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

Autor: Maksemous N; Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Ave, Brisbane, QLD, 4059, Australia., Harder AVE; Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands., Ibrahim O; Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Ave, Brisbane, QLD, 4059, Australia., Vijfhuizen LS; Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands., Sutherland H; Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Ave, Brisbane, QLD, 4059, Australia., Pelzer N; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands., de Boer I; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands., Terwindt GM; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands., Lea RA; Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Ave, Brisbane, QLD, 4059, Australia., van den Maagdenberg AMJM; Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands. A.M.J.M.van_den_Maagdenberg@lumc.nl.; Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands. A.M.J.M.van_den_Maagdenberg@lumc.nl., Griffiths LR; Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Ave, Brisbane, QLD, 4059, Australia. lyn.griffiths@qut.edu.au.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2023 Jun; Vol. 60 (6), pp. 3034-3043. Date of Electronic Publication: 2023 Feb 14.
DOI: 10.1007/s12035-023-03255-5
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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