Early onset or syndromic epilepsy

Gene: CACNA1D

Green List (high evidence)

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

Green List (high evidence)

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

• 23913001
• 28472301

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments

I don't know

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

Green List (high evidence)

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

• 28472301
• 23913001

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments