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Early onset or syndromic epilepsy v2.498 | GABRD |
Ivone Leong Tag Q4_21_rating was removed from gene: GABRD. Tag Q4_21_NHS_review was removed from gene: GABRD. |
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Early onset or syndromic epilepsy v2.498 | GABRD | Sarah Leigh commented on gene: GABRD: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v2.498 | GABRD |
Ivone Leong Source Expert Review Green was added to GABRD. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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Early onset or syndromic epilepsy v2.470 | GABRD | Arina Puzriakova Tag Q4_21_rating tag was added to gene: GABRD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v2.470 | GABRD | Arina Puzriakova Classified gene: GABRD as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v2.470 | GABRD |
Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but this gene should now be promoted to Green at the next GMS panel update. New evidence identified by Helen Lord (OUH NHS) highlights at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene (PMID: 34633442). All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID. |
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Early onset or syndromic epilepsy v2.470 | GABRD | Arina Puzriakova Gene: gabrd has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v2.469 | GABRD | Arina Puzriakova Mode of pathogenicity for gene: GABRD 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v2.468 | GABRD | Arina Puzriakova Publications for gene: GABRD were set to 29785705 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v2.467 | GABRD | Arina Puzriakova Phenotypes for gene: GABRD were changed from {Epilepsy, idiopathic generalized, 10} 613060; {Epilepsy, juvenile myoclonic, susceptibility to} 613060; {Epilepsy, generalized, with febrile seizures plus, type 5, susceptibility to} 613060 to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060; {Generalized epilepsy with febrile seizures plus, type 5, susceptibility to}, OMIM:613060 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v2.466 | GABRD | Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: GABRD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v2.452 | GABRD |
Helen Lord changed review comment from: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onse epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4. From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher. The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic. The T291I variant was detected in an aff mother and her aff twin boys. The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients. All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD. The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits. Functional analysis suggests: P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaeed propensity to desensitise - LOF trait. The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait. No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis. The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~). The patient with the LOF variant has ASD, normal intelligence and no seizure history. In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder. One GOF variant was identifed (de novo) in a patient with ASD but no seizures. Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.; to: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onset epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4. From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher. The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic. The T291I variant was detected in an aff mother and her aff twin boys. The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients. All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD. The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits. Functional analysis suggests: P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaesed propensity to desensitise - LOF trait. The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait. No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis. The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~). The patient with the LOF variant has ASD, normal intelligence and no seizure history. In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder. One GOF variant was identifed (de novo) in a patient with ASD but no seizures. Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not. |
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Early onset or syndromic epilepsy v2.452 | GABRD | Helen Lord reviewed gene: GABRD: Rating: GREEN; Mode of pathogenicity: None; Publications: 34633442; Phenotypes: Neurodevelopmental disorders, generalised epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.191 | GABRD | Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.190 | GABRD | Rebecca Foulger Source NHS GMS was added to GABRD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.189 | GABRD | Rebecca Foulger reviewed gene: GABRD: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.188 | GABRD | Tracy Lester reviewed gene: GABRD: Rating: RED; Mode of pathogenicity: ; Publications: 15115768; Phenotypes: {Epilepsy, generalized, with febrile seizures plus, type 5, susceptibility to}, 613060 , {Epilepsy, idiopathic generalized, 10}, 613060 , {Epilepsy, juvenile myoclonic, susceptibility to}, 613060 ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.13 | GABRD | Deb Pal reviewed gene: GABRD: Rating: RED; Mode of pathogenicity: None; Publications: 15115768; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.485 | GABRD | Sarah Leigh Marked gene: GABRD as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.485 | GABRD | Sarah Leigh Gene: gabrd has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy | GABRD | Sarah Leigh classified GABRD as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy | GABRD | Sarah Leigh Added gene to panel |