Early onset or syndromic epilepsy

Gene: CPA6

Red List (low evidence)

The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 11:59 a.m. | Last Modified: 11 Oct 2023, 11:59 a.m.

Panel Version: 4.110

Red List (low evidence)

The pathology of this gene is predicated on two publications: Salzmann et al. (2012) PubMed: 21922598 and Sapio et al. (2012) PubMed: 23105115. Both of these publications were issued prior to large population-based allele assessments and the evidence for pathogenicity is reliant on circumstantial evidence. None of the variants that form the foundation of this disease link would have sufficient evidence in support pathogenicity using current classification criteria. This gene should be recategorized as having a Red rating.

Evidence against pathogenicity for the reported variants:
Salzmann et al. (2012) proposed haploinsufficiency rather than gain of function; however, there is no obvious constraint score across the length of the gene. Previously reported pathogenic variants are, in some cases (see below), present in gnomAD at allele frequencies contrary to the incidence of the associated condition.

CPA6 p.(Ala270Val) rs114402678 has been reported has a homozygous variant in gnomADv3.1.2 in the non-neuro sub category (only samples that were not collected as part of a neurologic or psychiatric case/control study, or samples collected as part of a neurologic or psychiatric case/control study but designated as controls). The allele frequency and the observed number of homozygotes is not significantly different from the number of expected homozygote alleles based on the Hardy-Weinberg equilibrium.

CPA6(NM_020361.5):c.799G>A p.(Gly267Arg) rs61738009 was reported as a heterozygous pathogenic variant; however, this variant has been reported in >860 heterozygous individuals in gnomADv2.1.1 and v3.1.2.

Created: 3 Jul 2023, 11:12 a.m. | Last Modified: 3 Jul 2023, 11:12 a.m.

Panel Version: 4.62

Mode of inheritance
Other

Publications

• PMID:21922598
• 23105115

Mode of pathogenicity
Other

In response to the red review from Ian Berry, I have removed the to_be_confirmed_NHSE tag and added tags proposing that this gene be demoted to red, so that it will be included in the next proposed changes report.

Created: 29 May 2023, 9:46 p.m. | Last Modified: 29 May 2023, 9:46 p.m.

Panel Version: 4.39

Red List (low evidence)

This gene should be retracted from the green list for all panels.
It is regarded as "disputed" and "refuted" evidence respectively by ClinGen curation.
The evidence supporting the association is largely based on observation of three variants which are common in the general population in studies by Salzmann et al 2012 & Sapio et al 2012.

https://www.deciphergenomics.org/sequence-variant/8-67483797-G-A/annotation/maf/both - this variant p.Ala270Val was seen in homozygosity in a small family but is also common in gnomAD with 2x homozygotes. It has not been replicated and is now considered benign/LB.

p.Gly267Arg and p.Gln207Glu were both observed in a single case by Sapio et al 2012, but these co-segregate extensively in gnomAD (approx. 1 in 160 European individuals has these variants, likely on the same haplotype) and no parental testing was done to determine phase. Both variants are likely to be benign.

There are no large cohort studies, functional evidence or other collaborating studies other than single observations since these two papers. The gene is not a particularly compelling candidate for epilepsy mechanistically and the animal model isn't convincing. This should not be green in my opinion and should be removed from this panel.

Created: 16 May 2023, 2:52 p.m. | Last Modified: 16 May 2023, 2:52 p.m.

Panel Version: 4.37

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

I don't know

The evidence in the literature for the associaton of this gene with autosomal domiant disease doesn't seem very convinicing

Created: 28 Jan 2021, 2:17 p.m. | Last Modified: 28 Jan 2021, 2:17 p.m.

Panel Version: 2.277

I don't know

Note heterozygous variants originally reported are present at high frequency in gnomad, especially African American cohorts (>250 hets, 0.3-0.9% MAF in this subpopulation) Sapio (2012), Salazza (2012), out of keeping with a Mendelian disorder.

Two reports of bi-allelic variants, some functional data.

Created: 4 Jan 2021, 1:17 a.m. | Last Modified: 4 Jan 2021, 1:17 a.m.

Panel Version: 2.250

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epilepsy, familial temporal lobe, 5 MIM#614417; Febrile seizures, familial, 11 MIM#614418

Publications

• 25875328
• 21922598
• 23105115

Green List (high evidence)

AR febrile seizures 11 (FEB11) and AD and AR familial temporal lobe epilepsy 5 (ELT5). In FEB11 - Salzmann et al, 2012 - 4 sibs born of consang Mroccan parents with highly variable manifestations of a seizure disorder. All 4 had febrile seizures and 1 laer developed temporal lobe epilepsy. Hom mutation in CPA6 - A270V. in vitro functional studies support LOF variant. ELT5 - Salzmann et al, 2012 - 3 unrelated caucasian patients with temporal lobe epilepsy - het mutation in CPA6 - G267R, In vitro functional studies support LOF variant. In one of these patients Sapio et al 2012 went on to idfentify a second het missense variant - Q207E, again expression studies support LOF. Sapio et al, 2012 - man with ETL5- seizures reported at aged 5 - het missense variant H196R no parental DNA. Functional studies were undertaken.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Epilepsy, familial temporal lobe, 5,614417; Febrile seizures, familial, 11,614418

Publications

• 23105115
• 21922598

Green List (high evidence)

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.

Created: 15 Mar 2022, 3:43 p.m. | Last Modified: 15 Mar 2022, 3:43 p.m.

Panel Version: 2.498

After consultation Helen Lord, recommend change of MOI to BIALLELIC, autosomal or pseudosomal

Created: 28 Jan 2021, 3:16 p.m. | Last Modified: 28 Jan 2021, 3:16 p.m.

Panel Version: 2.277

Associated with phenotypes in OMIM and not in Gen2Phen. At least 4 variants identified: p.A270V as a homozygote in four siblings with Febrile seizures, familial, 11 (MIM 614418)(PMID:21922598), variant p.G267R was reported as a heterozygote in 3 unrelated cases of Epilepsy, familial temporal lobe, 5 (MIM 614417), of which one individual also carried a second CPA6 variant p.Q207E (PMID 23105115) and p.H196R was reported in a further case of Epilepsy, familial temporal lobe, 5 (MIM 614417). Supporting functional studies were also provided for variants p.A270V, p.G267R and p.H196R (PMID 23105115).

Created: 9 Apr 2018, 10:48 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

I don't know

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

In 4 sibs, born of consanguineous Moroccan parents, with febrile seizures-11 (MIM:614418), Salzmann et al. (2012, PMID:21922598) identified a homozygous 809C-T transition in exon 8 of the CPA6 gene resulting in a A270V substitution.
In 1 of the patients originally reported by Salzmann as having a heterozygous G267R mutation in CPA6, Sapio et al 2012 (PMID:23105115) identified a second heterozygous missense mutation (Q207E) in CPA6- this patient is associated with famililal temporal lobe epilepsy-5 (MIM:614417) in OMIM.

Created: 11 May 2017, 1:12 p.m.

Comment on list classification: Insufficient data

Created: 8 May 2016, 6:59 p.m.