Background: Many hemiplegic migraine patients do not appear to have mutations in CACNA1A, ATP1A2, and SCN1A, the three main causal genes identified to date. PRRT2, in which mutations can cause paroxysmal movement disorders, has been proposed as a fourth hemiplegic migraine gene, and mutations in other genes, PNKD, SLC1A3, SLC2A1, SLC4A4, NOTCH3, KCNK18 and CSNK1D, have also been reported in hemiplegic and familial migraine. The objective of this study was to screen an Australian cohort of hemiplegic migraine patients, negative for mutations in CACNA1A, ATP1A2 and SCN1A, for pathogenic variants in the other known hemiplegic migraine genes.
Methods: Sanger sequencing was used to determine the presence of the recurrent PRRT2 c.649dupC (p.Arg217ProfsX8) frameshift mutation. Whole exome sequencing data for 104 of these individuals was analysed for potentially pathogenic variants in the remainder of PRRT2 coding exons, and other hemiplegic migraine genes.
Results: None of the patients had the previously reported PRRT2 c.649dupC mutation, however three functional PRRT2 variants were found: c.647C>T (p.Pro216Leu), c.650G>A (p.Arg217Gln) and c.1114C>T (p.Leu372Phe). Variants likely to contribute to or cause hemiplegic migraine were also identified in the SLC4A4 (c.1805A>G; p.Lys602Arg), SLC2A1 (c.929C>T; p.Thr310Ile) and CSNK1D c.775C>T (p.Arg259Cys) genes, in specific cases.
Conclusions: Variants that may contribute to or cause hemiplegic migraine were identified in PRRT2, SLC2A1, SLC4A4 and CSNK1D. Although rare, such genes should be considered in the diagnostic testing of HM patients. However, our study comprehensively shows that the majority of patients do not have exonic mutations in the known hemiplegic and familial migraine genes. Analysis of whole exome sequencing data suggests other genes that encode ion channels and neurotransmitter-related genes may be causal for hemiplegic migraine.