9 CHAPTER 9 202 gating properties of CaV3.3 channels, disrupt neuronal excitability and network activity, and have been associated with risk of developing schizophrenia and a range of neurodevelopmental disorders featuring developmental delay and epilepsy.56, 57 Moreover, using patch-clamp electrophysiology, we have shown various functional alterations of channel activity for selected Cav3.3 rare variants, providing further evidence that CACNA1I may play a role in the development of HM.58 Hence, the most likely scenario is that an increased burden of missense variants in CACNA1H and CACNA1I acts as a genetic modifier of disease risk. Such a modification of risk is not different when reviewing mutations that have been identified in some HM patients in a number of genes, including PRRT2,12 PNKD,59 SLC4A4,60 SLC1A3,61 and SLC2A1,62 that are primarily associated with movement or solute transport disorders. Our study has some limitations. First of all, contrary to what is commonly undertaken in genetics, we considered both rare and common variants as an overarching burden of missense variants in this study. To support the validity of this approach we used the Dutch replication cohort to validate findings from the Australian cohort. Further replication efforts in other independent cohorts would be of benefit in future studies of these genes. Secondly, as this study is the first of its kind, we narrowed the genes targeted to CACNA1x ion channels, due to known association of genes of this family with HM. However, the burden of variants in additional genes is likely to play a role in determining HM disease risk. Thirdly, we have used summary statistics for the controls that prevented us to compare ancestry of cases and controls together, although we ensured that both cases and controls were of European ancestry. Finally, the use of the gnomAD population as a control cohort means that we are not comparing truly matched populations. Both in our case cohorts and the gnomAD cohort there are slightly more female than male participants, that is the female: male ratio for the cases is ~1.97:1 and for the controls it is ~1.27:1, which may result in a slight confounding effect, as does differences in environmental and cultural differences that could not be controlled in our study. Conclusion This study provides evidence that increased burden of missense variants in the amount of variants and the number of subjects carrying a variant in CACNA1H and CACNA1I exists for HM, and that these genes can modify HM disease risk, supporting more complex types of heritability for HM, in addition to the strictly monogenic forms.
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