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

Maksemous, N.; Harder, A.V.E.; Ibrahim, O.; Vijfhuizen, L.S.; Sutherland, H.; Pelzer, N.; Boer, I. de; Terwindt, G.M.; Lea, R.A.; Maagdenberg, A.M.J.M. van den; Griffiths, L.R.

doi:doi:10.1007/s12035-023-03255-5

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 × 10⁻⁴), CACNA1H (p < 2.2 × 10⁻¹⁶) and CACNA1I (p < 2.2 × 10⁻¹⁶). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10⁻³Show more 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 × 10⁻⁴), CACNA1H (p < 2.2 × 10⁻¹⁶) and CACNA1I (p < 2.2 × 10⁻¹⁶). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10⁻³), CACNA1H (p < 2.2 × 10⁻¹⁶) and CACNA1I (p < 2.2 × 10⁻¹⁶). Both the number of variants and number of subjects were replicated for CACNA1H (p = 3.5 × 10⁻⁸; 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.
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Whole exome sequencing of hemiplegic migraine patients shows an increased burden of missense variants in CACNA1H and CACNA1I genes