WHOLE EXOME SEQUENCING OF HEMIPLEGIC MIGRAINE PATIENTS SHOWS AN INCREASED BURDEN OF MISSENSE VARIANTS IN CACNA1H AND CACNA1I GENES 199 9 Results Single-variant analysis No clear pathogenic mutations in CACNA1x genes were identified from the WES data in patients from either the Australian or the Dutch cohorts. However, the number of variants in CACNA1x genes prompted us to perform burden testing. In the Australian cohort we identified 79 different missense variants in the eight CACNA1x genes examined in the 184 HM patient group from Australia (Supplementary Table 1). All but seven of the variants had been previously identified (i.e. they have an rs number in dbSNP). The seven novel variants were all single-case across multiple different CACNA1x genes. In the Dutch cohort four different variants were identified in CACNA1I and ten in CACNA1H, all of which had been previously identified (Supplementary Table 2). Although some missense variants in CACNA1x genes were predicted to have a pathogenic potential there was not enough evidence for causality in a monogenic manner such as has been shown for the three well known HM genes. The results of the individual variant analyses indicate the existence of many variants across CACNA1x genes that in combination could plausibly confer increased susceptibility to HM, especially when considered collectively using burden analysis. Figure 2 Schematic representation of the α1 subunit Schematic representation of the α1 subunit, with the position of identified variants in this study, of the CaV3.2 and the CaV3.3 channel, encoded by the CACNA1H (A) and CACNA1I (B), respectively. Variants identified in the Australian HM cohort are depicted with a green dot and variants identified in the Dutch HM cohort are depicted with a red dot.
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