CACNA1H variants are not a cause of monogenic epilepsy

Abstract

CACNA1H genetic variants were originally reported in a childhood absence epilepsy cohort. Subsequently, genetic testing for CACNA1H became available and is currently offered by commercial laboratories. However, the current status of CACNA1H as a monogenic cause of epilepsy is controversial, highlighted by ClinGen's recent reclassification of CACNA1H as disputed. We analyzed published CACNA1H variants and those reported in ClinVar and found none would be classified as pathogenic or likely pathogenic per the American College of Medical Genetics classification criteria. Moreover, Cacna1h did not modify survival in a Dravet Syndrome mouse model. We observed a mild increase in susceptibility to hyperthermia-induced seizures in mice with reduced Cacna1h expression. Overall, we conclude that there is limited evidence that CACNA1H is a monogenic cause of epilepsy in humans and that this gene should be removed from commercial genetic testing panels to reduce the burden of variants of uncertain significance for healthcare providers, families and patients with epilepsy.

Keywords: CACNA1H; epilepsy; genetics; ion channel; seizure.

Figure 1.. Analysis of published or Clinvar ‘pathogenic’ missense calcium channel variants and effect of reduced Cacna1h expression in a Scn1a mouse model of Dravet syndrome.

(A) Distribution of CADD scores in CACNA1H. The CACNA1H_path distribution (n=35) is from published missense variants or Clinvar pathogenic or likely pathogenic missense variants as listed in Table 1. The CACNA1H_gnomAD distribution (n=1938) includes all CACNA1H missense variants in gnomAD. Error bars represent standard deviation. p = 0.9758 (Mann-Whitney ranksum). (B) Distribution of CADD scores in CACNA1A. The CACNA1A_path distribution (n=46) includes all Clinvar pathogenic or likely pathogenic missense variants. The CACNA1A_gnomAD distribution (n=910) includes all CACNA1A missense variants in gnomAD. Error bars represent standard deviation. p < 2.2e-16 (Mann-Whitney ranksum). (C) Distribution of CADD scores in CACNA1E. The CACNA1E_path distribution (n=17) is from published missense variants (K. L. Helbig et al., 2018) or Clinvar pathogenic or likely pathogenic missense variants. The CACNA1E_gnomAD distribution (n=821) is from CACNA1E missense variants in gnomAD. Error bars represent standard deviation. p = 0.003252 (Mann-Whitney ranksum). (D) Distribution of published or Clinvar ‘pathogenic’ missense variants in CACNA1H (Protter; see URLs). (E) Distribution of gnomAD missense variants in CACNA1H (Protter; see URLs). (F) Reduced Cacna1h expression does not affect survival in a mouse model of Dravet syndrome. p = 0.978 (Mantel-Cox logrank). (G) Reduced Cacna1h expression increases hyperthermia-induced seizure susceptibility. GTCS = generalized tonic-clonic seizure. p = 0.0332 (Mantel-Cox logrank).