Early onset or syndromic epilepsy
Gene: CACNA1D
Only 1 case reported with a hom variant who had epilepsy and deafness but wouldn't want to miss possible cases.Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
de novo gain-of-function mutations. AD primary aldosteronism, seizures and neurological abnormalities and AR sinoatrial node dysfunction and deafness (no seizures associated with this). AD condition: Scholl et al, 2013 sequenced this gene in 100 unrelated individuals with unexplained early onset primary aldosteronism - 2 girls with de novo heterozygous GOF missense variants. Both patients had seizures. A few other cases reported on HGMD Pro.Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Primary aldosteronism, seizures, and neurologic abnormalities,615474; Sinoatrial node dysfunction and deafness,614896
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments
Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex review from Helen Lord.Created: 7 Sep 2019, 10:42 a.m. | Last Modified: 7 Sep 2019, 10:42 a.m.
Panel Version: 1.274
Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
Comment on mode of inheritance: Primary aldosteronism, seizures, and neurologic abnormalities (MIM: 615474) has AD inheritance. Seizures are not generally reported for the biallelic disorder Sinoatrial node dysfunction and deafness (MIM:614896). However, PMID:30054272 report an Arabic individual from consanguineous parents with moderate hearing impairment, ID, DD and epilepsy and a homozygous missense variant in CACNA1D (Gln567His). Seizures began age 4 months. The individual also had a homozygous OTOG variant, but this was present in a heterozygous state in the gnomAD browser. Both parents were heterozygous for the OTOG and CACNA1D variants.Created: 15 Jul 2019, 12:32 p.m. | Last Modified: 15 Jul 2019, 12:32 p.m.
Panel Version: 1.157
Gain of function variants associated with Primary aldosteronism, seizures, and neurologic abnormalities 615474 in OMIM and as a probable G2P gene. At least 3 de novo variants reported in 3 unrelated cases. Global developmental delay and intellectual disability is associated with this phenotype.Created: 19 Dec 2017, 1:45 p.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Primary aldosteronism, seizures, and neurologic abnormalities 615474 AD; Sinoatrial node dysfunction and deafness 614896 AR
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Gene: cacna1d has been classified as Green List (High Evidence).
Mode of inheritance for gene: CACNA1D was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Source Wessex and West Midlands GLH was added to CACNA1D.
Source NHS GMS was added to CACNA1D.
Mode of pathogenicity for gene: CACNA1D was changed from None to Other
Publications for gene: CACNA1D were set to 28472301; 23913001; 30698561
Mode of inheritance for gene: CACNA1D was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CACNA1D were set to 28472301; 23913001
Sarah Leigh: Gain of function variants asso
CACNA1D was added to Genetic Epilepsy Syndromes panel. Sources: Expert Review Green,Literature
CACNA1D was created by Sarah Leigh