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09 Mar 2026	Early onset or syndromic epilepsy v8.127	FSD1L	Ida Ertmanska gene: FSD1L was added gene: FSD1L was added to Early onset or syndromic epilepsy. Sources: Literature Q1_26_promote_green tags were added to gene: FSD1L. Mode of inheritance for gene: FSD1L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FSD1L were set to 41720098; 41720099 Phenotypes for gene: FSD1L were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: FSD1L was set to GREEN Added comment: PMID: 41720098 Serpieri et al., 2026 Report of eleven individuals (including five fetuses) from six unrelated families harbouring biallelic FSD1L variants. Seq method: exome sequencing. Consanguinity was confirmed in 4/6 families, and suspected in the fifth. Phenotype spectrum: severe intellectual disability (5/5 assessed from 3 families), epilepsy (5 individuals from 3 families), severe hydrocephalus (3 families), vision deficit due to optic nerve hypoplasia/atrophy (3 families), spastic tetraparesis (2 families) corpus callosum hypoplasia/agenesis on MRI (5/5 families assessed), Variants detected - largely nonsense type: Family A - homozygous c.409T>G (p.Leu137Val); Family B - 3 affected fetuses homozygous for c.1411C>T (p.Gln471Ter); Family C - sibs compound het for c.1228T>G (p.Phe410Val) and c.1251_1252insTAA (p.Thr418Ter); Family D - affected individuals (1 fetal case) homozygous for c.1366G>C (p.Asp456His) - shown to impact splicing (r.406_442del), resulting in predicted p.Ser136LeufsTer19 change; Family E - affected child with homozygous c.835C>T (p.Arg279Ter) change; Family F - fetus homozygous for c.1260G>A (p.Trp420Ter); Functional evidence: Fsd1l depletion in mouse embryos recapitulated the ventricular dilation observed in affected fetuses. PMID 41720099 Lin et al., 2026 Report of 6 affected individuals from 4 families with retinitis pigmentosa. One individual underwent a full neurological evaluation, including brain neuroimaging, which revealed no evidence of central nervous system involvement. FSD1L variants detected: Family A: 2 sibs compound het for c.1049G>A (p.Arg350Gln) and c.1428del (p.Phe476Leufs∗22) Family B: individual comp het for c.488G>A (p.Arg163His), c.488G>A & c.745C>T (p.Arg249∗) Family C: 2 sibs compound het for c.488G>A (p.Arg163His) & c.226_227del (p.Ser77Argfs∗4) Family D: individual compound het for c.1037_1038delinsT (p.Pro346Leufs∗8) and c.1025+624_1025+649del Sibs from family A had mild neurological involvement (mild ID, spastic diplegia in one sibling). Authors note that "specific combination and functional severity of the two alleles likely determines the clinical outcome", with non-LoF variants causing a milder effect (e.g., isolated retinal phenotype). FSD1L is not yet associated with a phenotype in OMIM or Gene2Phenotype. Sources: Literature
21 Oct 2025	Early onset or syndromic epilepsy v8.53	PPOX	Ida Ertmanska changed review comment from: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). PMID: 8290408 Hift et al., 1993 Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly. Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71. PMID: 30861571 Al-Hage et al., 2019 A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq. PMID: 35164799 Vafaee-Shahi et al., 2022 Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed. PMID: 40114189 Kaiser et al., 2025 Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital. Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment. Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.; to: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). PMID: 8290408 Hift et al., 1993 Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly. Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71. PMID: 30861571 Al-Hage et al., 2019 A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq. PMID: 35164799 Vafaee-Shahi et al., 2022 Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed. PMID: 40114189 Kaiser et al., 2025 Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital. Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment. Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
21 Oct 2025	Early onset or syndromic epilepsy v8.53	PPOX	Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). PMID: 8290408 Hift et al., 1993 Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly. Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71. PMID: 30861571 Al-Hage et al., 2019 A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq. PMID: 35164799 Vafaee-Shahi et al., 2022 Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed. PMID: 40114189 Kaiser et al., 2025 Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital. Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment. Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). PMID: 8290408 Hift et al., 1993 Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly. Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71. PMID: 30861571 Al-Hage et al., 2019 A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq. PMID: 35164799 Vafaee-Shahi et al., 2022 Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed. PMID: 40114189 Kaiser et al., 2025 Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital. Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment. Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
21 Oct 2025	Early onset or syndromic epilepsy v8.53	PPOX	Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). PMID: 8290408 Hift et al., 1993 Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly. Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71. PMID: 30861571 Al-Hage et al., 2019 A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq. PMID: 35164799 Vafaee-Shahi et al., 2022 Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed. PMID: 40114189 Kaiser et al., 2025 2 siblings with Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital. Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment. Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). PMID: 8290408 Hift et al., 1993 Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly. Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71. PMID: 30861571 Al-Hage et al., 2019 A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq. PMID: 35164799 Vafaee-Shahi et al., 2022 Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed. PMID: 40114189 Kaiser et al., 2025 Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital. Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment. Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.
21 Oct 2025	Early onset or syndromic epilepsy v8.53	PPOX	Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). PMID: 8290408 Hift et al., 1993 Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly. Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71. PMID: 30861571 Al-Hage et al., 2019 A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq. PMID: 35164799 Vafaee-Shahi et al., 2022 Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed. PMID: 40114189 Kaiser et al., 2025 2 siblings with Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital. Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment. Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.
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
06 May 2024	Early onset or syndromic epilepsy v5.6	PIGM	Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
02 May 2024	Early onset or syndromic epilepsy v5.6	PIGM	Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: PIGM.
02 May 2024	Early onset or syndromic epilepsy v5.6	PIGM	Eleanor Williams reviewed gene: PIGM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
02 May 2024	Early onset or syndromic epilepsy v5.5	PIGM	Achchuthan Shanmugasundram Source Expert Review Green was added to PIGM. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
02 Apr 2024	Early onset or syndromic epilepsy v4.184	IKBKG	Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, 308300 to Incontinentia pigmenti, OMIM:308300
21 Nov 2023	Early onset or syndromic epilepsy v4.129	PIGM	Sarah Leigh Tag Q4_23_NHS_review was removed from gene: PIGM.
21 Nov 2023	Early onset or syndromic epilepsy v4.129	PIGM	Sarah Leigh changed review comment from: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition. To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations. Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; to: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition. To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations. Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100). Absence seizures were apparent in 5/7 individuals from 5/6 families with OMIM:610293 biallelic for rs587776528 (table 1, PMID: 31445883).
21 Nov 2023	Early onset or syndromic epilepsy v4.129	PIGM	Sarah Leigh Entity copied from Likely inborn error of metabolism - targeted testing not possible v4.77
21 Nov 2023	Early onset or syndromic epilepsy v4.129	PIGM	Sarah Leigh gene: PIGM was added gene: PIGM was added to Early onset or syndromic epilepsy. Sources: NHS GMS,Expert Review Amber,London North GLH promoter, non-coding-known-pathogenic, Q4_23_promote_green, Q4_23_NHS_review tags were added to gene: PIGM. Mode of inheritance for gene: PIGM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGM were set to 27604308; 16767100; 25293775; 17442906; 31445883 Phenotypes for gene: PIGM were set to Glycosylphosphatidylinositol deficiency, OMIM:610293
09 Aug 2022	Early onset or syndromic epilepsy v2.563	TFE3	Arina Puzriakova Phenotypes for gene: TFE3 were changed from TFE3-related intellectual disability with pigmentary mosaicism to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, OMIM:301066
24 May 2022	Early onset or syndromic epilepsy v2.530	PRPF8	Sarah Leigh gene: PRPF8 was added gene: PRPF8 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature Q2_22_rating tags were added to gene: PRPF8. Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRPF8 were set to 20811066; 23714367; 30420816; 31696658; 35543142 Phenotypes for gene: PRPF8 were set to PRPF8-related developmental disorder (monoallelic); Retinitis pigmentosa 13, OMIM:600059 Penetrance for gene: PRPF8 were set to unknown
02 Dec 2020	Early onset or syndromic epilepsy v2.227	TFE3	Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
05 Jan 2020	Early onset or syndromic epilepsy v2.0	RNF113A	Konstantinos Varvagiannis gene: RNF113A was added gene: RNF113A was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: RNF113A 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: RNF113A were set to 25612912; 31880405; 31793730; 29133357; 30506991; 15256591; 24026126; 23555887 Phenotypes for gene: RNF113A were set to ?Trichothiodystrophy 5, nonphotosensitive, 300953 Penetrance for gene: RNF113A were set to Complete Review for gene: RNF113A was set to GREEN Added comment: The gene has been reviewed for the ID panel. Seizures have been reported in 4 affected males from 3 families. From the ID panel: Nonphotosensitive trichothiodystrophy-5 (TTD5 - #300953) is caused by mutation in the RNF113A gene on Xq24. DD, ID and seizures are part of the phenotype in males. (Several) heterozygous females have not been reported to exhibit these features (DD/ID/seizures) although a single female in the first report had speech/motor delay and learning difficulties. Corbett et al (2015 - PMID: 25612912) reported on 2 cousins with profound ID and epilepsy among other principal features of the disorder. Linkage analysis (probably low(?) LOD score) localized the gene to a 7.75 Mb region on Xq and subsequent Sanger and exome sequencing identified an RNF113A stopgain variant in both (NM_006978.2:c.901C>T / p.Q301). Other X-chr variants did not segregate with the disorder. Previously sequencing of other trichothiodystrophy genes (in both) and CMA (X-chromosome BAC array / ISCA CMA) were non-diagnostic. The variant in this family was identified in a previous study (Tarpey et al 2009 - PMID: 19377476) but was 'incorrectly' discarded at the time due to a sequencing error in a control DNA sample (analysis repeated by Corbett et al). The same variant was also reported in 2 fetuses in a later report (PMID: 31793730). Mendelsohn et al (2019 - PMID: 31880405) reported on 2 unrelated affected males. The 1st presented with severe DD/ID (independent walking at 7y, single words/non-verbal with with special educational needs at 11y), seizures as well as typical features of the disorder. Metabolic work-up (incl. 7-DHCR) and genetic testing (Allagile, PFIC genes, CMA) were non-diagnostic. Duo WES revealed a frameshift variant [c.903_910delGCAGACCCA / p.(Gln302fs12)] inherited from the mother. Maternal XCI was completely skewed (100:0). The 2nd individual (briefly reported as REQ18-0616 by Monies et al - PMID: 31130284) presented global DD and seizures along with all other core features of the disorder at the age of 16m. Karyotype was normal. Exome revealed a frameshift variant [NM_006978.3:c.897_898delTG / p.(Cys299)]. Further evidence is based on the role of the RNA113A, being involved in mRNA splicing (/spiceosome function) [Gatti da Silva et al 2018 - PMID: 30506991 & many other Refs] as well in DNA repair (E3 ubiquitin-protein ligase in a mechanism for sensing DNA damage induced by alkylation) [Brickner et al 2017 - PMID: 29133357]. In the latter study, LCLs from individuals harboring Q301 were shown to be hypersensitive to an alkylating agent (MMS) which was also the case for an RNF113A knockdown cell line. The cells had reduced ASCC alkylation repair complex foci formation, which was rescued upon reconstitution of patient cells with wt RNF113A. Animal models : Disruption of rnf113a in zebrafish resulted among others in small head and underdeveloped gut (PMID cited : 15256591 - Amsterdam et al) similar to the microcephaly observed in several individuals and/or abnormal gut development/diarrhoea reported in few. Knockdown of the Drosophila ortholog (mdlc) led to reduced proliferation of neuroblasts. Neuronal differentiation was initiated but not completed. Expression of the full-length human gene rescued the CNS defects (discussed by Mendelsohn et al citing PMID: 24026126 - Carney et al). RNA-seq data from the same study were analyzed by Corbett et al, and differentialy expressed genes were enriched for genes involved in DNA damage response and repair. Knockdown of RNF-113 in C.elegans sensitises cells to UVA-induced DNA damage. RNF-113 was shown to be involved in interstrand DNA crosslink repair and interact with a RAD51C homolog (PMID cited: 23555887 - Lee et al). [Please consider upgrade/inclusion in other relevant panels eg. the 'Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome panel' where the gene has red rating]. Sources: Literature
27 Dec 2019	Early onset or syndromic epilepsy v2.0	TFE3	Konstantinos Varvagiannis reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30595499, 31833172, https://doi.org/10.1126/scisignal.aax0926; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of skin pigmentation, Coarse facial features, Seizures; Mode of inheritance: Other
13 Aug 2019	Early onset or syndromic epilepsy v1.213	IKBKG	Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM lists XLD inheritance for Incontinentia pigmenti (MIM:308300).
06 Aug 2019	Early onset or syndromic epilepsy v1.188	POMGNT1	Tracy Lester reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 15466003; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A, 3 253280, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation)type B, 3 613151, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 3 613157 , Retinitis pigmentosa 76 617123; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
06 Aug 2019	Early onset or syndromic epilepsy v1.188	IKBKG	Tracy Lester reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: ; Publications: 28870493, 28870493 ; Phenotypes: Incontinentia pigmenti, 308300, Immunodeficiency , 300636; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
06 Aug 2019	Early onset or syndromic epilepsy v1.188	DHDDS	Tracy Lester reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: ; Publications: 29100083; Phenotypes: ?Congenital disorder of glycosylation, 613861 , Developmental delay and seizures with or without movement abnormalities, 617836, Retinitis pigmentosa, 613861; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
25 Nov 2018	Early onset or syndromic epilepsy v0.1111	TELO2	Konstantinos Varvagiannis gene: TELO2 was added gene: TELO2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Mode of inheritance for gene: TELO2 was set to BIALLELIC, autosomal or pseudoautosomal Penetrance for gene: TELO2 were set to Complete Added comment: Biallelic mutations in TELO2 cause You-Hoover-Fong syndrome (MIM 616954). // PMID: 27132593 reports on 6 patients (from 4 non-consanguineous families) with biallelic TELO2 variants and a similar phenotype. Intellectual disability and microcephaly were universal features (6/6). Abnormal hearing (3/6), cortical visual impairment (3/6), abnormality of the cardiovascular system (3/6), behavioral problems (laughter outbursts in 3/6) and abnormal balance and movement disorder (6/6) were part of the phenotype. One individual had seizures. 5 missense variants and a complex allele with a stopgain variant localized in cis with a splice-site variant (NM_016111.3:c.514C>T or p.Gln172* in cis with c.2034+1G>A) are reported. As a result heterozygosity for the complex variant may be confounded with compound heterozygous state until segregation studies are performed. Functional studies support pathogenicity of the missense variants (reduced protein steady-state levels of TELO2 as well as TTI1 and TTI2 - the 2 other members of the TTT complex) suggesting loss of function. PMID: 28944240 reports on 2 sisters born to non-consanguineous parents. Both were compound heterozygous for 2 novel variants, a missense and a frameshift one. Severe microcephaly (-8.5 SD and -10.7 SD) and seizures were noted in both. The first sister passed away at the age of 2 months due to a respiratory infection. The other sister demonstrated a compatible, though much more severe phenotype (ID and microcephaly) with additional features (dwarfism, renal anomalies, retinitis pigmentosa, etc) compared to previously reported patients. // As a result this gene could possibly be considered for inclusion in this panel as amber (seizures in 3/8 patients reported to date - these individuals belonged to 2 different families) . Sources: Literature, Expert Review
19 Nov 2018	Early onset or syndromic epilepsy v0.924	IKBKG	Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Incontinentia pigmenti is confirmed by OMIM and Gene2Phenotype. There are >3 unrelated families with a variant in this gene diagnosed with incontinentia pigmenti who have seizures (PMID: 30151858,28794079,24339369). Neurological symptoms (including seizures) are affect ~30% of patients with incontinentia pigmenti (PMID:28870493).
15 Nov 2018	Early onset or syndromic epilepsy v0.894	IKBKG	Ivone Leong Phenotypes for gene: IKBKG were changed from to Incontinentia pigmenti, 308300