Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction.

OBJECTIVE: To utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting.

METHODS: A retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed. "Qualifying" variants were defined as coding, rare, and conserved. Additionally, "Key Qualifying" variants were Pathogenic/Likely Pathogenic, or "Clinical" based upon the presence of a corresponding diagnosis. Candidate association to CVS was based on a point system.

RESULTS: Thirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as "Highly likely" ( SCN4A , CACNA1A , CACNA1S , RYR2 , TRAP1 , MEFV ) or "Likely" ( SCN9A , TNFRSF1A , POLG , SCN10A , POGZ, TRPA1 ) CVS related. Nine additional genes ( OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3 , PPM1D , CHAMP1 , HMBS ) had sufficient evidence in the literature but not from our study participants. Candidate status for mitochondrial DNA was confirmed by the literature and our study data. Among the above-listed 22 CVS candidate genes, a Key Qualifying variant was identified in 31/80 (34%), and any Qualifying variant was present in 61/80 (76%) of participants. These findings were highly statistically significant ( p  < 0.0001, p  = 0.004, respectively) compared to an alternative hypothesis/control group regarding brain neurotransmitter receptor genes. Additional, post-analyses, less-intensive review of all genes (exome) outside our paroxysmal genes identified 13 additional genes as "Possibly" CVS related.

CONCLUSION: All 22 CVS candidate genes are associated with either cation transport or energy metabolism (14 directly, 8 indirectly). Our findings suggest a cellular model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle of cellular hyperexcitability. Among the non-paroxysmal genes identified, 5 are known causes of peripheral neuropathy. Our model is consistent with multiple current hypotheses of CVS.