WHOLE EXOME SEQUENCING OF HEMIPLEGIC MIGRAINE PATIENTS SHOWS AN INCREASED BURDEN OF MISSENSE VARIANTS IN CACNA1H AND CACNA1I GENES 193 9 Introduction Hemiplegic migraine (HM) is a rare subtype of migraine with aura with attacks that are associated with motor weakness or hemiplegia during the aura phase.1 HM is clinically and genetically heterogeneous2-4 and can be subdivided in familial hemiplegic migraine (FHM) and sporadic hemiplegic migraine (SHM), distinguished by having a positive or negative family history for HM, respectively.1 A subset of HM patients exhibits an autosomal dominant phenotype with single high-penetrant causal mutations present in ion transport genes CACNA1A, ATP1A2 or SCN1A.5-7 However, in many HM patients no such pathogenic mutation has been detected.8, 9 Whereas evidence is accumulating that loss-of-function mutations in PRRT2,10 a key component of the Ca2+-dependent neurotransmitter release machinery, 11 are involved in HM, the gene more likely acts as a modifier of disease.12 This suggests that HM, in a set of patients, may be regarded a complex disorder with multiple genetic factors contributing to the phenotype. Most relevant, a Finnish polygenic risk score study of genome-wide association study (GWAS) data has shown that HM patients without a highpenetrant disease-causing mutation in a known HM gene carry an excess of common (frequency > 1%) variants compared to patients suffering from common (complex) migraine subtypes.13 Following along this line of evidence, it has been hypothesized that complex disorders can be the result of an accumulation of genetic variants in a disease pathway, where the crossing of a certain threshold leads to disease.14 Moreover, current evidence indicates that complex traits are likely to be underpinned by a combination of multiple common and rare variants.15-17 Here we set out to investigate the contribution of modulatory genetic effects that can be studied through testing the synergistic burden of (functional) variants, best annotated as missense variants, rather than a single causative mutation. Burden can be regarded as an accumulation of variants that are more often present in cases compared to controls. We hypothesise here that the burden of missense variants in certain ion channel genes might be involved in the disease pathology of HM. CACNA1A was the first HM gene discovered and encodes the pore‐forming α1A subunit of the neuronal voltage‐gated calcium channel (VGCC) CaV2.1 (P/Q‐type). 5, 18 Ca V2.1 channels are predominantly localized at presynaptic terminals and play a prominent role in controlling neurotransmitter release at most synapses of the nervous system.19-21 CACNA1A is a member of a family of rather conserved α1 subunit genes, hereafter referred to as “CACNA1x”, which are part of VGCCs that are classified as either high-voltage-activated (HVA) or low-voltage-activated (LVA) channels that are present on the membranes of excitable cells (Figure 1).22, 23 Ca V channels are typically composed of multiple subunits namely an α1, a β, an α2/δ, and a γ subunit. An α1 subunit has 24 transmembrane segments and forms the pore through which calcium ions pass into the cell. The main characteristic of the various CaV channel types is primarily determined by the type of α1 subunit, so the presence of either α1A, α1B, α1C, α1D, α1E, α1F, α1G, α1H, α1I or α1S. Given the
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