM:615457; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
16 Jun 2025	Severe early-onset obesity v5.10	MC3R	Achchuthan Shanmugasundram Classified gene: MC3R as Red List (low evidence)
16 Jun 2025	Severe early-onset obesity v5.10	MC3R	Achchuthan Shanmugasundram Gene: mc3r has been classified as Red List (Low Evidence).
16 Jun 2025	Severe early-onset obesity v5.9	MC3R	Achchuthan Shanmugasundram Phenotypes for gene: MC3R were changed from obesity to {Obesity, severe, susceptibility to, BMIQ9}, OMIM:602025
16 Jun 2025	Severe early-onset obesity v5.8	MC3R	Achchuthan Shanmugasundram Publications for gene: MC3R were set to PMID: 31090190
16 Jun 2025	Severe early-onset obesity v5.7	MC3R	Achchuthan Shanmugasundram edited their review of gene: MC3R: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
16 Jun 2025	Severe early-onset obesity v5.7	MC3R	Achchuthan Shanmugasundram reviewed gene: MC3R: Rating: RED; Mode of pathogenicity: None; Publications: 31090190; Phenotypes: {Obesity, severe, susceptibility to, BMIQ9}, OMIM:602025; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
16 Jun 2025	Severe early-onset obesity v5.7	TRPC5	Achchuthan Shanmugasundram Classified gene: TRPC5 as Amber List (moderate evidence)
16 Jun 2025	Severe early-onset obesity v5.7	TRPC5	Achchuthan Shanmugasundram Gene: trpc5 has been classified as Amber List (Moderate Evidence).
16 Jun 2025	Severe early-onset obesity v5.6	TRPC5	Achchuthan Shanmugasundram Phenotypes for gene: TRPC5 were changed from obesity to Obesity, HP:0001513
16 Jun 2025	Severe early-onset obesity v5.5	TRPC5	Achchuthan Shanmugasundram Publications for gene: TRPC5 were set to PMID: 38959890
16 Jun 2025	Severe early-onset obesity v5.4	TRPC5	Achchuthan Shanmugasundram reviewed gene: TRPC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 38959890; Phenotypes: Obesity, HP:0001513; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
16 Jun 2025	Thoracic aortic aneurysm or dissection (GMS) v4.2	COL3A1	Arina Puzriakova Phenotypes for gene: COL3A1 were changed from Ehlers-Danlos syndrome, type IV, 130050; Loeys-Dietz syndrome; Ehlers-Danlos syndrome, vascular type (130050) to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
16 Jun 2025	Thoracic aortic aneurysm or dissection v1.128	COL3A1	Arina Puzriakova Phenotypes for gene: COL3A1 were changed from Loeys-Dietz syndrome; Ehlers-Danlos syndrome, type IV, 130050; Ehlers-Danlos syndrome, vascular type (130050) to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
16 Jun 2025	Bleeding and platelet disorders v4.2	COL3A1	Arina Puzriakova Phenotypes for gene: COL3A1 were changed from Ehlers-Danlos syndrome, vascular type, 130050 to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
16 Jun 2025	Fetal anomalies v6.6	COL3A1	Arina Puzriakova Phenotypes for gene: COL3A1 were changed from HP:0002126; HP:0001883; HP:0006496 to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
16 Jun 2025	Ehlers Danlos syndrome with a likely monogenic cause v4.2	COL3A1	Arina Puzriakova Phenotypes for gene: COL3A1 were changed from Ehlers-Danlos syndrome, vascular type, OMIM:130050 to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
16 Jun 2025	Primary ciliary disorders v1.45	WFDC2	Arina Puzriakova Publications for gene: WFDC2 were set to 38626355
16 Jun 2025	Primary ciliary disorders v1.44	WFDC2	Arina Puzriakova Classified gene: WFDC2 as Red List (low evidence)
16 Jun 2025	Primary ciliary disorders v1.44	WFDC2	Arina Puzriakova Added comment: Comment on list classification: PMID: 38626355; 4040104214 - individuals from 14 families have been reported with biallelic variants in this gene and bronchiectasis, nasal polyposis and sinopulmonary disease. Ciliary structure, beat frequency and coordination, as well as mucus viscosity were all within normal range and therefore this gene does not seem relevant to this panel. Rating Red.
16 Jun 2025	Primary ciliary disorders v1.44	WFDC2	Arina Puzriakova Gene: wfdc2 has been classified as Red List (Low Evidence).
16 Jun 2025	Autoinflammatory disorders v2.29	RIPK1	Achchuthan Shanmugasundram Classified gene: RIPK1 as Amber List (moderate evidence)
16 Jun 2025	Autoinflammatory disorders v2.29	RIPK1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available for the association of both monoallelic and biallelic variants in RIPK1 gene with autoinflammatory disease phenotypes (MIMs #618852 & 618108). Hence, this gene can be promoted to green rating in the next GMS update.
16 Jun 2025	Autoinflammatory disorders v2.29	RIPK1	Achchuthan Shanmugasundram Gene: ripk1 has been classified as Amber List (Moderate Evidence).
16 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.18	RIPK1	Achchuthan Shanmugasundram Phenotypes for gene: RIPK1 were changed from Immunodeficiency 57, 618108; Severe immunodeficiency, arthritis, and intestinal inflammation to Autoinflammation with episodic fever and lymphadenopathy, OMIM:618852; Immunodeficiency 57 with autoinflammation, OMIM: 618108
16 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.4	WFDC2	Arina Puzriakova Publications for gene: WFDC2 were set to 38626355
16 Jun 2025	Autoinflammatory disorders v2.28	RIPK1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: RIPK1. Tag Q2_25_ NHS_review tag was added to gene: RIPK1.
16 Jun 2025	Autoinflammatory disorders v2.28	RIPK1	Achchuthan Shanmugasundram Phenotypes for gene: RIPK1 were changed from Autoinflammation with episodic fever and lymphadenopathy (autosomal dominant); Immunodeficiency 57 with autoinflammation (autosomal recessive) to Autoinflammation with episodic fever and lymphadenopathy, OMIM:618852; Immunodeficiency 57 with autoinflammation, OMIM: 618108
16 Jun 2025	Autoinflammatory disorders v2.27	RIPK1	Achchuthan Shanmugasundram Publications for gene: RIPK1 were set to PMID: 31911632; PMID: 31827281; PMID:31827280; PMID: 39557292; PMID: 37452601; PMID:35716229; PMID:35786329
16 Jun 2025	Autoinflammatory disorders v2.26	RIPK1	Achchuthan Shanmugasundram reviewed gene: RIPK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30026316, 31827280, 31827281, 31911632, 35716229, 35786329, 39557292; Phenotypes: Autoinflammation with episodic fever and lymphadenopathy, OMIM:618852, Immunodeficiency 57 with autoinflammation, OMIM: 618108; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
16 Jun 2025	Primary ciliary disorders v1.43	WFDC2	Arina Puzriakova Phenotypes for gene: WFDC2 were changed from Nasal Polyposis; Bronchiectasis to Bronchiectasis and nasal polyposis, OMIM:620984
16 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.3	WFDC2	Arina Puzriakova Phenotypes for gene: WFDC2 were changed from bronchiectasis, MONDO:0004822; Nasal polyposis, HP:0100582 to Bronchiectasis and nasal polyposis, OMIM:620984
16 Jun 2025	Autoinflammatory disorders v2.26	RELA	Arina Puzriakova Publications for gene: RELA were set to PMID: 36926348; PMID: 32969189; PMID: 35412596; PMID: 28600438
16 Jun 2025	Autoinflammatory disorders v2.25	RELA	Arina Puzriakova Tag Q2_23_NHS_review was removed from gene: RELA. Tag Q2_25_ NHS_review tag was added to gene: RELA.
16 Jun 2025	Autoinflammatory disorders v2.25	RELA	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: RELA. Tag Q2_23_NHS_review tag was added to gene: RELA.
16 Jun 2025	Autoinflammatory disorders v2.25	RELA	Arina Puzriakova Classified gene: RELA as Amber List (moderate evidence)
16 Jun 2025	Autoinflammatory disorders v2.25	RELA	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least 7 unrelated cases identified in literature with monoallelic RELA variants and Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287 which is characterised predominantly by intermittent fevers and chronic mucocutaneous ulceration although clinical presentation can be variable.
16 Jun 2025	Autoinflammatory disorders v2.25	RELA	Arina Puzriakova Gene: rela has been classified as Amber List (Moderate Evidence).
16 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.17	TBK1	Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed before, there is sufficient evidence available for the association of monoallelic TBK1 variants to this panel based on {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8} phenotype (MIM #617900). There is sufficient evidence available now (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder (MIM # 620880). Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
16 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.17	TBK1	Achchuthan Shanmugasundram Mode of inheritance for gene: TBK1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
16 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.16	TBK1	Achchuthan Shanmugasundram Phenotypes for gene: TBK1 were changed from Herpes simplex encephalitis, susceptibility to; Herpetic encephalitis (HSE); {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8} 617900; Herpes simplex virus 1 encephalitis; Defects in Intrinsic and Innate Immunity to {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8}, OMIM:617900; Autoinflammation with arthritis and vasculitis, OMIM:620880
16 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.15	TBK1	Achchuthan Shanmugasundram Publications for gene: TBK1 were set to 22851595; 26513235
16 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.14	TBK1	Achchuthan Shanmugasundram Tag Q2_25_ MOI tag was added to gene: TBK1.
16 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.14	TBK1	Achchuthan Shanmugasundram reviewed gene: TBK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34363755; Phenotypes: {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8}, OMIM:617900, Autoinflammation with arthritis and vasculitis, OMIM:620880; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
16 Jun 2025	Autoinflammatory disorders v2.24	TBK1	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.
16 Jun 2025	Autoinflammatory disorders v2.24	TBK1	Achchuthan Shanmugasundram changed review comment from: PMID:34363755 reported the identification of homozygous loss-of-function variants in TBK1 gene in four patients from three unrelated families. All of them presented with chronic and systemic autoinflammation, but not severe viral infections. Supporting functional evidence is also available. This gene has already been associated with relevant phenotypes in OMIM (MIM #620880).; to: PMID:34363755 reported the identification of three different homozygous loss-of-function variants in TBK1 gene in four patients from three unrelated families. All of them presented with chronic and systemic autoinflammation, but not severe viral infections. Supporting functional evidence is also available. This gene has already been associated with relevant phenotypes in OMIM (MIM #620880).
16 Jun 2025	Autoinflammatory disorders v2.24	TBK1	Achchuthan Shanmugasundram Classified gene: TBK1 as Amber List (moderate evidence)
16 Jun 2025	Autoinflammatory disorders v2.24	TBK1	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.
16 Jun 2025	Autoinflammatory disorders v2.24	TBK1	Achchuthan Shanmugasundram Gene: tbk1 has been classified as Amber List (Moderate Evidence).
16 Jun 2025	Autoinflammatory disorders v2.23	TBK1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: TBK1. Tag Q2_25_ NHS_review tag was added to gene: TBK1.
16 Jun 2025	Autoinflammatory disorders v2.23	TBK1	Achchuthan Shanmugasundram Phenotypes for gene: TBK1 were changed from chronic and systemic autoinflammation driven by TNF-induced cell death to Autoinflammation with arthritis and vasculitis, OMIM:620880
16 Jun 2025	Autoinflammatory disorders v2.22	TBK1	Achchuthan Shanmugasundram Publications for gene: TBK1 were set to PMID: 34363755; PMID: 34210994; PMID: 28148298; PMID: 34363755
16 Jun 2025	Autoinflammatory disorders v2.21	TBK1	Achchuthan Shanmugasundram reviewed gene: TBK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34363755; Phenotypes: Autoinflammation with arthritis and vasculitis, OMIM:620880; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
16 Jun 2025	Autoinflammatory disorders v2.21	RELA	Arina Puzriakova Phenotypes for gene: RELA were changed from Autoinflammatory disease, familial, behcet-like 3 to Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287
16 Jun 2025	Autoinflammatory disorders v2.20	POMP	Arina Puzriakova Classified gene: POMP as Amber List (moderate evidence)
16 Jun 2025	Autoinflammatory disorders v2.20	POMP	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least 4 unrelated cases with neonatal onset inflammatory disease and heterozygous LOF variants in the POMP gene (PMID: 26524591; 29805043; 38111302)
16 Jun 2025	Autoinflammatory disorders v2.20	POMP	Arina Puzriakova Gene: pomp has been classified as Amber List (Moderate Evidence).
16 Jun 2025	Autoinflammatory disorders v2.19	POMP	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: POMP. Tag Q2_25_ NHS_review tag was added to gene: POMP.
16 Jun 2025	Autoinflammatory disorders v2.19	POMP	Arina Puzriakova Publications for gene: POMP were set to PMID: 38111302; PMID: 29805043
16 Jun 2025	Palmoplantar keratoderma and erythrokeratodermas v1.32	POMP	Arina Puzriakova Classified gene: POMP as Green List (high evidence)
16 Jun 2025	Palmoplantar keratoderma and erythrokeratodermas v1.32	POMP	Arina Puzriakova Added comment: Comment on list classification: Promoting from Red to Green to match the latest rating on the GMS panels (R165/R166)
16 Jun 2025	Palmoplantar keratoderma and erythrokeratodermas v1.32	POMP	Arina Puzriakova Gene: pomp has been classified as Green List (High Evidence).
16 Jun 2025	Autoinflammatory disorders v2.18	POMP	Arina Puzriakova Phenotypes for gene: POMP were changed from Proteasome-associated autoinflammatory syndrome 2 to Proteasome-associated autoinflammatory syndrome 2, OMIM:618048
16 Jun 2025	Autoinflammatory disorders v2.17	IKBKG	Arina Puzriakova Publications for gene: IKBKG were set to PMID: 35289316
16 Jun 2025	Autoinflammatory disorders v2.16	IKBKG	Arina Puzriakova Classified gene: IKBKG as Amber List (moderate evidence)
16 Jun 2025	Autoinflammatory disorders v2.16	IKBKG	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Variants in the IKBKG gene (also known as NEMO) can be linked to a autoinflammatory disorder characterised by the onset of systemic autoinflammation in the first months of life. Clinical manifestations are variable but include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. At least 9 unrelated cases have been reported, including two females (PMID: 31874111; 35120036; 35289316; 39264518).
16 Jun 2025	Autoinflammatory disorders v2.16	IKBKG	Arina Puzriakova Gene: ikbkg has been classified as Amber List (Moderate Evidence).
16 Jun 2025	Autoinflammatory disorders v2.15	IKBKG	Arina Puzriakova Phenotypes for gene: IKBKG were changed from Autoinflammatory disease, systemic, X-linked to Autoinflammatory disease, systemic, X-linked, OMIM:301081
16 Jun 2025	Autoinflammatory disorders v2.14	IKBKG	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: IKBKG. Tag Q2_25_ NHS_review tag was added to gene: IKBKG.
16 Jun 2025	Renal tubulopathies v5.5	OCRL	Arina Puzriakova Phenotypes for gene: OCRL were changed from Dent disease 2, 300555. Lowe syndrome, 309000 to Dent disease 2, OMIM:300555
16 Jun 2025	Renal tubulopathies v5.4	CLCN5	Arina Puzriakova Phenotypes for gene: CLCN5 were changed from Dent disease, 300009. Hypophosphatemic rickets, 300554. Nephrolithiasis, type I, 310468. Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis, 308990 to Dent disease 1, OMIM:300009
16 Jun 2025	Renal tubulopathies v5.3	OCRL	Arina Puzriakova changed review comment from: Comment on list classification: Upgrading from Red to Amber but this gene should be promoted to Green at the next GMS panel update, in line with the review by Beccy Cummings (NHS). Variants in the CLCN5 gene cause Dent disease, a disorder of proximal renal tubular dysfunction, which could plausibly be picked up via this panel and therefore warrants inclusion.; to: Comment on list classification: Upgrading from Red to Amber but this gene should be promoted to Green at the next GMS panel update, in line with the review by Beccy Cummings (NHS). Variants in the OCRL gene cause Dent disease, a disorder of proximal renal tubular dysfunction, which could plausibly be picked up via this panel and therefore warrants inclusion.
16 Jun 2025	Renal tubulopathies v5.3	OCRL	Arina Puzriakova Classified gene: OCRL as Amber List (moderate evidence)
16 Jun 2025	Renal tubulopathies v5.3	OCRL	Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but this gene should be promoted to Green at the next GMS panel update, in line with the review by Beccy Cummings (NHS). Variants in the CLCN5 gene cause Dent disease, a disorder of proximal renal tubular dysfunction, which could plausibly be picked up via this panel and therefore warrants inclusion.
16 Jun 2025	Renal tubulopathies v5.3	OCRL	Arina Puzriakova Gene: ocrl has been classified as Amber List (Moderate Evidence).
16 Jun 2025	Renal tubulopathies v5.2	OCRL	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: OCRL. Tag Q2_25_ NHS_review tag was added to gene: OCRL.
16 Jun 2025	Renal tubulopathies v5.2	CLCN5	Arina Puzriakova Classified gene: CLCN5 as Amber List (moderate evidence)
16 Jun 2025	Renal tubulopathies v5.2	CLCN5	Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but this gene should be promoted to Green at the next GMS panel update, in line with the review by Beccy Cummings (NHS). Variants in the CLCN5 gene cause Dent disease, a disorder of proximal renal tubular dysfunction, which could plausibly be picked up via this panel and therefore warrants inclusion.
16 Jun 2025	Renal tubulopathies v5.2	CLCN5	Arina Puzriakova Gene: clcn5 has been classified as Amber List (Moderate Evidence).
16 Jun 2025	Renal tubulopathies v5.1	CLCN5	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: CLCN5. Tag Q2_25_ NHS_review tag was added to gene: CLCN5.
16 Jun 2025	Intellectual disability v9.24	CLCN5	Arina Puzriakova Mode of inheritance for gene: CLCN5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
13 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.14	ELF4	Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder, the MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next GMS update.; to: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder, the MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next GMS update. The 'Skewed X-inactivation' tag has also been added as skewed X chromosome inactivation patterns were observed in all three female patients in the same publication.
13 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.14	ELF4	Achchuthan Shanmugasundram Tag Skewed X-inactivation tag was added to gene: ELF4.
13 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.14	ELF4	Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder, the MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next GMS update.
13 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.14	ELF4	Achchuthan Shanmugasundram Mode of inheritance for gene: ELF4 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
13 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.13	ELF4	Achchuthan Shanmugasundram Phenotypes for gene: ELF4 were changed from Inflammatory bowel disease; Mucosal inflammation; Fever; Ulcers; Behcet-like disease; X-linked hypogammaglobulinemia with isolated growth hormone deficiency to Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074
13 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.12	ELF4	Achchuthan Shanmugasundram Publications for gene: ELF4 were set to 16264330; 34326534
13 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.11	ELF4	Achchuthan Shanmugasundram Tag Q2_25_ MOI tag was added to gene: ELF4. Tag Q2_25_expert_review tag was added to gene: ELF4.
13 Jun 2025	Autoinflammatory disorders v2.14	ELF4	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for this gene-disease association and hence this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available for this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS update.
13 Jun 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.11	ELF4	Achchuthan Shanmugasundram reviewed gene: ELF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34326534, 35266071, 36823308, 38231408, 38773005, 39563044, 39976696; Phenotypes: Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
13 Jun 2025	Autoinflammatory disorders v2.14	ELF4	Achchuthan Shanmugasundram Classified gene: ELF4 as Amber List (moderate evidence)
13 Jun 2025	Autoinflammatory disorders v2.14	ELF4	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for this gene-disease association and hence this gene can be promoted to green rating in the next GMS update.
13 Jun 2025	Autoinflammatory disorders v2.14	ELF4	Achchuthan Shanmugasundram Gene: elf4 has been classified as Amber List (Moderate Evidence).
13 Jun 2025	Autoinflammatory disorders v2.13	ELF4	Achchuthan Shanmugasundram Phenotypes for gene: ELF4 were changed from Autoinflammatory syndrome, familial, X-linked, Behcet-like 2 to Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074
13 Jun 2025	Autoinflammatory disorders v2.12	ELF4	Achchuthan Shanmugasundram Publications for gene: ELF4 were set to PMID: 35266071; PMID: 34326534; PMID: 39976696; PMID: 39563044; PMID: 38773005; PMID: 38231408; PMID: 36823308
13 Jun 2025	Autoinflammatory disorders v2.11	ELF4	Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous variants and autoinflammatory disorder, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'. The 'skewed X-inactivation' tag has also been added.; to: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder in PMID:39976696, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'. The 'Skewed X-inactivation' tag has also been added as skewed X chromosome inactivation patterns were observed in all three female patients in the same publication.
13 Jun 2025	Autoinflammatory disorders v2.11	ELF4	Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous variants and autoinflammatory disorder, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'. The 'skewed X-inactivation' tag has also been added.
13 Jun 2025	Autoinflammatory disorders v2.11	ELF4	Achchuthan Shanmugasundram Mode of inheritance for gene: ELF4 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)
13 Jun 2025	Autoinflammatory disorders v2.10	ELF4	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: ELF4. Tag Q2_25_ NHS_review tag was added to gene: ELF4.
13 Jun 2025	Autoinflammatory disorders v2.10	ELF4	Achchuthan Shanmugasundram Tag Skewed X-inactivation tag was added to gene: ELF4.
13 Jun 2025	Autoinflammatory disorders v2.10	ELF4	Achchuthan Shanmugasundram edited their review of gene: ELF4: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
13 Jun 2025	Autoinflammatory disorders v2.10	ELF4	Achchuthan Shanmugasundram edited their review of gene: ELF4: Added comment: PMID:34326534 - Two variants identified in three unrelated males with autoinflammatory disease characterised by fever, oral ulcers and mucosal inflammation. Supported by functional studies and mouse model. PMID:35266071 - Paediatric male patient identified with a hemizygous variant and was suffering from recurrent viral and bacterial respiratory infection, refractory oral ulcer, constipation, and arthritis. Supported by functional studies and mouse model. PMID:36823308 - Five more male patients presenting mainly with oral ulcer, inflammatory bowel disease-like symptoms, fever of unknown origin, anaemia, or systemic lupus erythematosus. PMID:38231408 - An international cohort of fourteen patients exhibiting a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anaemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. PMID:38773005 - A 11-year-old boy presented with a Behcet's-like phenotype including elevated inflammatory indicators, ileocecal ulcers and inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-alpha blocker. Supporting functional studies available. PMID:39563044 - Two male patients presented with recurrent oral ulcers and abdominal pain and had significant increase in inflammatory markers, multiple intestinal ulcers, and both patients developed intestinal fistulas. PMID:39976696 - Three unrelated paediatric female patients, who are all heterozygous for ELF4 variants. Similar to reported male patients, the main clinical features include recurring oral ulcers, abdominal pain and diarrhoea with colonoscopy showing ulcers in the colon. Skewed X chromosome inactivation patterns were observed in all three female patients, with over-inactivation of the X chromosome carrying the wild-type allele confirmed in two of them.; Changed publications to: 34326534, 35266071, 36823308, 38231408, 38773005, 39563044, 39976696
13 Jun 2025	Autoinflammatory disorders v2.10	ELF4	Achchuthan Shanmugasundram reviewed gene: ELF4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
13 Jun 2025	Autoinflammatory disorders v2.10	COPA	Achchuthan Shanmugasundram Tag Q2_25_ NHS_review tag was added to gene: COPA.
13 Jun 2025	Autoinflammatory disorders v2.10	ALPK1	Achchuthan Shanmugasundram Tag Q2_25_ NHS_review tag was added to gene: ALPK1.
13 Jun 2025	Autoinflammatory disorders v2.10	ALPK1	Achchuthan Shanmugasundram Classified gene: ALPK1 as Amber List (moderate evidence)
13 Jun 2025	Autoinflammatory disorders v2.10	ALPK1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available for the association of ALPK1 with an auto-inflammatory condition, ROSAH. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
13 Jun 2025	Autoinflammatory disorders v2.10	ALPK1	Achchuthan Shanmugasundram Gene: alpk1 has been classified as Amber List (Moderate Evidence).
13 Jun 2025	Autoinflammatory disorders v2.9	ALPK1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: ALPK1.
13 Jun 2025	Autoinflammatory disorders v2.9	ALPK1	Achchuthan Shanmugasundram Phenotypes for gene: ALPK1 were changed from Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, and migraine Headache syndrome (ROSAH) to ROSAH syndrome, OMIM:614979
13 Jun 2025	Autoinflammatory disorders v2.8	ALPK1	Achchuthan Shanmugasundram Publications for gene: ALPK1 were set to PMID: 30967659; PMID: 36332842; PMID: 38251500; PMID: 40069099; PMID: 35868845
13 Jun 2025	Autoinflammatory disorders v2.7	ALPK1	Achchuthan Shanmugasundram Mode of pathogenicity for gene: ALPK1 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
13 Jun 2025	GI tract tumours v1.26	MBD4	Arina Puzriakova Classified gene: MBD4 as Green List (high evidence)
13 Jun 2025	GI tract tumours v1.26	MBD4	Arina Puzriakova Gene: mbd4 has been classified as Green List (High Evidence).
13 Jun 2025	Autoinflammatory disorders v2.6	ALPK1	Achchuthan Shanmugasundram changed review comment from: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association. Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation. In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease. This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.; to: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association. Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation. In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease. Gain-of-function missense variants in ALPK1 were reported to cause ROSAH in PMID:35868845. This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.
13 Jun 2025	GI tract tumours v1.25	MBD4	Arina Puzriakova Classified gene: MBD4 as Amber List (moderate evidence)
13 Jun 2025	GI tract tumours v1.25	MBD4	Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, upgrading from Amber to Green.
13 Jun 2025	GI tract tumours v1.25	MBD4	Arina Puzriakova Gene: mbd4 has been classified as Amber List (Moderate Evidence).
13 Jun 2025	GI tract tumours v1.24	MBD4	Arina Puzriakova Publications for gene: MBD4 were set to 12417741; 30049810; 32239153; 35460607
13 Jun 2025	GI tract tumours v1.23	MBD4	Arina Puzriakova Phenotypes for gene: MBD4 were changed from Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2, OMIM:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
13 Jun 2025	Inherited predisposition to acute myeloid leukaemia (AML) v3.4	MBD4	Arina Puzriakova Phenotypes for gene: MBD4 were changed from Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2, OMIM:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
13 Jun 2025	Haematological malignancies cancer susceptibility v4.25	MBD4	Arina Puzriakova Phenotypes for gene: MBD4 were changed from Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2, OMIM:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
13 Jun 2025	Inherited polyposis and early onset colorectal cancer - germline testing v3.5	MBD4	Arina Puzriakova Phenotypes for gene: MBD4 were changed from Tumor predisposition syndrome 2:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2, OMIM:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
13 Jun 2025	Inherited polyposis and early onset colorectal cancer - germline testing v3.4	MBD4	Arina Puzriakova Phenotypes for gene: MBD4 were changed from Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
13 Jun 2025	Inherited polyposis and early onset colorectal cancer - germline testing v3.3	MBD4	Arina Puzriakova Publications for gene: MBD4 were set to 12417741; 30049810; 32239153; 35460607
13 Jun 2025	Inherited polyposis and early onset colorectal cancer - germline testing v3.2	MBD4	Arina Puzriakova Classified gene: MBD4 as Amber List (moderate evidence)
13 Jun 2025	Inherited polyposis and early onset colorectal cancer - germline testing v3.2	MBD4	Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, submitting again as it should be updated to Green at the next GMS panel update. This gene is also now green on the R347 signed-off panel (v3.0).
13 Jun 2025	Inherited polyposis and early onset colorectal cancer - germline testing v3.2	MBD4	Arina Puzriakova Gene: mbd4 has been classified as Amber List (Moderate Evidence).
13 Jun 2025	Autoinflammatory disorders v2.6	ALPK1	Achchuthan Shanmugasundram commented on gene: ALPK1: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association. Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation. In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease. This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.
13 Jun 2025	Inherited polyposis and early onset colorectal cancer - germline testing v3.1	MBD4	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MBD4. Tag Q2_25_ NHS_review tag was added to gene: MBD4.
13 Jun 2025	Familial tumours of the nervous system v2.3	CDKN2A	Arina Puzriakova Classified gene: CDKN2A as Amber List (moderate evidence)
13 Jun 2025	Familial tumours of the nervous system v2.3	CDKN2A	Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, it should be updated to Green at the next GMS panel update. Melanoma and neural system tumor syndrome (OMIM:155755) associated with heterozygous variants in the CDKN2A gene is characterised by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma.
13 Jun 2025	Familial tumours of the nervous system v2.3	CDKN2A	Arina Puzriakova Gene: cdkn2a has been classified as Amber List (Moderate Evidence).
13 Jun 2025	Familial tumours of the nervous system v2.2	CDKN2A	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: CDKN2A. Tag Q2_25_ NHS_review tag was added to gene: CDKN2A.
13 Jun 2025	Familial tumours of the nervous system v2.2	CDKN2A	Arina Puzriakova Phenotypes for gene: CDKN2A were changed from MELANOMA; PANCREATIC CANCER; ASTROCYTOMA; GLIOBLASTOMA; SCHWANNOMA; NEUROFIBROMA; MENINGIOMA; MALIGNANT PERIPHERAL NERVE SHEATH TUMOURS to {Melanoma and neural system tumor syndrome}, OMIM:155755; MELANOMA; PANCREATIC CANCER; ASTROCYTOMA; GLIOBLASTOMA; SCHWANNOMA; NEUROFIBROMA; MENINGIOMA; MALIGNANT PERIPHERAL NERVE SHEATH TUMOURS
13 Jun 2025	Autoinflammatory disorders v2.6	ALPK1	Achchuthan Shanmugasundram Source Literature was added to ALPK1.
13 Jun 2025	Autoinflammatory disorders v2.5	ALPK1	Achchuthan Shanmugasundram reviewed gene: ALPK1: 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: 30967659, 35868845, 36332842, 38251500, 40069099; Phenotypes: ROSAH syndrome, OMIM:614979; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
13 Jun 2025	Inherited breast cancer and ovarian cancer v2.15	BARD1	Arina Puzriakova Publications for gene: BARD1 were set to 33471991; 37592023; 15342711
13 Jun 2025	Inherited ovarian cancer (without breast cancer) v4.6	BARD1	Arina Puzriakova Phenotypes for gene: BARD1 were changed from {Breast cancer, susceptibility to}, 114480; Breast Cancer to {Breast cancer, susceptibility to}, OMIM:114480
13 Jun 2025	Inherited ovarian cancer (without breast cancer) v4.5	BARD1	Arina Puzriakova Mode of inheritance for gene: BARD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
13 Jun 2025	Familial breast cancer v1.24	BARD1	Arina Puzriakova Publications for gene: BARD1 were set to
13 Jun 2025	Familial breast cancer v1.23	BARD1	Arina Puzriakova Classified gene: BARD1 as Green List (high evidence)
13 Jun 2025	Familial breast cancer v1.23	BARD1	Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on breast cancer panels. Therefore, upgrading from Red to Green.
13 Jun 2025	Familial breast cancer v1.23	BARD1	Arina Puzriakova Gene: bard1 has been classified as Green List (High Evidence).
13 Jun 2025	Familial breast cancer v1.22	BARD1	Arina Puzriakova Mode of inheritance for gene: BARD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
13 Jun 2025	Inherited breast cancer and ovarian cancer v2.14	BARD1	Arina Puzriakova Classified gene: BARD1 as Amber List (moderate evidence)
13 Jun 2025	Inherited breast cancer and ovarian cancer v2.14	BARD1	Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, it should be updated to Green at the next GMS panel update.
13 Jun 2025	Inherited breast cancer and ovarian cancer v2.14	BARD1	Arina Puzriakova Gene: bard1 has been classified as Amber List (Moderate Evidence).
13 Jun 2025	Inherited breast cancer and ovarian cancer v2.13	BARD1	Arina Puzriakova commented on gene: BARD1
13 Jun 2025	Inherited breast cancer and ovarian cancer v2.13	BARD1	Arina Puzriakova Publications for gene: BARD1 were set to PMID: 33471991
13 Jun 2025	Familial breast cancer v1.21	BARD1	Arina Puzriakova Phenotypes for gene: BARD1 were changed from {Breast cancer, susceptibility to}, 114480; Breast Cancer to {Breast cancer, susceptibility to}, OMIM:114480
13 Jun 2025	Inherited breast cancer and ovarian cancer v2.12	BARD1	Arina Puzriakova Phenotypes for gene: BARD1 were changed from breast cancer to {Breast cancer, susceptibility to}, OMIM:114480
13 Jun 2025	Inherited breast cancer and ovarian cancer v2.11	BARD1	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: BARD1. Tag Q2_25_ NHS_review tag was added to gene: BARD1.
12 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.2	CCDC65	Arina Puzriakova Publications for gene: CCDC65 were set to
12 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.1	CCDC65	Arina Puzriakova Tag founder-effect tag was added to gene: CCDC65.
12 Jun 2025	Undiagnosed metabolic disorders v1.629	USF1	Achchuthan Shanmugasundram Tag Q1_25_ demote_amber was removed from gene: USF1. Tag Q1_25_ NHS_review was removed from gene: USF1. Tag Q1_25_ MOI was removed from gene: USF1. Tag Q1_25_ promote_green was removed from gene: USF1. Tag Q1_25_ demote_red was removed from gene: USF1. Tag Q1_25_ expert_review was removed from gene: USF1. Tag Q1_25_ phenotype was removed from gene: USF1.
11 Jun 2025	Cerebral vascular malformations v4.4	ANO1	Eleanor Williams commented on gene: ANO1
11 Jun 2025	Likely inborn error of metabolism v8.54	TEFM	Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
11 Jun 2025	Likely inborn error of metabolism v8.54	TEFM	Achchuthan Shanmugasundram Added comment: Comment on list classification: TEFM has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/TEFM/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
11 Jun 2025	Likely inborn error of metabolism v8.54	TEFM	Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
10 Jun 2025	Likely inborn error of metabolism v8.53	TEFM	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: TEFM.
10 Jun 2025	Likely inborn error of metabolism v8.53	TEFM	Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
10 Jun 2025	Likely inborn error of metabolism v8.53	TEFM	Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
10 Jun 2025	Likely inborn error of metabolism v8.52	TEFM	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
10 Jun 2025	Likely inborn error of metabolism v8.52	TEFM	Achchuthan Shanmugasundram gene: TEFM was added gene: TEFM was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS,Literature Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TEFM were set to 36823193 Phenotypes for gene: TEFM were set to Combined oxidative phosphorylation deficiency 58, OMIM:620451
10 Jun 2025	Likely inborn error of metabolism v8.51	TAMM41	Achchuthan Shanmugasundram Classified gene: TAMM41 as Amber List (moderate evidence)
10 Jun 2025	Likely inborn error of metabolism v8.51	TAMM41	Achchuthan Shanmugasundram Added comment: Comment on list classification: TAMM41 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/TAMM41/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
10 Jun 2025	Likely inborn error of metabolism v8.51	TAMM41	Achchuthan Shanmugasundram Gene: tamm41 has been classified as Amber List (Moderate Evidence).
10 Jun 2025	Likely inborn error of metabolism v8.50	TAMM41	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: TAMM41.
10 Jun 2025	Likely inborn error of metabolism v8.50	TAMM41	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
10 Jun 2025	Likely inborn error of metabolism v8.50	TAMM41	Achchuthan Shanmugasundram gene: TAMM41 was added gene: TAMM41 was added to Likely inborn error of metabolism. Sources: NHS GMS,Literature,Expert Review Green Mode of inheritance for gene: TAMM41 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TAMM41 were set to 35321494 Phenotypes for gene: TAMM41 were set to Combined oxidative phosphorylation deficiency 56, OMIM:620139
10 Jun 2025	Likely inborn error of metabolism v8.49	SUPV3L1	Achchuthan Shanmugasundram reviewed gene: SUPV3L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
10 Jun 2025	Likely inborn error of metabolism v8.49	SUPV3L1	Achchuthan Shanmugasundram Tag Q1_25_ promote_green was removed from gene: SUPV3L1. Tag Q2_25_ promote_green tag was added to gene: SUPV3L1.
10 Jun 2025	Likely inborn error of metabolism v8.49	SUPV3L1	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
10 Jun 2025	Likely inborn error of metabolism v8.49	SUPV3L1	Achchuthan Shanmugasundram gene: SUPV3L1 was added gene: SUPV3L1 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber Q1_25_ promote_green tags were added to gene: SUPV3L1. Mode of inheritance for gene: SUPV3L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SUPV3L1 were set to 35023579; 39596606 Phenotypes for gene: SUPV3L1 were set to Mitochondrial RNA Helicase SUPV3L1-Associated neurodegenerative syndrome
10 Jun 2025	Likely inborn error of metabolism v8.48	SPATA5	Achchuthan Shanmugasundram Classified gene: SPATA5 as Amber List (moderate evidence)
10 Jun 2025	Likely inborn error of metabolism v8.48	SPATA5	Achchuthan Shanmugasundram Added comment: Comment on list classification: SPATA5 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SPATA5/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
10 Jun 2025	Likely inborn error of metabolism v8.48	SPATA5	Achchuthan Shanmugasundram Gene: spata5 has been classified as Amber List (Moderate Evidence).
10 Jun 2025	Likely inborn error of metabolism v8.47	SPATA5	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SPATA5.
10 Jun 2025	Likely inborn error of metabolism v8.47	SPATA5	Achchuthan Shanmugasundram reviewed gene: SPATA5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
10 Jun 2025	Likely inborn error of metabolism v8.47	SPATA5	Achchuthan Shanmugasundram Deleted their review
10 Jun 2025	Likely inborn error of metabolism v8.47	SPATA5	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
10 Jun 2025	Likely inborn error of metabolism v8.47	SPATA5	Achchuthan Shanmugasundram gene: SPATA5 was added gene: SPATA5 was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS,Literature new-gene-name tags were added to gene: SPATA5. Mode of inheritance for gene: SPATA5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPATA5 were set to 27246907; 29343804; 26299366; 28293831; 30009132; 36849973 Phenotypes for gene: SPATA5 were set to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577 Penetrance for gene: SPATA5 were set to Complete
10 Jun 2025	Likely inborn error of metabolism v8.46	SLC25A36	Achchuthan Shanmugasundram Classified gene: SLC25A36 as Amber List (moderate evidence)
10 Jun 2025	Likely inborn error of metabolism v8.46	SLC25A36	Achchuthan Shanmugasundram Added comment: Comment on list classification: SLC25A36 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SLC25A36/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
10 Jun 2025	Likely inborn error of metabolism v8.46	SLC25A36	Achchuthan Shanmugasundram Gene: slc25a36 has been classified as Amber List (Moderate Evidence).
10 Jun 2025	Likely inborn error of metabolism v8.45	SLC25A36	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SLC25A36.
10 Jun 2025	Likely inborn error of metabolism v8.45	SLC25A36	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
10 Jun 2025	Likely inborn error of metabolism v8.45	SLC25A36	Achchuthan Shanmugasundram gene: SLC25A36 was added gene: SLC25A36 was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Green,Literature Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC25A36 were set to 34576089; 34971397; 36695547 Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8, OMIM:620211
09 Jun 2025	Likely inborn error of metabolism v8.44	SLC25A24	Achchuthan Shanmugasundram Classified gene: SLC25A24 as Amber List (moderate evidence)
09 Jun 2025	Likely inborn error of metabolism v8.44	SLC25A24	Achchuthan Shanmugasundram Added comment: Comment on list classification: SLC25A24 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SLC25A24/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
09 Jun 2025	Likely inborn error of metabolism v8.44	SLC25A24	Achchuthan Shanmugasundram Gene: slc25a24 has been classified as Amber List (Moderate Evidence).
09 Jun 2025	Likely inborn error of metabolism v8.43	SLC25A24	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SLC25A24.
09 Jun 2025	Likely inborn error of metabolism v8.43	SLC25A24	Achchuthan Shanmugasundram reviewed gene: SLC25A24: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
09 Jun 2025	Likely inborn error of metabolism v8.43	SLC25A24	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
09 Jun 2025	Likely inborn error of metabolism v8.43	SLC25A24	Achchuthan Shanmugasundram gene: SLC25A24 was added gene: SLC25A24 was added to Likely inborn error of metabolism. Sources: Expert list,NHS GMS,Expert Review Green Mode of inheritance for gene: SLC25A24 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC25A24 were set to 29903433; 29100093; 29100094 Phenotypes for gene: SLC25A24 were set to Fontaine progeroid syndrome, OMIM:612289; Fontaine progeroid syndrome, MONDO:0012853
09 Jun 2025	Mitochondrial disorders v9.19	SLC25A24	Achchuthan Shanmugasundram Phenotypes for gene: SLC25A24 were changed from Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853 to Fontaine progeroid syndrome, OMIM:612289; Fontaine progeroid syndrome, MONDO:0012853
09 Jun 2025	Likely inborn error of metabolism v8.42	QARS	Achchuthan Shanmugasundram Classified gene: QARS as Amber List (moderate evidence)
09 Jun 2025	Likely inborn error of metabolism v8.42	QARS	Achchuthan Shanmugasundram Added comment: Comment on list classification: QARS has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/QARS/). Hence, this gene can also be promoted to green rating on this panel in the next GMS update.
09 Jun 2025	Likely inborn error of metabolism v8.42	QARS	Achchuthan Shanmugasundram Gene: qars has been classified as Amber List (Moderate Evidence).
09 Jun 2025	Likely inborn error of metabolism v8.41	QARS	Achchuthan Shanmugasundram Phenotypes for gene: QARS were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, OMIM:615760
09 Jun 2025	Likely inborn error of metabolism v8.40	QARS	Achchuthan Shanmugasundram Publications for gene: QARS were set to 28620870; 25471517; 25432320; 25041233; 24656866
09 Jun 2025	Likely inborn error of metabolism v8.39	QARS	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: QARS.
09 Jun 2025	Likely inborn error of metabolism v8.39	QARS	Achchuthan Shanmugasundram reviewed gene: QARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32042906; Phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, OMIM:615760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
09 Jun 2025	Likely inborn error of metabolism v8.39	POLRMT	Achchuthan Shanmugasundram Classified gene: POLRMT as Amber List (moderate evidence)
09 Jun 2025	Likely inborn error of metabolism v8.39	POLRMT	Achchuthan Shanmugasundram Added comment: Comment on list classification: POLRMT has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/POLRMT/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
09 Jun 2025	Likely inborn error of metabolism v8.39	POLRMT	Achchuthan Shanmugasundram Gene: polrmt has been classified as Amber List (Moderate Evidence).
09 Jun 2025	Likely inborn error of metabolism v8.38	POLRMT	Achchuthan Shanmugasundram reviewed gene: POLRMT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
09 Jun 2025	Likely inborn error of metabolism v8.38	POLRMT	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: POLRMT.
09 Jun 2025	Likely inborn error of metabolism v8.38	POLRMT	Achchuthan Shanmugasundram Deleted their review
09 Jun 2025	Likely inborn error of metabolism v8.38	POLRMT	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.18
09 Jun 2025	Likely inborn error of metabolism v8.38	POLRMT	Achchuthan Shanmugasundram gene: POLRMT was added gene: POLRMT was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Green Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: POLRMT were set to 24386581; 33602924 Phenotypes for gene: POLRMT were set to Combined oxidative phosphorylation deficiency 55, OMIM:619743
07 Jun 2025	Likely inborn error of metabolism v8.37	PITRM1	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene has already been promoted to green rating on the Mitochondrial disorder panel. Hence, this gene can be promoted to green rating on this panel in the next GMS update.; to: Comment on list classification: This gene has already been promoted to green rating on the Mitochondrial disorders panel. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.37	PITRM1	Achchuthan Shanmugasundram Phenotypes for gene: PITRM1 were changed from Spinocerebellar ataxia, autosomal recessive 30, OMIM:61940 to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
07 Jun 2025	Likely inborn error of metabolism v8.36	PITRM1	Achchuthan Shanmugasundram Classified gene: PITRM1 as Amber List (moderate evidence)
07 Jun 2025	Likely inborn error of metabolism v8.36	PITRM1	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has already been promoted to green rating on the Mitochondrial disorder panel. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.36	PITRM1	Achchuthan Shanmugasundram Gene: pitrm1 has been classified as Amber List (Moderate Evidence).
07 Jun 2025	Likely inborn error of metabolism v8.35	PITRM1	Achchuthan Shanmugasundram Phenotypes for gene: PITRM1 were changed from mental retardation, spinocerebellar ataxia, cognitive decline and psychosis to Spinocerebellar ataxia, autosomal recessive 30, OMIM:61940
07 Jun 2025	Likely inborn error of metabolism v8.34	PITRM1	Achchuthan Shanmugasundram commented on gene: PITRM1: Zornitza Stark (Australian Genomics) reviewed on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/PITRM1/) that three families were reported with two unique variants, and mitochondrial dysfunction was identified in in vitro functional assays and mouse model.
07 Jun 2025	Likely inborn error of metabolism v8.34	PITRM1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: PITRM1.
07 Jun 2025	Likely inborn error of metabolism v8.34	PITRM1	Achchuthan Shanmugasundram reviewed gene: PITRM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Jun 2025	Mitochondrial disorders v9.18	PITRM1	Achchuthan Shanmugasundram Phenotypes for gene: PITRM1 were changed from mental retardation, spinocerebellar ataxia, cognitive decline and psychosis to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
07 Jun 2025	Ataxia and cerebellar anomalies - narrow panel v8.4	PITRM1	Achchuthan Shanmugasundram Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
07 Jun 2025	Likely inborn error of metabolism v8.34	MRPL49	Achchuthan Shanmugasundram Classified gene: MRPL49 as Amber List (moderate evidence)
07 Jun 2025	Likely inborn error of metabolism v8.34	MRPL49	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of MRPL49 with combined oxidative phosphorylation deficiency phenotype. This gene is currently being recommended for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/MRPL49/). Hence, this gene can also be considered for promotion to green rating on this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.34	MRPL49	Achchuthan Shanmugasundram Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
07 Jun 2025	Likely inborn error of metabolism v8.33	MRPL49	Achchuthan Shanmugasundram reviewed gene: MRPL49: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Jun 2025	Likely inborn error of metabolism v8.33	MRPL49	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.17
07 Jun 2025	Likely inborn error of metabolism v8.33	MRPL49	Achchuthan Shanmugasundram gene: MRPL49 was added gene: MRPL49 was added to Likely inborn error of metabolism. Sources: Expert Review Amber,Literature Q2_25_ promote_green tags were added to gene: MRPL49. Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPL49 were set to 40043708 Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732
07 Jun 2025	Likely inborn error of metabolism v8.32	MRPL39	Achchuthan Shanmugasundram Classified gene: MRPL39 as Amber List (moderate evidence)
07 Jun 2025	Likely inborn error of metabolism v8.32	MRPL39	Achchuthan Shanmugasundram Added comment: Comment on list classification: MRPL39 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/MRPL39/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.32	MRPL39	Achchuthan Shanmugasundram Gene: mrpl39 has been classified as Amber List (Moderate Evidence).
07 Jun 2025	Likely inborn error of metabolism v8.31	MRPL39	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MRPL39.
07 Jun 2025	Likely inborn error of metabolism v8.31	MRPL39	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.17
07 Jun 2025	Likely inborn error of metabolism v8.31	MRPL39	Achchuthan Shanmugasundram gene: MRPL39 was added gene: MRPL39 was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Green,Literature Mode of inheritance for gene: MRPL39 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPL39 were set to 37133451 Phenotypes for gene: MRPL39 were set to Combined oxidative phosphorylation deficiency 59, OMIM:620646
07 Jun 2025	Likely inborn error of metabolism v8.30	LIG3	Achchuthan Shanmugasundram Classified gene: LIG3 as Amber List (moderate evidence)
07 Jun 2025	Likely inborn error of metabolism v8.30	LIG3	Achchuthan Shanmugasundram Added comment: Comment on list classification: LIG3 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/LIG3/). As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.30	LIG3	Achchuthan Shanmugasundram Gene: lig3 has been classified as Amber List (Moderate Evidence).
07 Jun 2025	Likely inborn error of metabolism v8.29	LIG3	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: LIG3.
07 Jun 2025	Likely inborn error of metabolism v8.29	LIG3	Achchuthan Shanmugasundram Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion to Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780
07 Jun 2025	Likely inborn error of metabolism v8.28	LIG3	Achchuthan Shanmugasundram Marked gene: LIG3 as ready
07 Jun 2025	Likely inborn error of metabolism v8.28	LIG3	Achchuthan Shanmugasundram Gene: lig3 has been classified as Green List (High Evidence).
07 Jun 2025	Likely inborn error of metabolism v8.28	LIG3	Achchuthan Shanmugasundram reviewed gene: LIG3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Jun 2025	Mitochondrial disorders v9.17	LIG3	Achchuthan Shanmugasundram Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion to Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780
07 Jun 2025	White matter disorders and cerebral calcification - narrow panel v7.3	LIG3	Achchuthan Shanmugasundram Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion to Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780
07 Jun 2025	Likely inborn error of metabolism v8.28	LIG3	Achchuthan Shanmugasundram Entity copied from White matter disorders and cerebral calcification - narrow panel v7.2
07 Jun 2025	Likely inborn error of metabolism v8.28	LIG3	Achchuthan Shanmugasundram gene: LIG3 was added gene: LIG3 was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS,Literature Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIG3 were set to 33855352 Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
07 Jun 2025	Likely inborn error of metabolism v8.27	KIAA0391	Achchuthan Shanmugasundram Classified gene: KIAA0391 as Amber List (moderate evidence)
07 Jun 2025	Likely inborn error of metabolism v8.27	KIAA0391	Achchuthan Shanmugasundram Added comment: Comment on list classification: KIAA0391 (PRORP) has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/KIAA0391/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.27	KIAA0391	Achchuthan Shanmugasundram Gene: kiaa0391 has been classified as Amber List (Moderate Evidence).
07 Jun 2025	Likely inborn error of metabolism v8.26	KIAA0391	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: KIAA0391.
07 Jun 2025	Likely inborn error of metabolism v8.26	KIAA0391	Achchuthan Shanmugasundram reviewed gene: KIAA0391: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 54, OMIM:619737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Jun 2025	Likely inborn error of metabolism v8.26	KIAA0391	Achchuthan Shanmugasundram Deleted their review
07 Jun 2025	Likely inborn error of metabolism v8.26	KIAA0391	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.16
07 Jun 2025	Likely inborn error of metabolism v8.26	KIAA0391	Achchuthan Shanmugasundram gene: KIAA0391 was added gene: KIAA0391 was added to Likely inborn error of metabolism. Sources: Literature,NHS GMS,Expert Review Green new-gene-name tags were added to gene: KIAA0391. Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA0391 were set to 34715011 Phenotypes for gene: KIAA0391 were set to Combined oxidative phosphorylation deficiency 54, OMIM:619737
07 Jun 2025	Mitochondrial disorders v9.16	KIAA0391	Achchuthan Shanmugasundram Phenotypes for gene: KIAA0391 were changed from Hearing loss, intellectual disability to Combined oxidative phosphorylation deficiency 54, OMIM:619737
07 Jun 2025	Mitochondrial disorders v9.15	KIAA0391	Achchuthan Shanmugasundram edited their review of gene: KIAA0391: Changed phenotypes to: Combined oxidative phosphorylation deficiency 54, OMIM:619737; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Jun 2025	Likely inborn error of metabolism v8.25	IDH3A	Achchuthan Shanmugasundram Classified gene: IDH3A as Amber List (moderate evidence)
07 Jun 2025	Likely inborn error of metabolism v8.25	IDH3A	Achchuthan Shanmugasundram Added comment: Comment on list classification: IDH3A has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/IDH3A/) as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.25	IDH3A	Achchuthan Shanmugasundram Gene: idh3a has been classified as Amber List (Moderate Evidence).
07 Jun 2025	Likely inborn error of metabolism v8.24	HPDL	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating in this panel in the next GMS update.; to: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating on this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.24	IDH3A	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: IDH3A.
07 Jun 2025	Likely inborn error of metabolism v8.24	IDH3A	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
07 Jun 2025	Likely inborn error of metabolism v8.24	IDH3A	Achchuthan Shanmugasundram gene: IDH3A was added gene: IDH3A was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS Mode of inheritance for gene: IDH3A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IDH3A were set to 31012789; 30478029; 30058936; 28412069; 28058510 Phenotypes for gene: IDH3A were set to Retinitis pigmentosa 90, OMIM:619007; retinitis pigmentosa 90, MONDO:0033563
07 Jun 2025	Likely inborn error of metabolism v8.23	HPDL	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating in this panel in the next GMS update.; to: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating in this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.23	HPDL	Achchuthan Shanmugasundram Classified gene: HPDL as Amber List (moderate evidence)
07 Jun 2025	Likely inborn error of metabolism v8.23	HPDL	Achchuthan Shanmugasundram Added comment: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating in this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.23	HPDL	Achchuthan Shanmugasundram Gene: hpdl has been classified as Amber List (Moderate Evidence).
07 Jun 2025	Likely inborn error of metabolism v8.22	HPDL	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: HPDL.
07 Jun 2025	Likely inborn error of metabolism v8.22	HPDL	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
07 Jun 2025	Likely inborn error of metabolism v8.22	HPDL	Achchuthan Shanmugasundram gene: HPDL was added gene: HPDL was added to Likely inborn error of metabolism. Sources: Literature,NHS GMS,Expert Review Green gene-checked tags were added to gene: HPDL. Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HPDL were set to 32707086 Phenotypes for gene: HPDL were set to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities OMIM:619026; Spastic paraplegia 83, autosomal recessive OMIM:619027
07 Jun 2025	Likely inborn error of metabolism v8.21	CYCS	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: CYCS.
07 Jun 2025	Likely inborn error of metabolism v8.21	CYCS	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain. This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/) and can therefore be promoted to green rating in the next GMS update.; to: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain. This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/) and can therefore be promoted to green rating in this panel in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.21	CYCS	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain. This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/). This gene can therefore be promoted to green rating in the next GMS update.; to: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain. This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/) and can therefore be promoted to green rating in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.21	CYCS	Achchuthan Shanmugasundram Classified gene: CYCS as Amber List (moderate evidence)
07 Jun 2025	Likely inborn error of metabolism v8.21	CYCS	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain. This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/). This gene can therefore be promoted to green rating in the next GMS update.
07 Jun 2025	Likely inborn error of metabolism v8.21	CYCS	Achchuthan Shanmugasundram Gene: cycs has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Likely inborn error of metabolism v8.20	CYCS	Achchuthan Shanmugasundram Publications for gene: CYCS were set to 24326104; PMID: 18345000
06 Jun 2025	Likely inborn error of metabolism v8.19	CYCS	Achchuthan Shanmugasundram reviewed gene: CYCS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
06 Jun 2025	Likely inborn error of metabolism v8.19	COX6A2	Achchuthan Shanmugasundram Classified gene: COX6A2 as Amber List (moderate evidence)
06 Jun 2025	Likely inborn error of metabolism v8.19	COX6A2	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX6A2/).
06 Jun 2025	Likely inborn error of metabolism v8.19	COX6A2	Achchuthan Shanmugasundram Gene: cox6a2 has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Likely inborn error of metabolism v8.18	COX6A2	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: COX6A2.
06 Jun 2025	Likely inborn error of metabolism v8.18	COX6A2	Achchuthan Shanmugasundram reviewed gene: COX6A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Likely inborn error of metabolism v8.18	COX6A2	Achchuthan Shanmugasundram Deleted their review
06 Jun 2025	Likely inborn error of metabolism v8.18	COX6A2	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
06 Jun 2025	Likely inborn error of metabolism v8.18	COX6A2	Achchuthan Shanmugasundram gene: COX6A2 was added gene: COX6A2 was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Green Mode of inheritance for gene: COX6A2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COX6A2 were set to 23460811; 31155743; 32744742 Phenotypes for gene: COX6A2 were set to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
06 Jun 2025	Likely inborn error of metabolism v8.17	C2orf69	Achchuthan Shanmugasundram edited their review of gene: C2orf69: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Likely inborn error of metabolism v8.17	COX11	Achchuthan Shanmugasundram edited their review of gene: COX11: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Likely inborn error of metabolism v8.17	COX11	Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/C2orf69/).; to: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX11/).
06 Jun 2025	Likely inborn error of metabolism v8.17	COX11	Achchuthan Shanmugasundram Classified gene: COX11 as Amber List (moderate evidence)
06 Jun 2025	Likely inborn error of metabolism v8.17	COX11	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/C2orf69/).
06 Jun 2025	Likely inborn error of metabolism v8.17	COX11	Achchuthan Shanmugasundram Gene: cox11 has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Likely inborn error of metabolism v8.16	COX11	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: COX11.
06 Jun 2025	Likely inborn error of metabolism v8.16	COX11	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
06 Jun 2025	Likely inborn error of metabolism v8.16	COX11	Achchuthan Shanmugasundram gene: COX11 was added gene: COX11 was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COX11 were set to 36030551; 38068960 Phenotypes for gene: COX11 were set to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
06 Jun 2025	Likely inborn error of metabolism v8.15	C2orf69	Achchuthan Shanmugasundram Classified gene: C2orf69 as Amber List (moderate evidence)
06 Jun 2025	Likely inborn error of metabolism v8.15	C2orf69	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/C2orf69/).
06 Jun 2025	Likely inborn error of metabolism v8.15	C2orf69	Achchuthan Shanmugasundram Gene: c2orf69 has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Likely inborn error of metabolism v8.14	C2orf69	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: C2orf69.
06 Jun 2025	Likely inborn error of metabolism v8.14	C2orf69	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
06 Jun 2025	Likely inborn error of metabolism v8.14	C2orf69	Achchuthan Shanmugasundram gene: C2orf69 was added gene: C2orf69 was added to Likely inborn error of metabolism. Sources: Literature,NHS GMS,Expert Review Green gene-checked tags were added to gene: C2orf69. Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C2orf69 were set to 34038740; 33945503 Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency 53, OMIM:619423
06 Jun 2025	Likely inborn error of metabolism v8.13	TOMM7	Achchuthan Shanmugasundram Classified gene: TOMM7 as Amber List (moderate evidence)
06 Jun 2025	Likely inborn error of metabolism v8.13	TOMM7	Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with biallelic variants in TOMM7 gene and with Garg-Mishra progeroid syndrome (MIM #620601). This gene has already been recommended for promotion to green rating on R63 Possible mitochondrial disorder - nuclear genes (https://panelapp.genomicsengland.co.uk/panels/539/gene/TOMM7/) and Mitochondrial disorders (https://panelapp.genomicsengland.co.uk/panels/112/gene/TOMM7/) panels. Hence, this gene should also be recommended for promotion to green rating on this panel.
06 Jun 2025	Likely inborn error of metabolism v8.13	TOMM7	Achchuthan Shanmugasundram Gene: tomm7 has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Likely inborn error of metabolism v8.12	TOMM7	Achchuthan Shanmugasundram reviewed gene: TOMM7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Mitochondrial disorders v9.15	TOMM7	Achchuthan Shanmugasundram edited their review of gene: TOMM7: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Likely inborn error of metabolism v8.12	TOMM7	Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: TOMM7. Tag Q3_24_NHS_review was removed from gene: TOMM7. Tag Q2_25_ promote_green tag was added to gene: TOMM7.
06 Jun 2025	Likely inborn error of metabolism v8.12	TOMM7	Achchuthan Shanmugasundram Entity copied from Possible mitochondrial disorder - nuclear genes v4.6
06 Jun 2025	Likely inborn error of metabolism v8.12	TOMM7	Achchuthan Shanmugasundram gene: TOMM7 was added gene: TOMM7 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber Q3_24_promote_green, Q3_24_NHS_review tags were added to gene: TOMM7. Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOMM7 were set to 36282599; 36299998; 39333057 Phenotypes for gene: TOMM7 were set to Garg-Mishra progeroid syndrome, OMIM:620601; Garg-Mishra progeroid syndrome, MONDO:0957953
06 Jun 2025	Likely inborn error of metabolism v8.11	SQOR	Achchuthan Shanmugasundram Classified gene: SQOR as Amber List (moderate evidence)
06 Jun 2025	Likely inborn error of metabolism v8.11	SQOR	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is currently being recommended for green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SQOR/), as there are two unrelated families and some functional evidence available in support of the association of SQOR gene with Sulfide:quinone oxidoreductase deficiency. Hence, this gene should also be promoted to green rating on this panel.
06 Jun 2025	Likely inborn error of metabolism v8.11	SQOR	Achchuthan Shanmugasundram Gene: sqor has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Likely inborn error of metabolism v8.10	SQOR	Achchuthan Shanmugasundram Phenotypes for gene: SQOR were changed from Leigh syndrome to Sulfide:quinone oxidoreductase deficiency, OMIM:619221
06 Jun 2025	Mitochondrial disorders v9.15	SQOR	Achchuthan Shanmugasundram Phenotypes for gene: SQOR were changed from Leigh syndrome to Sulfide:quinone oxidoreductase deficiency, OMIM:619221
06 Jun 2025	Likely inborn error of metabolism v8.9	SQOR	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.14
06 Jun 2025	Likely inborn error of metabolism v8.9	SQOR	Achchuthan Shanmugasundram gene: SQOR was added gene: SQOR was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber Q2_25_ promote_green tags were added to gene: SQOR. Mode of inheritance for gene: SQOR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SQOR were set to 32160317 Phenotypes for gene: SQOR were set to Leigh syndrome
06 Jun 2025	Likely inborn error of metabolism v8.8	COX4I1	Achchuthan Shanmugasundram Phenotypes for gene: COX4I1 were changed from Mitochondrial Diseases; No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060
06 Jun 2025	Likely inborn error of metabolism v8.7	COX4I1	Achchuthan Shanmugasundram Publications for gene: COX4I1 were set to
06 Jun 2025	Likely inborn error of metabolism v8.7	COX4I1	Achchuthan Shanmugasundram Mode of inheritance for gene: COX4I1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Likely inborn error of metabolism v8.6	COX4I1	Achchuthan Shanmugasundram Classified gene: COX4I1 as Amber List (moderate evidence)
06 Jun 2025	Likely inborn error of metabolism v8.6	COX4I1	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should also be rated green on this panel as this has already been rated green on R356 Mitochondrial disorder with complex IV deficiency panel (https://panelapp.genomicsengland.co.uk/panels/537/gene/COX4I1/) and is being currently recommended for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX4I1/). There are two unrelated cases and functional evidence in support of the association of this gene with Mitochondrial complex IV deficiency.
06 Jun 2025	Likely inborn error of metabolism v8.6	COX4I1	Achchuthan Shanmugasundram Gene: cox4i1 has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Likely inborn error of metabolism v8.5	COX4I1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: COX4I1.
06 Jun 2025	Likely inborn error of metabolism v8.5	COX4I1	Achchuthan Shanmugasundram changed review comment from: This gene should also be rated green on this panel as this has already been rated green on R356 Mitochondrial disorder with complex IV deficiency panel (https://panelapp.genomicsengland.co.uk/panels/537/gene/COX4I1/) and is being currently recommended for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX4I1/). PMID:28766551 reported a 5-year-old girl identified with homozygous COX4I1 variant (p.(Lys101_Thr102delinsAsnSer)) and mitochondrial complex IV deficiency, which segregated with the disorder in the family. PMID:31290619 reported two brothers of Iraqi descent, identified with a homozygous missense variant in the COX4I1 gene (p.(Pro152Thr)) and mitochondrial complex IV deficiency, which also segregated with the disorder in the family. There is also functional evidence available from the above publications. This gene is also associated with relevant phenotypes in OMIM (MIM #619060).; to: PMID:28766551 reported a 5-year-old girl identified with homozygous COX4I1 variant (p.(Lys101_Thr102delinsAsnSer)) and mitochondrial complex IV deficiency, which segregated with the disorder in the family. PMID:31290619 reported two brothers of Iraqi descent, identified with a homozygous missense variant in the COX4I1 gene (p.(Pro152Thr)) and mitochondrial complex IV deficiency, which also segregated with the disorder in the family. There is also functional evidence available from the above publications. This gene is also associated with relevant phenotypes in OMIM (MIM #619060).
06 Jun 2025	Likely inborn error of metabolism v8.5	COX4I1	Achchuthan Shanmugasundram reviewed gene: COX4I1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28766551, 31290619, 33578848; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Mitochondrial disorders v9.14	TOMM7	Achchuthan Shanmugasundram Classified gene: TOMM7 as Amber List (moderate evidence)
06 Jun 2025	Mitochondrial disorders v9.14	TOMM7	Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are three unrelated cases reported with biallelic TOMM7 variants and this gene has already been recommended for green rating on R63 Possible mitochondrial disorder - nuclear genes (https://panelapp.genomicsengland.co.uk/panels/539/gene/TOMM7/) panel, this gene is being recommended for promotion to green rating on this panel too.
06 Jun 2025	Mitochondrial disorders v9.14	TOMM7	Achchuthan Shanmugasundram Gene: tomm7 has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Mitochondrial disorders v9.13	TOMM7	Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: TOMM7. Tag Q3_24_NHS_review was removed from gene: TOMM7. Tag Q2_25_ promote_green tag was added to gene: TOMM7.
06 Jun 2025	Mitochondrial disorders v9.13	TOMM7	Achchuthan Shanmugasundram Entity copied from Possible mitochondrial disorder - nuclear genes v4.6
06 Jun 2025	Mitochondrial disorders v9.13	TOMM7	Achchuthan Shanmugasundram gene: TOMM7 was added gene: TOMM7 was added to Mitochondrial disorders. Sources: Literature,Expert Review Amber Q3_24_promote_green, Q3_24_NHS_review tags were added to gene: TOMM7. Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOMM7 were set to 36282599; 36299998; 39333057 Phenotypes for gene: TOMM7 were set to Garg-Mishra progeroid syndrome, OMIM:620601; Garg-Mishra progeroid syndrome, MONDO:0957953
06 Jun 2025	Mitochondrial disorders v9.12	HSPA9	Achchuthan Shanmugasundram Classified gene: HSPA9 as Amber List (moderate evidence)
06 Jun 2025	Mitochondrial disorders v9.12	HSPA9	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has already been promoted to green rating on R63 Possible mitochondrial disorder - nuclear genes panel (https://panelapp.genomicsengland.co.uk/panels/539/gene/HSPA9/), in agreement with the NHS Genomic Medicine Service. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
06 Jun 2025	Mitochondrial disorders v9.12	HSPA9	Achchuthan Shanmugasundram Gene: hspa9 has been classified as Amber List (Moderate Evidence).
06 Jun 2025	Mitochondrial disorders v9.11	HSPA9	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: HSPA9.
06 Jun 2025	Mitochondrial disorders v9.11	HSPA9	Achchuthan Shanmugasundram Phenotypes for gene: HSPA9 were changed from EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia; Epiphyseal, Vertebral, Ear, Nose, plus associated findings to Even-plus syndrome, OMIM:616854; Anemia, sideroblastic, 4, OMIM:182170
06 Jun 2025	Mitochondrial disorders v9.10	HSPA9	Achchuthan Shanmugasundram Publications for gene: HSPA9 were set to PMID: 26598328
06 Jun 2025	Mitochondrial disorders v9.9	HSPA9	Achchuthan Shanmugasundram edited their review of gene: HSPA9: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Mitochondrial disorders v9.9	HSPA9	Achchuthan Shanmugasundram reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26491070, 26598328, 32869452, 35779070, 36052765; Phenotypes: Even-plus syndrome, OMIM:616854, Anemia, sideroblastic, 4, OMIM:182170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.6	COX14	Achchuthan Shanmugasundram Phenotypes for gene: COX14 were changed from ?Mitochondrial complex IV deficiency, 220110 to ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.5	COX14	Achchuthan Shanmugasundram Publications for gene: COX14 were set to
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.4	COX14	Achchuthan Shanmugasundram Classified gene: COX14 as Green List (high evidence)
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.4	COX14	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has also been demoted from green to amber on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX14/) in response to review from Zornitza Stark (Australian Genomics), and in agreement with the NHS Genomic Medicine Service. Hence, this gene is recommended for demotion on this panel and opinion is being sought from the NHS mitochondrial specialist teams on this.
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.4	COX14	Achchuthan Shanmugasundram Gene: cox14 has been classified as Green List (High Evidence).
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.3	COX14	Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: COX14. Tag Q2_25_ demote_amber tag was added to gene: COX14.
06 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.5	COX14	Achchuthan Shanmugasundram changed review comment from: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence. This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.; to: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence. This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.3	COX14	Achchuthan Shanmugasundram changed review comment from: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence. This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.; to: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence. This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.
06 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.5	COX14	Achchuthan Shanmugasundram changed review comment from: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence. This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.; to: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence. This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.3	COX14	Achchuthan Shanmugasundram reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22243966; Phenotypes: ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.5	COX14	Achchuthan Shanmugasundram Classified gene: COX14 as Green List (high evidence)
06 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.5	COX14	Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has also been demoted from green to amber on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX14/) in response to review from Zornitza Stark (Australian Genomics), and in agreement with the NHS Genomic Medicine Service. Hence, this gene is recommended for demotion on this panel and opinion is being sought from the NHS mitochondrial specialist teams on this.
06 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.5	COX14	Achchuthan Shanmugasundram Gene: cox14 has been classified as Green List (High Evidence).
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.3	BTD	Achchuthan Shanmugasundram changed review comment from: Zornitza Stark (Australian Genomics) has rated BTD red on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/BTD/) and has requested that the association between BTD variants and mitochondrial disease could be reviewed. This gene has been demoted to amber in Mitochondrial disorders panel after being reviewed and agreed by the NHS Genomic Medicine Service. Hence, this gene is now recommended for demotion to amber on this panel and opinion is being sought from NHS mitochondrial specialist teams on this.; to: Zornitza Stark (Australian Genomics) has rated BTD red on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/BTD/) and has requested that the association between BTD variants and mitochondrial disease could be reviewed. This gene has been demoted to amber in Mitochondrial disorders panel after being reviewed and agreed by the NHS Genomic Medicine Service. Hence, this gene is now recommended for demotion to amber on this panel and opinion is being sought from the NHS mitochondrial specialist teams on this.
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.3	ANO10	Achchuthan Shanmugasundram changed review comment from: Zornitza Stark (Australian Genomics) has rated ANO10 red on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/ANO10/) and has requested that the association between ANO10 variants and mitochondrial disease could be reviewed. She suggested that the reported CoQ10 deficiency appears to be secondary in the cited publication. This gene has been demoted to amber in Mitochondrial disorders panel after reviewed and agreed by the NHS Genomic Medicine Service. Hence, this gene is now being recommended for demotion to amber on this panel and opinion is being sought from NHS mitochondrial specialist teams on this.; to: Zornitza Stark (Australian Genomics) has rated ANO10 red on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/ANO10/) and has requested that the association between ANO10 variants and mitochondrial disease could be reviewed. She suggested that the reported CoQ10 deficiency appears to be secondary in the cited publication. This gene has been demoted to amber in Mitochondrial disorders panel after being reviewed and agreed by the NHS Genomic Medicine Service. Hence, this gene is now recommended for demotion to amber on this panel and opinion is being sought from the NHS mitochondrial specialist teams on this.
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.3	BTD	Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: BTD. Tag Q2_25_ demote_amber tag was added to gene: BTD.
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.3	BTD	Achchuthan Shanmugasundram reviewed gene: BTD: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.3	ANO10	Achchuthan Shanmugasundram Phenotypes for gene: ANO10 were changed from Spinocerebellar ataxia, autosomal recessive 10, 613728 to Spinocerebellar ataxia, autosomal recessive 10, OMIM:613728
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.2	ANO10	Achchuthan Shanmugasundram Publications for gene: ANO10 were set to
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.1	ANO10	Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: ANO10. Tag Q2_25_ demote_amber tag was added to gene: ANO10.
06 Jun 2025	Possible mitochondrial disorder - nuclear genes v4.1	ANO10	Achchuthan Shanmugasundram reviewed gene: ANO10: Rating: AMBER; Mode of pathogenicity: None; Publications: 25778941; Phenotypes: Spinocerebellar ataxia, autosomal recessive 10, OMIM:613728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Jun 2025	Dilated and arrhythmogenic cardiomyopathy v3.1	MYLK3	Matthew Edwards reviewed gene: MYLK3: Rating: AMBER; Mode of pathogenicity: None; Publications: 17885681, 31244672, 37128901, 32213617, 29235529, 30690923; Phenotypes: Dilated Cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
06 Jun 2025	Mitochondrial disorders v9.9	SQOR	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SQOR.
06 Jun 2025	Mitochondrial disorders v9.9	SQOR	Achchuthan Shanmugasundram reviewed gene: SQOR: Rating: GREEN; Mode of pathogenicity: None; Publications: 32160317; Phenotypes: Sulfide:quinone oxidoreductase deficiency, OMIM:619221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.4	SQOR	Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619221).
05 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.4	SQOR	Achchuthan Shanmugasundram Phenotypes for gene: SQOR were changed from Leigh syndrome to Sulfide:quinone oxidoreductase deficiency, OMIM:619221
05 Jun 2025	Mitochondrial disorders v9.9	SQOR	Achchuthan Shanmugasundram Classified gene: SQOR as Amber List (moderate evidence)
05 Jun 2025	Mitochondrial disorders v9.9	SQOR	Achchuthan Shanmugasundram Gene: sqor has been classified as Amber List (Moderate Evidence).
05 Jun 2025	Mitochondrial disorders v9.8	SQOR	Achchuthan Shanmugasundram Entity copied from Mitochondrial disorder with complex IV deficiency v4.3
05 Jun 2025	Mitochondrial disorders v9.8	SQOR	Achchuthan Shanmugasundram gene: SQOR was added gene: SQOR was added to Mitochondrial disorders. Sources: Literature,Expert Review Green Mode of inheritance for gene: SQOR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SQOR were set to 32160317 Phenotypes for gene: SQOR were set to Leigh syndrome
05 Jun 2025	Mitochondrial disorders v9.7	COX14	Achchuthan Shanmugasundram Phenotypes for gene: COX14 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110 to ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053
05 Jun 2025	Mitochondrial disorders v9.6	COX14	Achchuthan Shanmugasundram edited their review of gene: COX14: Changed phenotypes to: ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053
05 Jun 2025	Mitochondrial disorders v9.6	COX4I1	Achchuthan Shanmugasundram Phenotypes for gene: COX4I1 were changed from Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060 to Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060
05 Jun 2025	Mitochondrial disorders v9.5	COX4I1	Achchuthan Shanmugasundram Phenotypes for gene: COX4I1 were changed from No OMIM phenotype; Mitochondrial Diseases to Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060
05 Jun 2025	Mitochondrial disorders v9.5	COX4I1	Achchuthan Shanmugasundram Publications for gene: COX4I1 were set to
05 Jun 2025	Mitochondrial disorders v9.4	COX4I1	Achchuthan Shanmugasundram Classified gene: COX4I1 as Amber List (moderate evidence)
05 Jun 2025	Mitochondrial disorders v9.4	COX4I1	Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are two unrelated cases and functional evidence available in support of the association, this gene can be promoted to green rating in the next GMS update.
05 Jun 2025	Mitochondrial disorders v9.4	COX4I1	Achchuthan Shanmugasundram Gene: cox4i1 has been classified as Amber List (Moderate Evidence).
05 Jun 2025	Mitochondrial disorders v9.3	COX4I1	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: COX4I1.
05 Jun 2025	Mitochondrial disorders v9.3	COX4I1	Achchuthan Shanmugasundram reviewed gene: COX4I1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28766551, 31290619, 33578848; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.3	COX14	Achchuthan Shanmugasundram Publications for gene: COX14 were set to
05 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.2	COX14	Achchuthan Shanmugasundram Phenotypes for gene: COX14 were changed from ?Mitochondrial complex IV deficiency, 220110 to ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053
05 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.1	COX14	Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: COX14. Tag Q2_25_ demote_amber tag was added to gene: COX14.
05 Jun 2025	Mitochondrial disorder with complex IV deficiency v4.1	COX14	Achchuthan Shanmugasundram reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22243966; Phenotypes: ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Jun 2025	Hereditary neuropathy or pain disorder v7.1	RFC1	Lauren Turton Deleted their review
05 Jun 2025	Hereditary ataxia with onset in adulthood v8.5	RFC1	Lauren Turton Deleted their review
05 Jun 2025	Hereditary ataxia with onset in adulthood v8.5	RFC1	Lauren Turton Deleted their comment
05 Jun 2025	Hereditary neuropathy or pain disorder v7.1	RFC1	Lauren Turton reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36289003, 36478048, 35883251, 36250766, 36524104; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (OMIM: 614575); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Jun 2025	Hereditary ataxia with onset in adulthood v8.5	RFC1	Lauren Turton changed review comment from: In total 14 patients from 11 unrelated families who have clinically defined CANVAS and are compound heterozygous for a null allele with the (AAGGG)n expansion. Ronco et al., 2023 PMID: 36289003 7 patients from 5 unrelated families with clinically defined CANVAS with a heterozygous (AAGGG)n expansion in trans with a truncating RFC1 variant. Family 1 and family 4 has two affected siblings. Weber et al., 2023 PMID: 36478048 2 patients compound heterozygous for null variants with the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS. Benkirane et al. 2022 PMID: 35883251 2 patients compound heterozygous for null variants and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS. Arteche-López et al., 2023 PMID:36250766 2 affected sisters with a nonsense variant and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS. King et al., 2022 PMID: 36524104 1 patient with a nonsense variant confirmed in trans with the (AAGGG)n expansion, phenotype characteristic of CANVAS. Suggest that patients who have been tested for CANVAS, upon analysis of the WGS results if they are known to be heterozygous for (AAGGG)n then analysts should manually check for any LoF RFC1 variants.; to: In total 14 patients from 11 unrelated families who have clinically defined CANVAS and are compound heterozygous for a null allele with the (AAGGG)n expansion. Ronco et al., 2023 PMID: 36289003 7 patients from 5 unrelated families with clinically defined CANVAS with a heterozygous (AAGGG)n expansion in trans with a truncating RFC1 variant. Family 1 and family 4 has two affected siblings. Weber et al., 2023 PMID: 36478048 2 patients compound heterozygous for null variants with the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS. Benkirane et al. 2022 PMID: 35883251 2 patients compound heterozygous for null variants and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS. Arteche-López et al., 2023 PMID:36250766 2 affected sisters with a nonsense variant and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS. King et al., 2022 PMID: 36524104 1 patient with a nonsense variant confirmed in trans with the (AAGGG)n expansion, phenotype characteristic of CANVAS. Suggest that patients who have been tested for CANVAS, upon analysis of the WGS results if they are known to be heterozygous for (AAGGG)n then analysts should manually check for any LoF RFC1 variants.
05 Jun 2025	Hereditary ataxia with onset in adulthood v8.5	RFC1	Lauren Turton reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36289003, 36478048, 35883251, 36250766, 36524104; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (OMIM: 614575); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
04 Jun 2025	Autoinflammatory disorders v2.5	TBK1	Dorota Rowczenio gene: TBK1 was added gene: TBK1 was added to Autoinflammatory disorders. Sources: Expert list,Expert Review,Literature Mode of inheritance for gene: TBK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBK1 were set to PMID: 34363755; PMID: 34210994; PMID: 28148298; PMID: 34363755 Phenotypes for gene: TBK1 were set to chronic and systemic autoinflammation driven by TNF-induced cell death Review for gene: TBK1 was set to GREEN Added comment: Sources: Expert list, Expert Review, Literature
04 Jun 2025	Bardet Biedl syndrome v2.7	IFT57	Achchuthan Shanmugasundram Classified gene: IFT57 as Amber List (moderate evidence)
04 Jun 2025	Bardet Biedl syndrome v2.7	IFT57	Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is one patient and functional evidence reported, IFT57 should be rated amber with the current evidence.
04 Jun 2025	Bardet Biedl syndrome v2.7	IFT57	Achchuthan Shanmugasundram Gene: ift57 has been classified as Amber List (Moderate Evidence).
04 Jun 2025	Bardet Biedl syndrome v2.6	IFT57	Achchuthan Shanmugasundram Phenotypes for gene: IFT57 were changed from Bardet-Biedl syndrome to Bardet-Biedl syndrome, MONDO:0015229
04 Jun 2025	Bardet Biedl syndrome v2.5	IFT57	Achchuthan Shanmugasundram Publications for gene: IFT57 were set to PMID: 40273360
04 Jun 2025	Bardet Biedl syndrome v2.4	IFT57	Achchuthan Shanmugasundram reviewed gene: IFT57: Rating: AMBER; Mode of pathogenicity: None; Publications: 40273360; Phenotypes: Bardet-Biedl syndrome, MONDO:0015229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
04 Jun 2025	Autoinflammatory disorders v2.5	TMEM173	Dorota Rowczenio commented on gene: TMEM173
04 Jun 2025	Autoinflammatory disorders v2.5	RIPK1	Dorota Rowczenio gene: RIPK1 was added gene: RIPK1 was added to Autoinflammatory disorders. Sources: Expert list,Expert Review,Literature,Research Mode of inheritance for gene: RIPK1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: RIPK1 were set to PMID: 31911632; PMID: 31827281; PMID:31827280; PMID: 39557292; PMID: 37452601; PMID:35716229; PMID:35786329 Phenotypes for gene: RIPK1 were set to Autoinflammation with episodic fever and lymphadenopathy (autosomal dominant); Immunodeficiency 57 with autoinflammation (autosomal recessive) Review for gene: RIPK1 was set to GREEN Added comment: Sources: Expert list, Expert Review, Literature, Research
04 Jun 2025	Autoinflammatory disorders v2.5	ALPK1	Dorota Rowczenio changed review comment from: Sources: Expert list; to: Sources: Expert list
04 Jun 2025	Autoinflammatory disorders v2.5	RELA	Dorota Rowczenio gene: RELA was added gene: RELA was added to Autoinflammatory disorders. Sources: Expert list,Expert Review,Literature,Research Mode of inheritance for gene: RELA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RELA were set to PMID: 36926348; PMID: 32969189; PMID: 35412596; PMID: 28600438 Phenotypes for gene: RELA were set to Autoinflammatory disease, familial, behcet-like 3 Review for gene: RELA was set to GREEN Added comment: Sources: Expert list, Expert Review, Literature, Research
04 Jun 2025	Autoinflammatory disorders v2.5	POMP	Dorota Rowczenio gene: POMP was added gene: POMP was added to Autoinflammatory disorders. Sources: Expert Review,Literature,Research,ClinGen Mode of inheritance for gene: POMP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: POMP were set to PMID: 38111302; PMID: 29805043 Phenotypes for gene: POMP were set to Proteasome-associated autoinflammatory syndrome 2 Review for gene: POMP was set to GREEN Added comment: Sources: Expert Review, Literature, Research, ClinGen
04 Jun 2025	Autoinflammatory disorders v2.5	IKBKG	Dorota Rowczenio reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35120036, PMID: 35289316, PMID: 20133626, PMID: 21722947, PMID: 35163099, PMID: 39264518; Phenotypes: Autoinflammatory disease, systemic, X-linked; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
04 Jun 2025	Autoinflammatory disorders v2.5	ELF4	Dorota Rowczenio gene: ELF4 was added gene: ELF4 was added to Autoinflammatory disorders. Sources: Expert list,Literature Mode of inheritance for gene: ELF4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: ELF4 were set to PMID: 35266071; PMID: 34326534; PMID: 39976696; PMID: 39563044; PMID: 38773005; PMID: 38231408; PMID: 36823308 Phenotypes for gene: ELF4 were set to Autoinflammatory syndrome, familial, X-linked, Behcet-like 2 Review for gene: ELF4 was set to GREEN Added comment: Sources: Expert list, Literature
04 Jun 2025	Autoinflammatory disorders v2.5	COPA	Dorota Rowczenio reviewed gene: COPA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27048656, PMID: 31455335, PMID: 3976718, PMID: 34900872, PMID: 30385646, Jensson, B.O., Hansdottir, S., Arnadottir, G.A. et al. COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA . BMC Med Genet 18, 129 (2017).; Phenotypes: Autoimmune interstitial lung, joint, and kidney disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
04 Jun 2025	Autoinflammatory disorders v2.5	ALPK1	Dorota Rowczenio gene: ALPK1 was added gene: ALPK1 was added to Autoinflammatory disorders. Sources: Expert list Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ALPK1 were set to PMID: 30967659; PMID: 36332842; PMID: 38251500; PMID: 40069099; PMID: 35868845 Phenotypes for gene: ALPK1 were set to Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, and migraine Headache syndrome (ROSAH) Penetrance for gene: ALPK1 were set to unknown Review for gene: ALPK1 was set to GREEN Added comment: Sources: Expert list
04 Jun 2025	White matter disorders and cerebral calcification - narrow panel v7.2	NOTCH3	Lauren Turton reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: Spasticity, stroke, periatrial white matter volume loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
04 Jun 2025	Childhood onset hereditary spastic paraplegia v8.1	NOTCH3	Lauren Turton gene: NOTCH3 was added gene: NOTCH3 was added to Childhood onset hereditary spastic paraplegia. Sources: NHS GMS Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NOTCH3 were set to 39191170 Phenotypes for gene: NOTCH3 were set to Spasticity, stroke, periatrial white matter volume loss Review for gene: NOTCH3 was set to GREEN Added comment: Twenty-five patients from 17 unrelated families harbouring homozygous or compound heterozygous variants in NOTCH3. Among them 18 carried LoF variants. Patients had a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old. Showed that patients with the biallelic LoF variants had a different phenotype to that seen in CADASIL. Sources: NHS GMS
04 Jun 2025	Renal tubulopathies v5.1	OCRL	Beccy Cummings reviewed gene: OCRL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
04 Jun 2025	Renal tubulopathies v5.1	CLCN5	Beccy Cummings reviewed gene: CLCN5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
03 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.1	WFDC2	Steven Cowman edited their review of gene: WFDC2: Added comment: In addition to the 11 individuals reported in PMID 38626355 (see earlier review) there is now a further report (PMID 40401042) of three unrelated individuals from Japan with bronchiectasis who were all found to be homozygous for the same missense variant of WFDC2 (p.Cys97Trp). In keeping with the first series, all patients were reported to have upper lobe predominant bronchiectasis, sinus disease and low nasal NO, although ciliary ultrastructure was normal on EM and no pathogenic variants in CFTR or PCD-causing genes were found.; Changed publications to: PMID: 38626355, 40401042
03 Jun 2025	Respiratory ciliopathies including non-CF bronchiectasis v4.1	WFDC2	Steven Cowman changed review comment from: Reported in 11 individuals from 10 different families, all of whom had nasal polyposis and nine with diffuse bronchiectasis, aged between 7 and 52 years. All those tested had impaired lung function (8/11) and Pseudomonas isolation (8/11). The bronchiectasis was noted to have an upper-lobe predominance in a manner similar to CF. Low nasal NO levels were reported in all (9/11) tested individuals, although no disease causing variants were found in CFTR or PCD-related genes and mucociliary studies found clearance within the normal range, and EM in 8 individuals found normal ciliary ultrastructure. Sweat chloride was normal in all (9/11) tested individuals. Seven pathogenic WFDC2 variants were found, with one missense variant (c.145T>C; p.Cys49Arg) found in 12/22 alleles from 8/11 individuals. Expression analysis of healthy controls found WFDC2 to be expressed in the respiratory epithelium. Glycosylated WFDC2 protein was detectable in the saliva of a healthy control and one heterozygous mother of an affected individual, but not three tested affected individuals. Structural analysis suggested the c.145T>C mutation disrupts N-linked glycosylation of WFDC2 and hence impairs secretion. Sources: Literature; to: Reported in 11 individuals from 10 different families, all of whom had nasal polyposis and nine with diffuse bronchiectasis, aged between 7 and 52 years. All those tested had impaired lung function (8/11) and Pseudomonas isolation (8/11). The bronchiectasis was noted to have an upper-lobe predominance in a manner similar to CF. Low nasal NO levels were reported in all (9/11) tested individuals, although no disease causing variants were found in CFTR or PCD-related genes and mucociliary studies found clearance within the normal range, and EM in 8 individuals found normal ciliary ultrastructure. Sweat chloride was normal in all (9/11) tested individuals. Seven pathogenic WFDC2 variants were found, with one missense variant (c.145T>C; p.Cys49Arg) found in 12/22 alleles from 8/11 individuals. Expression analysis of healthy controls found WFDC2 to be expressed in the respiratory epithelium. Glycosylated WFDC2 protein was detectable in the saliva of a healthy control and one heterozygous mother of an affected individual, but not three tested affected individuals. Structural analysis suggested the c.145T>C mutation disrupts N-linked glycosylation of WFDC2 and hence impairs secretion. Sources: Literature
02 Jun 2025	Paediatric disorders - additional genes v7.1	MC4R	Ian Berry gene: MC4R was added gene: MC4R was added to Paediatric disorders - additional genes. Sources: Expert Review Mode of inheritance for gene: MC4R was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Penetrance for gene: MC4R were set to Incomplete Review for gene: MC4R was set to GREEN Added comment: Well-established OMIM association. Gene on R149 Severe Early Onset Obesity panel (green). Many R27 referrals include ID & obesity/overgrowth so may be a partial explanation for many patients referred. This is the primary/most common R149 gene that it not currently on the R27 panel and inclusion would minimise management of re-analysis requests for R149 for patient who meet both the R27 and potentially R149 eligibility criteria. Sources: Expert Review
02 Jun 2025	Familial tumours of the nervous system v2.1	CDKN2A	Terri McVeigh gene: CDKN2A was added gene: CDKN2A was added to Familial tumours of the nervous system. Sources: Expert Review,Literature Mode of inheritance for gene: CDKN2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDKN2A were set to PMID 24884915; 8317504; 9622062; 10797439; 17440112; 26794401; 29263814; 28699883; 28754699; 35422439; 38936911 Phenotypes for gene: CDKN2A were set to MELANOMA; PANCREATIC CANCER; ASTROCYTOMA; GLIOBLASTOMA; SCHWANNOMA; NEUROFIBROMA; MENINGIOMA; MALIGNANT PERIPHERAL NERVE SHEATH TUMOURS Penetrance for gene: CDKN2A were set to Incomplete Review for gene: CDKN2A was set to GREEN Added comment: Phenotype including neural tumours discussed at Joint Dutch/UKCGG Cancer Case Meeting 2025 Sources: Expert Review, Literature
02 Jun 2025	Inherited polyposis and early onset colorectal cancer - germline testing v3.1	MBD4	Terri McVeigh reviewed gene: MBD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35460607, 30049810, 35381620, 32421892, 32239153; Phenotypes: MBD4-Associated Neoplasia Syndrome: Colonic polyposis, colon cancer, uveal melanoma, acute myeloid leukaemia, schwannoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
02 Jun 2025	Inherited breast cancer and ovarian cancer v2.11	BARD1	Terri McVeigh gene: BARD1 was added gene: BARD1 was added to Inherited breast cancer and ovarian cancer. Sources: NHS GMS,Expert Review,Literature Mode of inheritance for gene: BARD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BARD1 were set to PMID: 33471991 Phenotypes for gene: BARD1 were set to breast cancer Penetrance for gene: BARD1 were set to Incomplete Review for gene: BARD1 was set to GREEN Added comment: Discussed at Cancer/Scientific Leads/UKCGG council meeting re Test Directory updates 2025/2026 (30/01/2025) - consensus was that evidence is sufficient to warrant addition of this gene to R208 panel. Strong evidence indicating that BARD1 is a moderate-risk breast cancer susceptibility gene, with risks associated with pathogenic variants in this gene similar to those associated with variants in other moderate risk genes already included on the panel (PMID: 33471991). We propose reporting should be restricted to truncating variants, and will provide gene-specific reporting guidance to GLHs via UKCGG/CanVIG as we have for other moderate risk genes (https://www.ukcgg.org/information-education/exceptional-variantsgene-specific-variant-reporting/) Sources: NHS GMS, Expert Review, Literature
29 May 2025	Adult onset neurodegenerative disorder v8.1	ISCA-37446-Loss	Lauren Turton Region: ISCA-37446-Loss was added Region: ISCA-37446-Loss was added to Adult onset neurodegenerative disorder. Sources: NHS GMS Mode of inheritance for Region: ISCA-37446-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: ISCA-37446-Loss were set to 24018986; 27017469 Phenotypes for Region: ISCA-37446-Loss were set to DIGEORGE SYNDROME; DGS (OMIM: 188400) Penetrance for Region: ISCA-37446-Loss were set to Complete Review for Region: ISCA-37446-Loss was set to AMBER Region: ISCA-37446-Loss was marked as current diagnostic Added comment: PMID: 24018986 159 adults diagnosed with 22q11.2DS. Four of 68 subjects (5.9%) aged 35 to 64 years with 22q11.2 deletions had been diagnosed as having PD (standardized morbidity ratio = 91.7; 95% CI, 25.0–234.8). Prevalence 5.9% in this cohort, however many of the individuals in 18-34 age group (n=90). PMID: 27017469 We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). In Sheffield we also have a case with DiGeorge syndrome, that was referred for genetic testing due to parkinsonism as the primary referral reason. The patient also had other clinical features compatible with DiGeorge syndrome. Added as amber as it is likely these patients will have other features that make them eligible for alternative panels such as R29. Sources: NHS GMS
27 May 2025	Retinal disorders v8.4	VSX2	Beisi Xu reviewed gene: VSX2: 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: 36264558, 24001013, 20414678; Phenotypes: NIGHT BLINDNESS, CONGENITAL STATIONARY, pan-bipolar cell dysfunction, LENS SUBLUXATION, Microphthalmia, isolated 2 610093, Microphthalmia/coloboma 3 610092, CATARACTS, IRIS ABNORMALITIES; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
27 May 2025	Childhood onset hereditary spastic paraplegia v8.1	ATXN10_ATTCT	Sarah Leigh Tag Q2_25_expert_review tag was added to STR: ATXN10_ATTCT.
27 May 2025	Ataxia and cerebellar anomalies - narrow panel v8.3	ATXN10_ATTCT	Sarah Leigh Tag Q2_25_expert_review tag was added to STR: ATXN10_ATTCT.
27 May 2025	Adult onset neurodegenerative disorder v8.1	CACNA1A_CAG	Sarah Leigh Tag Q2_25_expert_review tag was added to STR: CACNA1A_CAG.
27 May 2025	Ataxia and cerebellar anomalies - narrow panel v8.3	CACNA1A_CAG	Sarah Leigh Tag Q2_25_expert_review tag was added to STR: CACNA1A_CAG.
25 May 2025	Retinal disorders v8.4	DYRK1A	Siying Lin gene: DYRK1A was added gene: DYRK1A was added to Retinal disorders. Sources: Literature Mode of inheritance for gene: DYRK1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DYRK1A were set to PMID: 40405340; 36736451 Phenotypes for gene: DYRK1A were set to FEVR Mode of pathogenicity for gene: DYRK1A was set to Other Review for gene: DYRK1A was set to GREEN Added comment: PMID 36736451: one individual with DYRK1A syndrome and anomalous retinal vasculature. PMID 40405340: two individuals with FEVR-like presentations and later likely disease-causing DKRY1A variants identified; the retinal phenotype can be the presenting feature of DYRK1A syndrome Sources: Literature
23 May 2025	Monogenic hearing loss v5.8	GJB6	Eleanor Williams changed review comment from: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families. PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0. Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic Hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).; to: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families. PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and bilateral syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0. Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic bilateral hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).
23 May 2025	Monogenic hearing loss v5.8	GJB6	Eleanor Williams commented on gene: GJB6: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families. PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0. Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic Hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).
23 May 2025	Monogenic hearing loss v5.8	GJB6	Eleanor Williams Phenotypes for gene: GJB6 were changed from Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977 to Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977
23 May 2025	Malformations of cortical development v7.3	NFIA	Nour Elkhateeb gene: NFIA was added gene: NFIA was added to Malformations of cortical development. Sources: Literature Mode of inheritance for gene: NFIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NFIA were set to 36553517, Added comment: cortical malformations reported in PMID 36553517, and other CNS malformations reported in PMID 36553517 and PMID: 27081522 Sources: Literature
22 May 2025	Amelogenesis imperfecta v4.1	LAMC2	Claire Smith edited their review of gene: LAMC2: Added comment: PMID: 37228816 Bloch-Zupan et al. 2023 report one family with LAMC2 mutations as part of a larger panel of sequenced individuals. They report a single child as being affected with a hypoplastic/hypomature AI phenotype. The primary dentition is described as showing thin white opaque enamel. They identified a heterozygous LAMC2 variant NM_005562.3: c.493C>T; p.(Arg165Cys) with an allele frequency of 0.2% in GnomAD, predicted deleterious by SIFT (v4.0.3) and PolyPhen-2 and located in the Laminin EGF domain. The authors highlight that the enamel formation defects in mice (Wazen et al., 2016) and the patient’s phenotype are similar to the one another. The allele is inherited from her mother but the mother's phenotype was not available. Notably the patient was sequenced using whole exome sequencing using the following parameters: Non-pathogenic variants were filtered out via: 1) variants represented with an allele frequency of more than 1% in public variation databases including the 1,000 Genomes, the GnomAD database or their internal exome database, variants in 5′ or 3′ UTR, variants with intronic locations and no prediction of local splice effect, and synonymous variants without pathogenic prediction of local splice effect. Annotations of structural variations (SV) were performed by AnnotSV (Geoffroy et al., 2018). No other findings are presented for the individual. In conclusion, I do not believe this is strong enough evidence to conclude that this LAMC2 mutation is the cause of disease in this family due to the lack of phenotype information for the mother or any modelling of the effects of the variant, but it is suggestive and additional publications with further families might provide more solid evidence to elevate this gene to green. I would currently consider this gene to be rated amber.; Changed rating: AMBER; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
22 May 2025	Retinal disorders v8.4	CFI	Siying Lin gene: CFI was added gene: CFI was added to Retinal disorders. Sources: Literature Mode of inheritance for gene: CFI was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CFI were set to Early Onset Drsen Maculopathy Penetrance for gene: CFI were set to unknown Review for gene: CFI was set to AMBER Added comment: A rare heterozygous variant in CFI was identified in two Tunisian families: one affected by early-onset drusen maculopathy and the other by “advanced AMD,” although the age of onset in the latter is unknown (PMID: 25986072). Functional studies provide evidence that rare, highly penetrant CFI variants contribute to the genetic burden of AMD (PMIDs: 25788521, 23685748), supporting a potential mechanistic link between these variants and dominantly inherited early-onset drusen maculopathy. Sources: Literature
19 May 2025	Monogenic hearing loss v5.7	GJB6	Sarah Leigh Tag cnv tag was added to gene: GJB6. Tag Q2_25_ promote_green tag was added to gene: GJB6. Tag Q2_25_expert_review tag was added to gene: GJB6. Tag Q2_25_ NHS_review tag was added to gene: GJB6.
19 May 2025	Monogenic hearing loss v5.7	GJB6	Sarah Leigh Phenotypes for gene: GJB6 were changed from hearing loss; Deafness, autosomal dominant 3B, 612643; Deafness, autosomal recessive 1B, 612645; Deafness, digenic GJB2/GJB6, 220290; Ectodermal dysplasia 2, Clouston type, 129500; Nonsyndromic Hearing Loss, Dominant to Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977
19 May 2025	Monogenic hearing loss v5.6	GJB6	Sarah Leigh Publications for gene: GJB6 were set to 10471490; 11896458; 11807148; 15150777; 24522190; 29921236; 39498320; 19416251; 40369851
19 May 2025	Monogenic hearing loss v5.5	GJB6	Sarah Leigh reviewed gene: GJB6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 1B, OMIM:612645, autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977, Deafness, autosomal recessive 1B, OMIM:612645, autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
19 May 2025	Monogenic hearing loss v5.5	GJB2	Sarah Leigh Tag cnv tag was added to gene: GJB2.
19 May 2025	Monogenic hearing loss v5.5	GJB6	Sarah Leigh Publications for gene: GJB6 were set to 10471490; 24522190; 39498320; 19416251; 40369851
19 May 2025	Monogenic hearing loss v5.4	GJB6	Sarah Leigh Publications for gene: GJB6 were set to PMID:10471490; 10570462; 10610709; 11017065; 11807148; 11874494; 11896458; 12419304; 12490528; 12668604; 14571368; 15150777; 15213106; 15638823; 15994881; 17041943; 18324688; 20858605; 8663509; 9139825; 9799458
19 May 2025	Retinal disorders v8.4	CYP2U1	Cassandra Smith gene: CYP2U1 was added gene: CYP2U1 was added to Retinal disorders. Sources: Literature Mode of inheritance for gene: CYP2U1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYP2U1 were set to PMID: 26914923; 34828401; 39605873 Review for gene: CYP2U1 was set to GREEN Added comment: In some families, it appears visual symptoms may present before spasticity/neurological phenotype. PMID: 26914923 - Three patients from one family, where visual issues (pigmentary degenerative maculopathy) presented before spasticity. Biallelic loss of function variant identified PMID: 34828401 - Patient presenting with bilateral progressive visual loss and photophobia. Biallelic loss of function variant identified PMID: 39605873 - Two sibs with compound heterozygous variants. One had manifest neurological abnormalities since early childhood; the second had no neurological abnormalities. Both had opthalmological abnormalities Sources: Literature
16 May 2025	Holoprosencephaly v5.3	DISP1	Nour Elkhateeb reviewed gene: DISP1: Rating: ; Mode of pathogenicity: None; Publications: 38529886; Phenotypes: holoprosencephaly; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
13 May 2025	Intellectual disability v9.23	MRPL49	Sarah Leigh Classified gene: MRPL49 as Amber List (moderate evidence)
13 May 2025	Intellectual disability v9.23	MRPL49	Sarah Leigh Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
13 May 2025	Mitochondrial disorders v9.3	MRPL49	Sarah Leigh changed review comment from: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature; to: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant, and families F4 & F5 (with the same MRPL variant) although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature
13 May 2025	Intellectual disability v9.22	MRPL49	Sarah Leigh changed review comment from: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature; to: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant, and families F4 & F5 (with the same MRPL variant) although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature
13 May 2025	Monogenic hearing loss v5.3	MRPL49	Sarah Leigh changed review comment from: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature; to: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant, and families F4 & F5 (with the same MRPL variant) although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature
13 May 2025	Monogenic hearing loss v5.3	MRPL49	Sarah Leigh Tag Q2_25_expert_review tag was added to gene: MRPL49.
13 May 2025	Mitochondrial disorders v9.3	MRPL49	Sarah Leigh Classified gene: MRPL49 as Amber List (moderate evidence)
13 May 2025	Mitochondrial disorders v9.3	MRPL49	Sarah Leigh Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
13 May 2025	Intellectual disability v9.22	MRPL49	Sarah Leigh Marked gene: MRPL49 as ready
13 May 2025	Intellectual disability v9.22	MRPL49	Sarah Leigh Gene: mrpl49 has been classified as Red List (Low Evidence).
13 May 2025	Monogenic hearing loss v5.3	MRPL49	Sarah Leigh Classified gene: MRPL49 as Amber List (moderate evidence)
13 May 2025	Monogenic hearing loss v5.3	MRPL49	Sarah Leigh Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
13 May 2025	Monogenic hearing loss v5.2	MRPL49	Sarah Leigh gene: MRPL49 was added gene: MRPL49 was added to Monogenic hearing loss. Sources: Literature Q2_25_ promote_green tags were added to gene: MRPL49. Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPL49 were set to 40043708 Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732 Review for gene: MRPL49 was set to GREEN Added comment: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature
13 May 2025	Mitochondrial disorders v9.2	MRPL49	Sarah Leigh gene: MRPL49 was added gene: MRPL49 was added to Mitochondrial disorders. Sources: Literature Q2_25_ promote_green tags were added to gene: MRPL49. Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPL49 were set to 40043708 Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732 Review for gene: MRPL49 was set to GREEN Added comment: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature
13 May 2025	Intellectual disability v9.22	MRPL49	Sarah Leigh gene: MRPL49 was added gene: MRPL49 was added to Intellectual disability. Sources: Literature Q2_25_ promote_green tags were added to gene: MRPL49. Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPL49 were set to 40043708 Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732 Review for gene: MRPL49 was set to GREEN Added comment: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708). Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708) Sources: Literature
13 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.11	SRP72	Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SRP72. Tag Q2_25_expert_review tag was added to gene: SRP72.
13 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.11	SRP72	Sarah Leigh Added comment: Comment on phenotypes: Familial MDS/AML;inherited bone marrow failure syndromes (IBMFS);congenital neutropenia;Shwachman-Diamond syndrome
13 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.11	SRP72	Sarah Leigh Phenotypes for gene: SRP72 were changed from Familial MDS/AML; inherited bone marrow failure syndromes (IBMFS); congenital neutropenia; Shwachman-Diamond syndrome to Bone marrow failure syndrome 1, OMIM:614675; autosomal dominant aplasia and myelodysplasia, MONDO:0013851
13 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.10	SRP72	Sarah Leigh Publications for gene: SRP72 were set to 32098966
13 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.9	SRP72	Sarah Leigh reviewed gene: SRP72: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541560, 29146883; Phenotypes: Bone marrow failure syndrome 1, OMIM:614675, autosomal dominant aplasia and myelodysplasia, MONDO:0013851; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
13 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.9	SRP72	Sarah Leigh Classified gene: SRP72 as Amber List (moderate evidence)
13 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.9	SRP72	Sarah Leigh Gene: srp72 has been classified as Amber List (Moderate Evidence).
12 May 2025	Monogenic short stature v1.17	FBXO22	Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intrauterine growth restriction was reported in nine patients from eight families, and short stature was reported in eight patients from seven families. This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prominent prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous germline FBXO22 variants with loss-of-function effects segregating with the disease. Intrauterine growth restriction was reported in 11 patients from ten families, and short stature was reported in ten patients from nine families. This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.
12 May 2025	Haematological malignancies cancer susceptibility v4.24	SH2B3	Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SH2B3.
12 May 2025	Thrombocythaemia v1.6	SH2B3	Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SH2B3.
12 May 2025	Hereditary Erythrocytosis v2.13	SH2B3	Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SH2B3.
12 May 2025	Thrombocythaemia v1.6	SH2B3	Sarah Leigh Added comment: Comment on publications: https://doi.org/10.1182/blood-2024-210339 does not have a PMID number yet
12 May 2025	Thrombocythaemia v1.6	SH2B3	Sarah Leigh Publications for gene: SH2B3 were set to
12 May 2025	Thrombocythaemia v1.5	SH2B3	Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SH2B3. Tag Q2_25_ NHS_review tag was added to gene: SH2B3.
12 May 2025	Thrombocythaemia v1.5	SH2B3	Sarah Leigh reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28484264, 27237057, 23908464; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
12 May 2025	Haematological malignancies cancer susceptibility v4.24	SH2B3	Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SH2B3.
12 May 2025	Haematological malignancies cancer susceptibility v4.24	SH2B3	Sarah Leigh reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28484264, 27237057, 23908464; Phenotypes: SH2B3 associated susceptibility to acute lymphoblastic leukemia, SH2B3 associated susceptibility to myeloproliferative neoplasms; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
12 May 2025	Intellectual disability v9.21	FBXO22	Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intellectual disability was reported in six patients from five families. This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prominent prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous germline FBXO22 variants with loss-of-function effects segregating with the disease. Intellectual disability was reported in seven patients from six families. This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.
12 May 2025	Haematological malignancies cancer susceptibility v4.24	SH2B3	Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464; 27913496; 39316992; 28484264; 27237057
12 May 2025	Haematological malignancies cancer susceptibility v4.23	SH2B3	Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464; 27913496; 39316992; 28484264
12 May 2025	Haematological malignancies cancer susceptibility v4.22	SH2B3	Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464; 27913496; 39316992
12 May 2025	Haematological malignancies cancer susceptibility v4.21	SH2B3	Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464; 27913496
12 May 2025	Haematological malignancies cancer susceptibility v4.20	SH2B3	Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464
12 May 2025	Haematological malignancies cancer susceptibility v4.19	NAPRT	Sarah Leigh edited their review of gene: NAPRT: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
12 May 2025	Haematological malignancies cancer susceptibility v4.19	NAPRT	Sarah Leigh Mode of inheritance for gene: NAPRT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
12 May 2025	Haematological malignancies cancer susceptibility v4.18	NAPRT	Sarah Leigh edited their review of gene: NAPRT: Added comment: Two monoallelic NAPRT variants have been reported in two unrelated cases with myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML)(PMID: 32098966; https://doi.org/10.1182/blood.V122.21.2803.2803). This is insufficient evidence to warrant a green gene rating.; Changed rating: AMBER; Changed phenotypes to: myelodysplastic syndrome (MDS), acute myeloid leukemia (AML); Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
12 May 2025	Haematological malignancies cancer susceptibility v4.18	NAPRT	Sarah Leigh Mode of inheritance for gene: NAPRT was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
12 May 2025	Haematological malignancies cancer susceptibility v4.17	NAPRT	Sarah Leigh Classified gene: NAPRT as Amber List (moderate evidence)
12 May 2025	Haematological malignancies cancer susceptibility v4.17	NAPRT	Sarah Leigh Gene: naprt has been classified as Amber List (Moderate Evidence).
12 May 2025	Intellectual disability v9.21	RAB3A	Sarah Leigh changed review comment from: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. This gene is appropriate for the Hereditary ataxia with onset in adulthood panel as PMID: 40166812 states "The median age at onset was 26.5 (interquartile range (IQR) 22–32) with gait ataxia as the first symptom in all probands.", In addition, the authors also present supportive functional studies.; to: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. The neurodevelopmental disorder associated with variants towards the 3' end of the gene: (NM_002866.5) c.565G>T, p.(Glu189) and c.628C>T, p.(Gln210), included global developmental delay and learning disability (PMID: 40166812, table S4). In addition, the authors also present supportive functional studies for the RAB3A variants.
12 May 2025	Intellectual disability v9.21	RAB3A	Sarah Leigh edited their review of gene: RAB3A: Changed rating: AMBER
12 May 2025	Intellectual disability v9.21	RAB3A	Sarah Leigh Tag Q2_25_ promote_green was removed from gene: RAB3A. Tag Q2_25_ NHS_review was removed from gene: RAB3A.
12 May 2025	Intellectual disability v9.21	RAB3A	Sarah Leigh Entity copied from Hereditary ataxia with onset in adulthood v8.5
12 May 2025	Intellectual disability v9.21	RAB3A	Sarah Leigh gene: RAB3A was added gene: RAB3A was added to Intellectual disability. Sources: Research,Expert Review Amber Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: RAB3A. Mode of inheritance for gene: RAB3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAB3A were set to 36928819; 40166812 Phenotypes for gene: RAB3A were set to RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay Penetrance for gene: RAB3A were set to Complete
09 May 2025	Monogenic short stature v1.17	FBXO22	Achchuthan Shanmugasundram Tag Q2_25_ NHS_review was removed from gene: FBXO22.
09 May 2025	Monogenic short stature v1.17	FBXO22	Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intellectual disability was reported in six patients from five families. This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intrauterine growth restriction was reported in nine patients from eight families, and short stature was reported in eight patients from seven families. This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.
09 May 2025	Monogenic short stature v1.17	FBXO22	Achchuthan Shanmugasundram Entity copied from Intellectual disability v9.20
09 May 2025	Monogenic short stature v1.17	FBXO22	Achchuthan Shanmugasundram gene: FBXO22 was added gene: FBXO22 was added to Monogenic short stature. Sources: Literature,Expert Review Amber Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: FBXO22. Mode of inheritance for gene: FBXO22 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FBXO22 were set to 40215970 Phenotypes for gene: FBXO22 were set to Tayoun-Maawali syndrome, OMIM:621184
09 May 2025	Intellectual disability v9.20	FBXO22	Achchuthan Shanmugasundram Classified gene: FBXO22 as Amber List (moderate evidence)
09 May 2025	Intellectual disability v9.20	FBXO22	Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
09 May 2025	Intellectual disability v9.20	FBXO22	Achchuthan Shanmugasundram Gene: fbxo22 has been classified as Amber List (Moderate Evidence).
09 May 2025	Intellectual disability v9.19	FBXO22	Achchuthan Shanmugasundram Phenotypes for gene: FBXO22 were changed from neurodevelopmental delay; malformations; OMIM# 621184 to Tayoun-Maawali syndrome, OMIM:621184
09 May 2025	Intellectual disability v9.18	FBXO22	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: FBXO22. Tag Q2_25_ NHS_review tag was added to gene: FBXO22.
09 May 2025	Intellectual disability v9.18	FBXO22	Achchuthan Shanmugasundram reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: None; Publications: 40215970; Phenotypes: Tayoun-Maawali syndrome, OMIM:621184; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
09 May 2025	Cerebral vascular malformations v4.4	CCER2	Achchuthan Shanmugasundram Classified gene: CCER2 as Amber List (moderate evidence)
09 May 2025	Cerebral vascular malformations v4.4	CCER2	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexandra Njegic, PMID:27717682 reported the identification of CCER2 variants in two pedigrees with Moyamoya disease. One of the monozygotic twins from family 2 with the missense variant was unaffected suggesting reduced penetrance. Although CCER2 variants were identified in three of 135 MMD probands additionally sequenced, two of them had RNF213 p.Arg4810Lys founder variant, and one had Graves disease. In silicon functional analysis predicts that these variants promote aggregation or oligomerization of their protein product. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. This gene should be rated amber with current evidence.
09 May 2025	Cerebral vascular malformations v4.4	CCER2	Achchuthan Shanmugasundram Gene: ccer2 has been classified as Amber List (Moderate Evidence).
09 May 2025	Cerebral vascular malformations v4.3	CCER2	Achchuthan Shanmugasundram Phenotypes for gene: CCER2 were changed from Moyamoya Disease to Moyamoya Disease, MONDO:0016820
09 May 2025	Cerebral vascular malformations v4.2	CCER2	Achchuthan Shanmugasundram reviewed gene: CCER2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27717682; Phenotypes: Moyamoya Disease, MONDO:0016820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
09 May 2025	Severe early-onset obesity v5.4	GNB1	Achchuthan Shanmugasundram Classified gene: GNB1 as Amber List (moderate evidence)
09 May 2025	Severe early-onset obesity v5.4	GNB1	Achchuthan Shanmugasundram Gene: gnb1 has been classified as Amber List (Moderate Evidence).
09 May 2025	Severe early-onset obesity v5.3	GNB1	Achchuthan Shanmugasundram changed review comment from: PMID:38596856 reported three unrelated cases reported with either splicing or truncating variants in GNB1 gene and obesity. Although two of them were reported to start gain weight before 5 years of age, there were no information on their weight or BMI at onset. Hence, we cannot determine the severity of obesity at onset. The third case was reported to have obesity around 9 years of age. This study also reviewed previously published cases, where two cases were reported with early-onset obesity (<5 years). However, not much information was available to ascertain the severity. As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf), the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years. Hence, this gene should be rated amber with the current evidence.; to: PMID:38596856 reported three unrelated cases reported with either splicing or truncating variants in GNB1 gene and obesity. Although two of them were reported to start gain weight before 5 years of age, there were no information on their weight or BMI at onset. Hence, we cannot determine the severity of obesity at onset. The third case was reported to have obesity around 9 years of age. This study also reviewed previously published cases, where two cases were reported with early-onset obesity (<5 years). However, complete information was not available to ascertain the severity. As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf), the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years. Hence, this gene should be rated amber with the current evidence.
09 May 2025	Severe early-onset obesity v5.3	GNB1	Achchuthan Shanmugasundram edited their review of gene: GNB1: Added comment: PMID:38596856 reported three unrelated cases reported with either splicing or truncating variants in GNB1 gene and obesity. Although two of them were reported to start gain weight before 5 years of age, there were no information on their weight or BMI at onset. Hence, we cannot determine the severity of obesity at onset. The third case was reported to have obesity around 9 years of age. This study also reviewed previously published cases, where two cases were reported with early-onset obesity (<5 years). However, not much information was available to ascertain the severity. As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf), the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years. Hence, this gene should be rated amber with the current evidence.; Changed rating: AMBER
09 May 2025	Severe early-onset obesity v5.3	GNB1	Achchuthan Shanmugasundram Publications for gene: GNB1 were set to
09 May 2025	Severe early-onset obesity v5.2	GNB1	Achchuthan Shanmugasundram Phenotypes for gene: GNB1 were changed from PMID: 38596856 to Obesity, HP:0001513
09 May 2025	Severe early-onset obesity v5.1	GNB1	Achchuthan Shanmugasundram reviewed gene: GNB1: Rating: RED; Mode of pathogenicity: None; Publications: 38596856; Phenotypes: Obesity, HP:0001513; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
08 May 2025	Childhood onset hereditary spastic paraplegia v8.1	ATL1	Cassandra Smith reviewed gene: ATL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24473461, 26888483, 37927245, 39003427; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
08 May 2025	Structural eye disease v4.9	CYP1B1	Arina Puzriakova Phenotypes for gene: CYP1B1 were changed from Primary Congenital Glaucoma; Peters anomaly, 604229; Glaucoma 3, Primary Congenital, A; Glaucoma 3, Primary Congenital, A, GLC3A, 231300; Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset; GLC3A; primary congenital glaucoma; 231300 to Anterior segment dysgenesis 6, multiple subtypes, OMIML617315; Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, OMIM:231300; Primary Congenital Glaucoma
08 May 2025	Autoinflammatory disorders v2.5	COPA	Arina Puzriakova Classified gene: COPA as Amber List (moderate evidence)
08 May 2025	Autoinflammatory disorders v2.5	COPA	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
08 May 2025	Autoinflammatory disorders v2.5	COPA	Arina Puzriakova Gene: copa has been classified as Amber List (Moderate Evidence).
08 May 2025	Autoinflammatory disorders v2.4	COPA	Arina Puzriakova gene: COPA was added gene: COPA was added to Autoinflammatory disorders. Sources: Literature Q2_25_ promote_green tags were added to gene: COPA. Mode of inheritance for gene: COPA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: COPA were set to 25894502; 31455335; 38175705 Phenotypes for gene: COPA were set to {Autoinflammation and autoimmunity, systemic, with immune dysregulation}, OMIM:616414; COPA syndrome Review for gene: COPA was set to GREEN Added comment: Heterozygous variants in the COPA gene cause an autoinflammatory disorder that affects multiple organ systems. Affected individuals usually present in the first decade of life with variable features including interstitial lung disease with or without pulmonary hemorrhage, inﬂammatory arthritis, recurrent infections, and renal disease. Laboratory studies show evidence of systemic inflammation. At least 9 unrelated families with more than 20 affected individuals have been reported in the literature (PMIDs: PMID: 25894502; 31455335; 38175705). Variant hotspots include the WD40 domain and the C-terminal domain of the COPA protein. Sources: Literature
08 May 2025	Bardet Biedl syndrome v2.4	IFT57	Krista Bukele gene: IFT57 was added gene: IFT57 was added to Bardet Biedl syndrome. Sources: Literature Mode of inheritance for gene: IFT57 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IFT57 were set to PMID: 40273360 Phenotypes for gene: IFT57 were set to Bardet-Biedl syndrome Penetrance for gene: IFT57 were set to unknown Review for gene: IFT57 was set to AMBER Added comment: PMID: 40273360 described one case with Bardet-Biedl syndrome and biallelic variant in IFT57 with some functional evidence. Sources: Literature
07 May 2025	Haematological malignancies cancer susceptibility v4.16	NAPRT	Sarah Leigh Added comment: Comment on publications: https://doi.org/10.1182/blood.V122.21.2803.2803 there is no PMID for this article
07 May 2025	Haematological malignancies cancer susceptibility v4.16	NAPRT	Sarah Leigh Publications for gene: NAPRT were set to 32098966
07 May 2025	Haematological malignancies cancer susceptibility v4.15	DNAH9	Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: DNAH9.
07 May 2025	Haematological malignancies cancer susceptibility v4.15	DNAH9	Sarah Leigh reviewed gene: DNAH9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 May 2025	Haematological malignancies cancer susceptibility v4.15	DNAH9	Sarah Leigh Publications for gene: DNAH9 were set to 32098966; 26492932
07 May 2025	Haematological malignancies cancer susceptibility v4.14	DNAH9	Sarah Leigh Publications for gene: DNAH9 were set to 32098966
07 May 2025	Haematological malignancies cancer susceptibility v4.13	DNAH9	Sarah Leigh Classified gene: DNAH9 as Amber List (moderate evidence)
07 May 2025	Haematological malignancies cancer susceptibility v4.13	DNAH9	Sarah Leigh Gene: dnah9 has been classified as Amber List (Moderate Evidence).
07 May 2025	Haematological malignancies cancer susceptibility v4.12	DHX34	Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: DHX34.
07 May 2025	Haematological malignancies cancer susceptibility v4.12	DHX34	Sarah Leigh reviewed gene: DHX34: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
07 May 2025	Haematological malignancies cancer susceptibility v4.12	DHX34	Sarah Leigh Classified gene: DHX34 as Amber List (moderate evidence)
07 May 2025	Haematological malignancies cancer susceptibility v4.12	DHX34	Sarah Leigh Gene: dhx34 has been classified as Amber List (Moderate Evidence).
07 May 2025	Haematological malignancies cancer susceptibility v4.11	DHX34	Sarah Leigh Phenotypes for gene: DHX34 were changed from Thrombocytopenia; Neutropenia; Pancytopenia; AML to myelodysplastic syndrome; acute myeloid leukemia
07 May 2025	Haematological malignancies cancer susceptibility v4.10	ADA	Sarah Leigh Phenotypes for gene: ADA were changed from severe combined immunodeficiency to Severe combined immunodeficiency due to ADA deficiency, OMIM: 102700
07 May 2025	Haematological malignancies cancer susceptibility v4.9	ADA	Sarah Leigh Classified gene: ADA as Amber List (moderate evidence)
07 May 2025	Haematological malignancies cancer susceptibility v4.9	ADA	Sarah Leigh Gene: ada has been classified as Amber List (Moderate Evidence).
07 May 2025	Haematological malignancies cancer susceptibility v4.8	ADA	Sarah Leigh reviewed gene: ADA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
07 May 2025	Haematological malignancies cancer susceptibility v4.8	TCF3	Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: TCF3. Tag Q2_25_expert_review tag was added to gene: TCF3.
07 May 2025	Haematological malignancies cancer susceptibility v4.8	TCF3	Sarah Leigh reviewed gene: TCF3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: B-cell acute lymphoblastic leukemia, MONDO:0004947; Mode of inheritance: None
07 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.8	COPA	Arina Puzriakova Publications for gene: COPA were set to 28956095; 25894502; 29137621
07 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.7	COPA	Arina Puzriakova Phenotypes for gene: COPA were changed from Autoimmune inflammatoy arthritis and interstial lung disease, 616414; Autoimmune interstitial lung disease-arthritis syndrome; COPA syndrome; Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production; Autoinflammatory Disorders to {Autoinflammation and autoimmunity, systemic, with immune dysregulation}, OMIM:616414
07 May 2025	COVID-19 research v1.143	COPA	Arina Puzriakova Phenotypes for gene: COPA were changed from Autoimmune interstitial lung disease-arthritis syndrome; Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production; Autoinflammatory Disorders; Autoimmune inflammatoy arthritis and interstial lung disease, 616414; COPA syndrome to {Autoinflammation and autoimmunity, systemic, with immune dysregulation}, OMIM:616414
07 May 2025	Intellectual disability v9.18	SMARCA1	Sarah Leigh Phenotypes for gene: SMARCA1 were changed from Coffin-Siris Syndrome; ORPHA1465 to X-linked intellectual disability, MONDO:0100284
07 May 2025	Intellectual disability v9.17	SMARCA1	Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SMARCA1.
07 May 2025	Intellectual disability v9.17	SMARCA1	Sarah Leigh Classified gene: SMARCA1 as Amber List (moderate evidence)
07 May 2025	Intellectual disability v9.17	SMARCA1	Sarah Leigh Gene: smarca1 has been classified as Amber List (Moderate Evidence).
07 May 2025	Intellectual disability v9.16	SMARCA1	Sarah Leigh reviewed gene: SMARCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479843, 27457812, 33057194, 40316778; Phenotypes: X-linked intellectual disability, MONDO:0100284; Mode of inheritance: None
06 May 2025	Intellectual disability v9.16	SMARCA1	Sarah Leigh Publications for gene: SMARCA1 were set to 26539891; 26740508
06 May 2025	Retinal disorders v8.4	RBP3	Arina Puzriakova Phenotypes for gene: RBP3 were changed from Retinitis pigmentosa 66 , OMIM:615233 to Retinitis pigmentosa 66, OMIM:615233
06 May 2025	Retinal disorders v8.3	RBP3	Arina Puzriakova Publications for gene: RBP3 were set to Review of the literature from Stephanie Barton - Arno et al (2015) Lack of Interphotoreceptor Retinoid Binding Protein Caused by Homozygous Mutation of RBP3 Is Associated With High Myopia and Retinal Dystrophy. Invest Ophthalmol Vis Sci. Apr; 56(4):2358-65: Two novel homozygous nonsense mutations (c.1530T>A; p.Y510* and c.3454G>T; p.E1152) in RBP3 were identified in four patients from two families. All four patients had a similar, unusual retinal dystrophy characterized by childhood onset high myopia, generalized rod and cone dysfunction, and an unremarkable fundus appearance. The FAF imaging showed multiple paracentral foci of low autofluorescence in one patient and patchy increased FAF in the region of the vascular arcades in another. The OCT showed loss of outer retinal bands over peripheral macular areas in all 4 cases; Abu-Safieh et al (2013) Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. Feb; 23(2):236-47; NM_002900.2 RBP3 :c.1162C>T; p.(Arg388) identified in homozygous state in patient with sporadic RP; Li et al (2013) Secretory defect and cytotoxicity: the potential disease mechanisms for the retinitis pigmentosa (RP)-associated interphotoreceptor retinoid-binding protein (IRBP). J Biol Chem. Apr 19; 288(16):11395-406: Functional studies to assess pathogenicity of a missense change, D1080N, that was identified in a homozygous state in a patient with ARRP by Den Hollander et al 2009. The mutation abolished IRBP secretion and induced endoplasmic reticulum stress by forming insoluble IRBP-containing complexes via disulfide bonds. Conclude that Loss of normal function and gain of cytotoxic function are the likely mechanisms for retinal degeneration.
06 May 2025	Retinal disorders v8.2	RBP3	Arina Puzriakova Phenotypes for gene: RBP3 were changed from Eye Disorders; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa; ?Retinitis pigmentosa 66, 615233 to Retinitis pigmentosa 66 , OMIM:615233
06 May 2025	Ectodermal dysplasia v4.4	TWIST2	Arina Puzriakova Classified gene: TWIST2 as Amber List (moderate evidence)
06 May 2025	Ectodermal dysplasia v4.4	TWIST2	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
06 May 2025	Ectodermal dysplasia v4.4	TWIST2	Arina Puzriakova Gene: twist2 has been classified as Amber List (Moderate Evidence).
06 May 2025	Ectodermal dysplasia v4.3	TWIST2	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: TWIST2.
06 May 2025	Ectodermal dysplasia v4.3	TWIST2	Arina Puzriakova edited their review of gene: TWIST2: Changed phenotypes to: Ablepharon-macrostomia syndrome, OMIM:200110 (AD), Barber-Say syndrome, OMIM:209885 (AD), Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR)
06 May 2025	Ectodermal dysplasia v4.3	TWIST2	Arina Puzriakova edited their review of gene: TWIST2: Changed rating: GREEN
06 May 2025	Ectodermal dysplasia v4.3	TWIST2	Arina Puzriakova edited their review of gene: TWIST2: Added comment: This gene is associated with multiple overlapping phenotypes which could be considered as types of ectodermal dysplasia: - Ablepharon-macrostomia syndrome, OMIM:200110 (AD) - sparse hair, redundant skin, facial dysmorphism - Barber-Say syndrome, OMIM:209885 (AD) - hypertrichosis, sparse lashes, skin hyperlaxity and redundancy, facial dysmorphism - Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR) - sparse hair, distichiasis and/or absent eyelashes, redundant skin, bitemporal skin lesions, facial dysmorphism; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
06 May 2025	Ectodermal dysplasia v4.3	TWIST2	Arina Puzriakova changed review comment from: Comment on mode of inheritance: TWIST2 is associated with two phenotypes which could be relevant to this panel - Ablepharon-macrostomia syndrome, OMIM:200110 (AD) and Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR). Therefore setting MOI to both mono- and biallelic.; to: Comment on mode of inheritance: TWIST2 is associated with multiple phenotypes which could be relevant to this panel - Ablepharon-macrostomia syndrome, OMIM:200110 (AD), Barber-Say syndrome, OMIM:209885 (AD) and Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR). Therefore setting MOI to both mono- and biallelic.
06 May 2025	Ectodermal dysplasia v4.3	TWIST2	Arina Puzriakova Phenotypes for gene: TWIST2 were changed from Focal facial dermal dysplasia 3, Setleis type to Ablepharon-macrostomia syndrome, OMIM:200110 (AD); Barber-Say syndrome, OMIM:209885 (AD); Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR)
06 May 2025	Ectodermal dysplasia v4.2	TWIST2	Arina Puzriakova Added comment: Comment on mode of inheritance: TWIST2 is associated with two phenotypes which could be relevant to this panel - Ablepharon-macrostomia syndrome, OMIM:200110 (AD) and Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR). Therefore setting MOI to both mono- and biallelic.
06 May 2025	Ectodermal dysplasia v4.2	TWIST2	Arina Puzriakova Mode of inheritance for gene: TWIST2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
06 May 2025	Breast cancer pertinent cancer susceptibility v2.13	PTEN	Arina Puzriakova Classified gene: PTEN as Red List (low evidence)
06 May 2025	Breast cancer pertinent cancer susceptibility v2.13	PTEN	Arina Puzriakova Added comment: Comment on list classification: Germline PTEN variants confer up to 85% lifetime risk of female breast cancer. Inclusion on this panel should therefore be reviewed by the expert group at the next GMS panel update.
06 May 2025	Breast cancer pertinent cancer susceptibility v2.13	PTEN	Arina Puzriakova Gene: pten has been classified as Red List (Low Evidence).
06 May 2025	Breast cancer pertinent cancer susceptibility v2.12	PTEN	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: PTEN. Tag Q2_25_expert_review tag was added to gene: PTEN.
06 May 2025	Intellectual disability v9.15	ATM	Arina Puzriakova changed review comment from: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel. Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration rather than primary ID that is a hallmark of the disorder.; to: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel. Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline which is secondary to neurodegeneration rather than a primary ID that is a hallmark of the disorder.
06 May 2025	Intellectual disability v9.15	ATM	Arina Puzriakova changed review comment from: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel. Biallelic variants in this gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration.; to: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel. Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration rather than primary ID that is a hallmark of the disorder.
06 May 2025	Intellectual disability v9.15	ATM	Arina Puzriakova Classified gene: ATM as Green List (high evidence)
06 May 2025	Intellectual disability v9.15	ATM	Arina Puzriakova Added comment: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel. Biallelic variants in this gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration.
06 May 2025	Intellectual disability v9.15	ATM	Arina Puzriakova Gene: atm has been classified as Green List (High Evidence).
06 May 2025	Intellectual disability v9.14	ATM	Arina Puzriakova Tag Q2_25_ demote_red tag was added to gene: ATM. Tag Q2_25_expert_review tag was added to gene: ATM.
06 May 2025	Intellectual disability v9.14	MAP4K4	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MAP4K4.
06 May 2025	Intellectual disability v9.14	MAP4K4	Arina Puzriakova Classified gene: MAP4K4 as Amber List (moderate evidence)
06 May 2025	Intellectual disability v9.14	MAP4K4	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update - at least 26 individuals from 21 families reported with Rasopathy-like phenotype (PMID: 37126546). Clinical presentation is varied, but most display symptoms of neurodevelopmental conditions with features overlapping those observed in patients with RASopathies. DD/ID was one of the most common features (ID reported in 8/21 cases).
06 May 2025	Intellectual disability v9.14	MAP4K4	Arina Puzriakova Gene: map4k4 has been classified as Amber List (Moderate Evidence).
06 May 2025	Intellectual disability v9.13	MAP4K4	Arina Puzriakova Entity copied from DDG2P v6.1
06 May 2025	Intellectual disability v9.13	MAP4K4	Arina Puzriakova gene: MAP4K4 was added gene: MAP4K4 was added to Intellectual disability. Sources: Literature,Expert Review Green,DD-Gene2Phenotype gene-checked tags were added to gene: MAP4K4. Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAP4K4 were set to 36469137; 28518170; 37126546; 37126546 Phenotypes for gene: MAP4K4 were set to MAP4K4-related neurodevelopmental disorder with/without congenital anomalies; multiple congenital anomalies; neurodevelopmental differences Mode of pathogenicity for gene: MAP4K4 was set to Other
06 May 2025	RASopathies v1.83	MAP4K4	Arina Puzriakova Tag gene-checked tag was added to gene: MAP4K4.
06 May 2025	RASopathies v1.83	MAP4K4	Arina Puzriakova Publications for gene: MAP4K4 were set to PMID: 37126546
06 May 2025	RASopathies v1.82	MAP4K4	Arina Puzriakova Classified gene: MAP4K4 as Green List (high evidence)
06 May 2025	RASopathies v1.82	MAP4K4	Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to rate as Green - at least 26 individuals from 21 families reported with Rasopathy-like phenotype (PMID: 37126546)
06 May 2025	RASopathies v1.82	MAP4K4	Arina Puzriakova Gene: map4k4 has been classified as Green List (High Evidence).
06 May 2025	Hereditary ataxia with onset in adulthood v8.5	RAB3A	Sarah Leigh changed review comment from: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. The authors also present supportive functional studies.; to: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. This gene is appropriate for the Hereditary ataxia with onset in adulthood panel as PMID: 40166812 states "The median age at onset was 26.5 (interquartile range (IQR) 22–32) with gait ataxia as the first symptom in all probands.", In addition, the authors also present supportive functional studies.
06 May 2025	Hereditary ataxia with onset in adulthood v8.5	RAB3A	Sarah Leigh Entity copied from Ataxia and cerebellar anomalies - narrow panel v8.3
06 May 2025	Hereditary ataxia with onset in adulthood v8.5	RAB3A	Sarah Leigh gene: RAB3A was added gene: RAB3A was added to Hereditary ataxia with onset in adulthood. Sources: Expert Review Amber,Research Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: RAB3A. Mode of inheritance for gene: RAB3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAB3A were set to 36928819; 40166812 Phenotypes for gene: RAB3A were set to RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay Penetrance for gene: RAB3A were set to Complete
02 May 2025	Retinal disorders v8.1	RLBP1	Cassandra Smith reviewed gene: RLBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
02 May 2025	Retinal disorders v8.1	RDH5	Cassandra Smith reviewed gene: RDH5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
02 May 2025	Retinal disorders v8.1	KIAA1549	Cassandra Smith reviewed gene: KIAA1549: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
02 May 2025	Congenital disorders of glycosylation v7.4	MAN2B2	Arina Puzriakova Classified gene: MAN2B2 as Amber List (moderate evidence)
02 May 2025	Congenital disorders of glycosylation v7.4	MAN2B2	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.
02 May 2025	Congenital disorders of glycosylation v7.4	MAN2B2	Arina Puzriakova Gene: man2b2 has been classified as Amber List (Moderate Evidence).
02 May 2025	Congenital disorders of glycosylation v7.3	MAN2B2	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MAN2B2. Tag Q2_25_ NHS_review tag was added to gene: MAN2B2.
02 May 2025	Likely inborn error of metabolism v8.5	MAN2B2	Arina Puzriakova Classified gene: MAN2B2 as Amber List (moderate evidence)
02 May 2025	Likely inborn error of metabolism v8.5	MAN2B2	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.
02 May 2025	Likely inborn error of metabolism v8.5	MAN2B2	Arina Puzriakova Gene: man2b2 has been classified as Amber List (Moderate Evidence).
02 May 2025	Congenital disorders of glycosylation v7.3	MAN2B2	Arina Puzriakova reviewed gene: MAN2B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38622837; Phenotypes: Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
02 May 2025	Likely inborn error of metabolism v8.4	MAN2B2	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MAN2B2. Tag Q2_25_ NHS_review tag was added to gene: MAN2B2.
02 May 2025	Likely inborn error of metabolism v8.4	MAN2B2	Arina Puzriakova reviewed gene: MAN2B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38622837; Phenotypes: Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
02 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.6	MAN2B2	Arina Puzriakova Classified gene: MAN2B2 as Amber List (moderate evidence)
02 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.6	MAN2B2	Arina Puzriakova Added comment: Comment on list classification: Upgrading to Amber as another patient has been identified with biallelic variants (c.384G>T; c.926T>A) in the MAN2B2 gene, who displayed immune dysregulation as part of the phenotype (PMID: 38622837)
02 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.6	MAN2B2	Arina Puzriakova Gene: man2b2 has been classified as Amber List (Moderate Evidence).
02 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.5	MAN2B2	Arina Puzriakova Publications for gene: MAN2B2 were set to 31775018
02 May 2025	Likely inborn error of metabolism v8.4	MAN2B2	Arina Puzriakova Publications for gene: MAN2B2 were set to 31775018; 35637269
02 May 2025	Congenital disorders of glycosylation v7.3	MAN2B2	Arina Puzriakova Publications for gene: MAN2B2 were set to 31775018; 35637269
02 May 2025	Likely inborn error of metabolism v8.3	MAN2B2	Arina Puzriakova Phenotypes for gene: MAN2B2 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140
02 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.4	MAN2B2	Arina Puzriakova Phenotypes for gene: MAN2B2 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140
02 May 2025	Congenital disorders of glycosylation v7.2	MAN2B2	Arina Puzriakova Phenotypes for gene: MAN2B2 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140
02 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.3	AICDA	Arina Puzriakova changed review comment from: Current literature strongly supports that heterozygous stop-gain variants are the primary variants linked to autosomal dominant forms of AICDA-related Hyper-IgM syndrome. These loss-of-function variants are well-documented to cause haploinsufficiency or a dominant-negative effect. In contrast, missense variants lack robust evidence for pathogenicity in the context of dominant disease. Missense variants have only been reported in recessive cases, often with functional validation. ClinGen only lists LOF variants associated with autosomal dominant form of Hyper-IgM syndrome Type 2 (https://search.clinicalgenome.org/CCID:004081).; to: Review based on feedback from Dr Julio Rodríguez López (Santiago Clinic Hospital CHUS, Spain): Current literature strongly supports that heterozygous stop-gain variants are the primary variants linked to autosomal dominant forms of AICDA-related Hyper-IgM syndrome. These loss-of-function variants are well-documented to cause haploinsufficiency or a dominant-negative effect. In contrast, missense variants lack robust evidence for pathogenicity in the context of dominant disease. Missense variants have only been reported in recessive cases, often with functional validation. ClinGen only lists LOF variants associated with autosomal dominant form of Hyper-IgM syndrome Type 2 (https://search.clinicalgenome.org/CCID:004081).
02 May 2025	Likely inborn error of metabolism v8.2	ARSG	Sadaf Naz reviewed gene: ARSG: Rating: GREEN; Mode of pathogenicity: None; Publications: 29300381, 32455177, 33300174, 33629623, 34223797, 35226187; Phenotypes: Usher syndrome, type IV; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 May 2025	Intellectual disability v9.12	SEL1L	Achchuthan Shanmugasundram Classified gene: SEL1L as Amber List (moderate evidence)
01 May 2025	Intellectual disability v9.12	SEL1L	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julia Baptista, there is sufficient evidence available (three unrelated families) for the association of this gene with intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
01 May 2025	Intellectual disability v9.12	SEL1L	Achchuthan Shanmugasundram Gene: sel1l has been classified as Amber List (Moderate Evidence).
01 May 2025	Intellectual disability v9.11	SEL1L	Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation. PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia, leading to its exclusion from being causal for these patients. This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation. PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
01 May 2025	Intellectual disability v9.11	SEL1L	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SEL1L. Tag Q2_25_ NHS_review tag was added to gene: SEL1L.
01 May 2025	Intellectual disability v9.11	SEL1L	Achchuthan Shanmugasundram Phenotypes for gene: SEL1L were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia, OMIM:621068; ?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, OMIM:621067
01 May 2025	Intellectual disability v9.10	SEL1L	Achchuthan Shanmugasundram Publications for gene: SEL1L were set to 37943610, 37943617
01 May 2025	Intellectual disability v9.9	SEL1L	Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation. PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia (33), leading to its exclusion from being causal for these patients. This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation. PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia, leading to its exclusion from being causal for these patients. This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
01 May 2025	Intellectual disability v9.9	SEL1L	Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation. PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation. PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia (33), leading to its exclusion from being causal for these patients. This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
01 May 2025	Intellectual disability v9.9	SEL1L	Achchuthan Shanmugasundram reviewed gene: SEL1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 37943610, 37943617; Phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia, OMIM:621068, ?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, OMIM:621067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 May 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3	JAG2	Achchuthan Shanmugasundram Classified gene: JAG2 as Amber List (moderate evidence)
01 May 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3	JAG2	Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available (16 unrelated families) for the association of JAG2 with Limb-girdle muscular dystrophy-27 (MIM #619566). Hence, this gene should be promoted to green rating in the next GMS update.
01 May 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3	JAG2	Achchuthan Shanmugasundram Gene: jag2 has been classified as Amber List (Moderate Evidence).
01 May 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.2	JAG2	Achchuthan Shanmugasundram Phenotypes for gene: JAG2 were changed from Limb-girdle muscular dystrophy-27 (OMIM: 619566) to Muscular dystrophy, limb-girdle, autosomal recessive 27, OMIM:619566
01 May 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.1	JAG2	Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: JAG2. Tag Q2_25_ NHS_review tag was added to gene: JAG2.
01 May 2025	Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.1	JAG2	Achchuthan Shanmugasundram reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33861953, 39121631, 39649397; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 27, OMIM:619566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 May 2025	Intellectual disability v9.9	MECP2	Arina Puzriakova Phenotypes for gene: MECP2 were changed from Rett syndrome, 312750Mental retardation, X-linked, syndromic 13, 300055Rett syndrome, preserved speech variant, 312750Encephalopathy, neonatal severe, 300673{Autism susceptibility, X-linked 3}, 300496Angelman syndrome, 105830Mental retardation, X-linked syndromic, Lubs type, 300260; RETT SYNDROME (RTT)[ to Encephalopathy, neonatal severe, OMIM:300673; Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055; Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260; Rett syndrome, OMIM:312750; Rett syndrome, atypical, OMIM:312750; Rett syndrome, preserved speech variant, OMIM:312750
01 May 2025	Intellectual disability v9.8	TAF2	Arina Puzriakova Phenotypes for gene: TAF2 were changed from Mental retardation, autosomal recessive 40, OMIM:615599 to Intellectual developmental disorder, autosomal recessive 40, OMIM:615599
01 May 2025	Early onset or syndromic epilepsy v8.3	SYNGAP1	Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from Mental retardation, autosomal dominant 5 to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
01 May 2025	Hereditary ataxia with onset in adulthood v8.4	SYNGAP1	Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from Autosomal dominant mental retardation 5, 612621 to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
01 May 2025	Fetal anomalies v6.5	SYNGAP1	Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from EPILEPTIC ENCEPHALOPATHY; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 5 to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
01 May 2025	Intellectual disability v9.7	SYNGAP1	Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from Mental retardation, autosomal dominant 5, 612621; EPILEPTIC ENCEPHALOPATHY to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
01 May 2025	Cerebral vascular malformations v4.2	SIRT1	Arina Puzriakova Classified gene: SIRT1 as Red List (low evidence)
01 May 2025	Cerebral vascular malformations v4.2	SIRT1	Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single case has been reported to date. Additional evidence is required before attributing causality.
01 May 2025	Cerebral vascular malformations v4.2	SIRT1	Arina Puzriakova Gene: sirt1 has been classified as Red List (Low Evidence).
01 May 2025	White matter disorders and cerebral calcification - narrow panel v7.2	EPB41L3	Arina Puzriakova Entity copied from Intellectual disability v9.6
01 May 2025	White matter disorders and cerebral calcification - narrow panel v7.2	EPB41L3	Arina Puzriakova gene: EPB41L3 was added gene: EPB41L3 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: EPB41L3. Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EPB41L3 were set to 39292993 Phenotypes for gene: EPB41L3 were set to Developmental disorder with seizures and myelination defects
01 May 2025	Early onset or syndromic epilepsy v8.2	EPB41L3	Arina Puzriakova Entity copied from Intellectual disability v9.6
01 May 2025	Early onset or syndromic epilepsy v8.2	EPB41L3	Arina Puzriakova gene: EPB41L3 was added gene: EPB41L3 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: EPB41L3. Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EPB41L3 were set to 39292993 Phenotypes for gene: EPB41L3 were set to Developmental disorder with seizures and myelination defects
01 May 2025	Intellectual disability v9.6	EPB41L3	Arina Puzriakova Classified gene: EPB41L3 as Amber List (moderate evidence)
01 May 2025	Intellectual disability v9.6	EPB41L3	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
01 May 2025	Intellectual disability v9.6	EPB41L3	Arina Puzriakova Gene: epb41l3 has been classified as Amber List (Moderate Evidence).
01 May 2025	Intellectual disability v9.5	EPB41L3	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: EPB41L3. Tag Q2_25_ NHS_review tag was added to gene: EPB41L3.
01 May 2025	Intellectual disability v9.5	EPB41L3	Arina Puzriakova reviewed gene: EPB41L3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39292993; Phenotypes: Developmental disorder with seizures and myelination defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 May 2025	Intellectual disability v9.5	EPB41L3	Arina Puzriakova Phenotypes for gene: EPB41L3 were changed from developmental delay; intellectual disability; seizures; hypotonia; neuroregression to Developmental disorder with seizures and myelination defects
01 May 2025	Severe microcephaly v8.2	EEF1D	Arina Puzriakova Entity copied from Intellectual disability v9.4
01 May 2025	Severe microcephaly v8.2	EEF1D	Arina Puzriakova gene: EEF1D was added gene: EEF1D was added to Severe microcephaly. Sources: Expert Review Amber,Literature Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: EEF1D. Mode of inheritance for gene: EEF1D was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EEF1D were set to 36576126; 30787422; 38083972; 28097321 Phenotypes for gene: EEF1D were set to Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, OMIM:621150
01 May 2025	Intellectual disability v9.4	EEF1D	Arina Puzriakova Phenotypes for gene: EEF1D were changed from Neurodevelopmental disorder; OMIM#621150 to Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, OMIM:621150
01 May 2025	Intellectual disability v9.3	EEF1D	Arina Puzriakova Classified gene: EEF1D as Amber List (moderate evidence)
01 May 2025	Intellectual disability v9.3	EEF1D	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
01 May 2025	Intellectual disability v9.3	EEF1D	Arina Puzriakova Gene: eef1d has been classified as Amber List (Moderate Evidence).
01 May 2025	Intellectual disability v9.2	EEF1D	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: EEF1D. Tag Q2_25_ NHS_review tag was added to gene: EEF1D.
01 May 2025	Intellectual disability v9.2	EEF1D	Arina Puzriakova reviewed gene: EEF1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 28097321, 30787422, 36576126, 38083972; Phenotypes: Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, OMIM:621150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 May 2025	Haematological malignancies cancer susceptibility v4.8	TCF3	Sarah Leigh Publications for gene: TCF3 were set to 36576946
01 May 2025	Haematological malignancies cancer susceptibility v4.7	TCF3	Sarah Leigh Classified gene: TCF3 as Amber List (moderate evidence)
01 May 2025	Haematological malignancies cancer susceptibility v4.7	TCF3	Sarah Leigh Gene: tcf3 has been classified as Amber List (Moderate Evidence).
01 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.3	SLCO2A1	Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SLCO2A1. Tag Q2_25_expert_review tag was added to gene: SLCO2A1.
01 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.3	SLCO2A1	Sarah Leigh reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
01 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.3	SLCO2A1	Sarah Leigh Phenotypes for gene: SLCO2A1 were changed from Prostaglandin transporter deficiency to Hypertrophic osteoarthropathy, primary, autosomal recessive 2 OMIM:614441; hypertrophic osteoarthropathy, primary, autosomal recessive, 2, MONDO:0013756; Hypertrophic osteoarthropathy, primary, autosomal dominant, OMIM:167100; hypertrophic osteoarthropathy, primary, autosomal dominant, MONDO:0008172
01 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.2	SLCO2A1	Sarah Leigh Publications for gene: SLCO2A1 were set to 29313109
01 May 2025	Skeletal dysplasia v8.4	SLCO2A1	Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SLCO2A1.
01 May 2025	Autosomal recessive primary hypertrophic osteoarthropathy v1.14	SLCO2A1	Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SLCO2A1. Tag Q2_25_expert_review tag was added to gene: SLCO2A1.
01 May 2025	Autosomal recessive primary hypertrophic osteoarthropathy v1.14	SLCO2A1	Sarah Leigh Publications for gene: SLCO2A1 were set to
01 May 2025	Skeletal dysplasia v8.4	SLCO2A1	Sarah Leigh edited their review of gene: SLCO2A1: Added comment: SLCO2A1 variants are associated with autosomal recessive and autosomal dominant forms of primary hypertrophic osteoarthropathy (OMIM:614441, OMIM:167100) in numerous cases (PMID:23509104; 27134495; 33852188; 22331663; 27134495).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
01 May 2025	Autosomal recessive primary hypertrophic osteoarthropathy v1.13	SLCO2A1	Sarah Leigh reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
01 May 2025	Fetal anomalies v6.4	C1orf127	Arina Puzriakova commented on gene: C1orf127: Added new-gene-name tag, new approved HGNC gene symbol for C1orf127 is CIROZ
01 May 2025	Laterality disorders and isomerism v4.3	C1orf127	Arina Puzriakova commented on gene: C1orf127: Added new-gene-name tag, new approved HGNC gene symbol for C1orf127 is CIROZ
01 May 2025	Fetal anomalies v6.4	C1orf127	Arina Puzriakova Tag new-gene-name tag was added to gene: C1orf127.
01 May 2025	Laterality disorders and isomerism v4.3	C1orf127	Arina Puzriakova Tag new-gene-name tag was added to gene: C1orf127.
01 May 2025	Fetal anomalies v6.4	C1orf127	Arina Puzriakova Classified gene: C1orf127 as Amber List (moderate evidence)
01 May 2025	Fetal anomalies v6.4	C1orf127	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
01 May 2025	Fetal anomalies v6.4	C1orf127	Arina Puzriakova Gene: c1orf127 has been classified as Amber List (Moderate Evidence).
01 May 2025	Skeletal dysplasia v8.4	SLCO2A1	Sarah Leigh Publications for gene: SLCO2A1 were set to
01 May 2025	Laterality disorders and isomerism v4.3	C1orf127	Arina Puzriakova Classified gene: C1orf127 as Amber List (moderate evidence)
01 May 2025	Laterality disorders and isomerism v4.3	C1orf127	Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
01 May 2025	Laterality disorders and isomerism v4.3	C1orf127	Arina Puzriakova Gene: c1orf127 has been classified as Amber List (Moderate Evidence).
01 May 2025	Laterality disorders and isomerism v4.2	C1orf127	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: C1orf127. Tag Q2_25_ NHS_review tag was added to gene: C1orf127.
01 May 2025	Fetal anomalies v6.3	C1orf127	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: C1orf127. Tag Q2_25_ NHS_review tag was added to gene: C1orf127.
01 May 2025	Fetal anomalies v6.3	C1orf127	Arina Puzriakova reviewed gene: C1orf127: Rating: GREEN; Mode of pathogenicity: None; Publications: 39753129; Phenotypes: Heterotaxy, visceral, 14, autosomal, OMIM:621080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 May 2025	Laterality disorders and isomerism v4.2	C1orf127	Arina Puzriakova reviewed gene: C1orf127: Rating: GREEN; Mode of pathogenicity: None; Publications: 39753129; Phenotypes: Heterotaxy, visceral, 14, autosomal, OMIM:621080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
01 May 2025	Fetal anomalies v6.3	C1orf127	Arina Puzriakova Phenotypes for gene: C1orf127 were changed from Heterotaxy to Heterotaxy, visceral, 14, autosomal, OMIM:621080
01 May 2025	Laterality disorders and isomerism v4.2	C1orf127	Arina Puzriakova Phenotypes for gene: C1orf127 were changed from Heterotaxy to Heterotaxy, visceral, 14, autosomal, OMIM:621080
01 May 2025	Skeletal dysplasia v8.3	SLCO2A1	Sarah Leigh Phenotypes for gene: SLCO2A1 were changed from Hypertrophic osteoarthropathy, primary, autosomal recessive 2 614441; Hypertrophic osteoarthropathy, primary, autosomal recessive 2 614441 to Hypertrophic osteoarthropathy, primary, autosomal recessive 2 OMIM:614441; hypertrophic osteoarthropathy, primary, autosomal recessive, 2, MONDO:0013756; Hypertrophic osteoarthropathy, primary, autosomal dominant, OMIM:167100; hypertrophic osteoarthropathy, primary, autosomal dominant, MONDO:0008172
01 May 2025	Autosomal recessive primary hypertrophic osteoarthropathy v1.13	SLCO2A1	Sarah Leigh Phenotypes for gene: SLCO2A1 were changed from Hypertrophic osteoarthropathy, primary, autosomal recessive 2 OMIM:614441 to Hypertrophic osteoarthropathy, primary, autosomal recessive 2 OMIM:614441; hypertrophic osteoarthropathy, primary, autosomal recessive, 2, MONDO:0013756; Hypertrophic osteoarthropathy, primary, autosomal dominant, OMIM:167100; hypertrophic osteoarthropathy, primary, autosomal dominant, MONDO:0008172
01 May 2025	Hereditary ataxia with onset in adulthood v8.3	NEU1	Arina Puzriakova Classified gene: NEU1 as Amber List (moderate evidence)
01 May 2025	Hereditary ataxia with onset in adulthood v8.3	NEU1	Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in the NEU1 gene are associated with Sialidosis (OMIM: 256550). Both Sialidosis Type I (milder, late-onset) and Sialidosis Type II (more severe, early-onset) can present with ataxia as part of a systemic neurological condition. Overall there are sufficient unrelated cases to warrant inclusion on this panel.
01 May 2025	Hereditary ataxia with onset in adulthood v8.3	NEU1	Arina Puzriakova Gene: neu1 has been classified as Amber List (Moderate Evidence).
01 May 2025	Ataxia and cerebellar anomalies - narrow panel v8.3	NEU1	Arina Puzriakova Classified gene: NEU1 as Amber List (moderate evidence)
01 May 2025	Ataxia and cerebellar anomalies - narrow panel v8.3	NEU1	Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in the NEU1 gene are associated with Sialidosis (OMIM: 256550). Both Sialidosis Type I (milder, late-onset) and Sialidosis Type II (more severe, early-onset) can present with ataxia as part of a systemic neurological condition. Overall there are sufficient unrelated cases to warrant inclusion on this panel.
01 May 2025	Ataxia and cerebellar anomalies - narrow panel v8.3	NEU1	Arina Puzriakova Gene: neu1 has been classified as Amber List (Moderate Evidence).
01 May 2025	Ataxia and cerebellar anomalies - narrow panel v8.2	NEU1	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: NEU1. Tag Q2_25_ NHS_review tag was added to gene: NEU1.
01 May 2025	Hereditary ataxia with onset in adulthood v8.2	NEU1	Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: NEU1. Tag Q2_25_ NHS_review tag was added to gene: NEU1.
01 May 2025	Intellectual disability v9.2	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis, type I, 256550Sialidosis, type II, 256550; SIALIDOSIS (SIALIDOSIS) to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
01 May 2025	Hereditary ataxia with onset in adulthood v8.2	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from Ataxia; myoclonus to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; Ataxia; Myoclonus
01 May 2025	Likely inborn error of metabolism v8.2	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis type II; Sialidosis, type I; Sialidosis (Oligosaccharidoses); Mucolipidosis, Type I; Sialidosis to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; Mucolipidosis, Type I
01 May 2025	Fetal anomalies v6.2	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from SIALIDOSIS to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
01 May 2025	Undiagnosed metabolic disorders v1.629	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis (Oligosaccharidoses); Sialidosis; Sialidosis, type I; Sialidosis type II; Mucolipidosis, Type I to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; Mucolipidosis, Type I
01 May 2025	Skeletal dysplasia v8.2	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis, type II 256550; Sialidosis, type I 256550 to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
01 May 2025	Ataxia and cerebellar anomalies - narrow panel v8.2	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from Ataxia; myoclonus to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; Ataxia; Myoclonus
01 May 2025	Fetal hydrops v1.89	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis, type I, 256550; Sialidosis, type II, 256550; Sialidosis; fetal hydrops; Hydrops fetalis (type II, congenital) to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; fetal hydrops; Hydrops fetalis (type II, congenital)
01 May 2025	Mucopolysaccharideosis, Gaucher, Fabry v1.3	NEU1	Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis; Sialidosis, type I; Sialidosis type II; Mucolipidosis, Type I to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
01 May 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.1	AICDA	Arina Puzriakova commented on gene: AICDA: Current literature strongly supports that heterozygous stop-gain variants are the primary variants linked to autosomal dominant forms of AICDA-related Hyper-IgM syndrome. These loss-of-function variants are well-documented to cause haploinsufficiency or a dominant-negative effect. In contrast, missense variants lack robust evidence for pathogenicity in the context of dominant disease. Missense variants have only been reported in recessive cases, often with functional validation. ClinGen only lists LOF variants associated with autosomal dominant form of Hyper-IgM syndrome Type 2 (https://search.clinicalgenome.org/CCID:004081).
30 Apr 2025	Hereditary neuropathy v1.497	ARHGAP19	Shahryar Alavi gene: ARHGAP19 was added gene: ARHGAP19 was added to Hereditary neuropathy. Sources: Research Mode of inheritance for gene: ARHGAP19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARHGAP19 were set to https://www.medrxiv.org/content/10.1101/2024.05.10.24306768v1 Phenotypes for gene: ARHGAP19 were set to neuropathy; Charcot-Marie-Tooth disease Penetrance for gene: ARHGAP19 were set to Complete Mode of pathogenicity for gene: ARHGAP19 was set to Other Review for gene: ARHGAP19 was set to GREEN Added comment: A comprehensive study on loss of function variants of the ARHGAP19 gene from several unrelated families shows that homozygous mutations cause early-onset motor-predominant neuropathy. Biochemical assays revealed that GAP domain variants cause loss of protein function. Fruit fly and Zebrafish loss of function models also showed movement deficits. RNA-Seq analysis confirmed downregulation of ARHGAP19 as well as cell cycle, motor and muscular cytoskeleton pathways in patients compared to controls. The paper is under review. Sources: Research
30 Apr 2025	Unexplained young onset end-stage renal disease v12.8		Achchuthan Shanmugasundram Panel version 12.7 has been signed off on 2025-04-30
30 Apr 2025	Unexplained death in infancy and sudden unexplained death in childhood v21.5		Achchuthan Shanmugasundram Panel version 21.4 has been signed off on 2025-04-30
30 Apr 2025	Rare multisystem ciliopathy Super panel v21.2		Eleanor Williams Panel version 21.1 has been signed off on 2025-04-30
30 Apr 2025	Hypotonic infant v44.5		Arina Puzriakova Panel version 44.4 has been signed off on 2025-04-30
30 Apr 2025	Paediatric disorders v72.2		Eleanor Williams Panel version 72.1 has been signed off on 2025-04-30
30 Apr 2025	Hereditary ataxia and cerebellar anomalies - childhood onset v22.2		Arina Puzriakova Panel version 22.1 has been signed off on 2025-04-30
30 Apr 2025	Sudden unexplained death or survivors of a cardiac event v22.8		Achchuthan Shanmugasundram Panel version 22.7 has been signed off on 2025-04-30
30 Apr 2025	Cystic renal disease v12.3		Arina Puzriakova Panel version 12.2 has been signed off on 2025-04-30
30 Apr 2025	Childhood onset leukodystrophy v30.2		Arina Puzriakova Panel version 30.1 has been signed off on 2025-04-30
30 Apr 2025	Other rare neuromuscular disorders v30.5		Eleanor Williams Panel version 30.4 has been signed off on 2025-04-30
30 Apr 2025	Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.3		Sarah Leigh Panel version 2.2 has been signed off on 2025-04-30
30 Apr 2025	Haematuria v2.16		Sarah Leigh Panel version 2.15 has been signed off on 2025-04-30
30 Apr 2025	Hereditary systemic amyloidosis v1.25		Sarah Leigh Panel version 1.24 has been signed off on 2025-04-30
30 Apr 2025	PTEN Hamartoma Tumour Syndrome v1.3		Eleanor Williams Panel version 1.2 has been signed off on 2025-04-30
30 Apr 2025	Distal myopathies v6.5		Sarah Leigh Panel version 6.4 has been signed off on 2025-04-30
30 Apr 2025	Progressive cardiac conduction disease v2.11		Eleanor Williams Panel version 2.10 has been signed off on 2025-04-30
30 Apr 2025	Paediatric motor neuronopathies v3.10		Eleanor Williams Panel version 3.9 has been signed off on 2025-04-30
30 Apr 2025	Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.7		Eleanor Williams Panel version 3.6 has been signed off on 2025-04-30
30 Apr 2025	Long QT syndrome v3.11		Eleanor Williams Panel version 3.10 has been signed off on 2025-04-30
30 Apr 2025	Paroxysmal central nervous system disorders v4.1		Eleanor Williams Panel version 4.0 has been signed off on 2025-04-30
30 Apr 2025	Paroxysmal central nervous system disorders v4.0		Eleanor Williams promoted panel to version 4.0
30 Apr 2025	Palmoplantar keratodermas v4.1		Eleanor Williams Panel version 4.0 has been signed off on 2025-04-30
30 Apr 2025	Palmoplantar keratodermas v4.0		Eleanor Williams promoted panel to version 4.0
30 Apr 2025	Paediatric pseudo-obstruction syndrome v2.1		Eleanor Williams Panel version 2.0 has been signed off on 2025-04-30
30 Apr 2025	Paediatric pseudo-obstruction syndrome v2.0		Eleanor Williams promoted panel to version 2.0
30 Apr 2025	Paediatric or syndromic cardiomyopathy v7.1		Eleanor Williams Panel version 7.0 has been signed off on 2025-04-30
30 Apr 2025	Paediatric or syndromic cardiomyopathy v7.0		Eleanor Williams promoted panel to version 7.0
30 Apr 2025	Paediatric disorders - additional genes v7.1		Eleanor Williams Panel version 7.0 has been signed off on 2025-04-30
30 Apr 2025	Paediatric disorders - additional genes v7.0		Eleanor Williams promoted panel to version 7.0
30 Apr 2025	Osteogenesis imperfecta v5.1		Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
30 Apr 2025	Osteogenesis imperfecta v5.0		Eleanor Williams promoted panel to version 5.0
30 Apr 2025	Optic neuropathy v5.1		Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
30 Apr 2025	Optic neuropathy v5.0		Eleanor Williams promoted panel to version 5.0
30 Apr 2025	Unexplained young onset end-stage renal disease - additional genes v1.2		Achchuthan Shanmugasundram Panel version 1.1 has been signed off on 2025-04-30
30 Apr 2025	Tubulointerstitial kidney disease v3.6		Achchuthan Shanmugasundram Panel version 3.5 has been signed off on 2025-04-30
30 Apr 2025	Ophthalmological ciliopathies v5.1		Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
30 Apr 2025	Ophthalmological ciliopathies v5.0		Eleanor Williams promoted panel to version 5.0
30 Apr 2025	Sickle cell, thalassaemia and other haemoglobinopathies v2.3		Achchuthan Shanmugasundram Panel version 2.2 has been signed off on 2025-04-30
30 Apr 2025	Short QT syndrome v3.15		Achchuthan Shanmugasundram Panel version 3.14 has been signed off on 2025-04-30
30 Apr 2025	Neuronal ceroid lipofuscinosis v3.1		Eleanor Williams Panel version 3.0 has been signed off on 2025-04-30
30 Apr 2025	Iron metabolism disorders - NOT common HFE mutations v3.1		Sarah Leigh Panel version 3.0 has been signed off on 2025-04-30
30 Apr 2025	Iron metabolism disorders - NOT common HFE mutations v3.0		Sarah Leigh promoted panel to version 3.0
30 Apr 2025	Neuronal ceroid lipofuscinosis v3.0		Eleanor Williams promoted panel to version 3.0
30 Apr 2025	Rhabdomyolysis and metabolic muscle disorders v5.5		Achchuthan Shanmugasundram Panel version 5.4 has been signed off on 2025-04-30
30 Apr 2025	Neurological ciliopathies v6.1		Eleanor Williams Panel version 6.0 has been signed off on 2025-04-30
30 Apr 2025	Intellectual disability v9.1		Sarah Leigh Panel version 9.0 has been signed off on 2025-04-30
30 Apr 2025	Neurological ciliopathies v6.0		Eleanor Williams promoted panel to version 6.0
30 Apr 2025	White matter disorders and cerebral calcification - narrow panel v7.1		Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2025-04-30
30 Apr 2025	Intellectual disability v9.0		Sarah Leigh promoted panel to version 9.0
30 Apr 2025	White matter disorders and cerebral calcification - narrow panel v7.0		Achchuthan Shanmugasundram promoted panel to version 7.0
30 Apr 2025	Nephrocalcinosis or nephrolithiasis v5.1		Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
30 Apr 2025	Nephrocalcinosis or nephrolithiasis v5.0		Eleanor Williams promoted panel to version 5.0
30 Apr 2025	Inherited pancreatic cancer v3.1		Sarah Leigh Panel version 3.0 has been signed off on 2025-04-30
30 Apr 2025	Vascular skin disorders v2.1		Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2025-04-30

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