Whole exome sequencing of hemiplegic migraine patients shows an increased burden of missense variants in CACNA1H and CACNA1I genes

Abstract text (incl. figure legends and references)

Background: Hemiplegic migraine (HM) is a migraine subtype with aura characterized by attacks associated with motor weakness. Given that causal mutations in the voltage-gated calcium channel a1A subunit gene CACNA1A have been found in a subset of HM patients, we investigated whether there is an increased burden in HM of missense variants in other CACNA1x genes.

Methods: Whole exome sequencing data of a clinically-referred Australian cohort of unrelated HM patients (n = 187), along with public data from Genome Aggregation Database (gnomAD v2.1.1) as controls, was used for a comprehensive analysis of missense variants in CACNA1x genes that included burden testing with the TRAPD package. Replication was performed in a Dutch clinical HM cohort (n = 32).

Results: Individual variant analysis of the Australian cohort revealed variants in multiple CACNA1x genes. Using TRAPD, we found a significant burden of missense variants in CACNA1H (p = 8.84 x 10-79) and CACNA1I (p = 3.00 x 10-169) in the Australian cohort that replicated in Dutch patients (CACNA1H, p = 0.012 and CACNA1I, p = 0.044), although CACNA1I did not remain significant after correction for multiple testing. The burden effect was slightly higher for CACNA1I (OR = 1.43, 95% CI:1.28 - 1.58) than for CACNA1H (OR = 1.83, 95% CI:1.54 - 2.12).

Conclusion: Our data suggest that HM, in the absence of a single causal mutation in CACNA1A, ATP1A2, or SCN1A, is a complex trait, in which, at least to certain extent, increased burden of missense variants in CACNA1H and CACNA1I increases the risk of disease.