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Papers of the Week

Papers: 11 Feb 2023 - 17 Feb 2023


Genetics, Human Studies


2023 Feb 14

Mol Neurobiol


Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes.


Maksemous N, Harder AVE, Ibrahim O, Vijfhuizen LS, Sutherland H, Pelzer N, de Boer I, Terwindt GM, Lea RA, van den Maagdenberg AMJM, Griffiths LR


Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the “CACNA1x gene family”. Whole exome sequencing data of an Australian cohort of unrelated HM patients (n = 184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in CACNA1x genes. We performed both a variant and a subject burden test. We found a significant burden for the number of variants in CACNA1E (p = 1.3 × 10), CACNA1H (p < 2.2 × 10) and CACNA1I (p < 2.2 × 10). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10), CACNA1H (p < 2.2 × 10) and CACNA1I (p < 2.2 × 10). Both the number of variants and number of subjects were replicated for CACNA1H (p = 3.5 × 10; p = 0.012) and CACNA1I (p = 0.019, p = 0.044), respectively, in a Dutch clinical HM cohort (n = 32), albeit that CACNA1I did not remain significant after multiple testing correction. Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in CACNA1H and CACNA1I may contribute to the risk of disease.