AUTHOR=Bar Omri , Ebenau Laurie , Weiner Kellee , Mintz Mark , Boles Richard G. 

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

JOURNAL=Frontiers in Neurology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1151835

DOI=10.3389/fneur.2023.1151835

ISSN=1664-2295

ABSTRACT=<sec><title>Objective</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>Thirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as “Highly likely” (<italic>SCN4A</italic>, <italic>CACNA1A</italic>, <italic>CACNA1S</italic>, <italic>RYR2</italic>, <italic>TRAP1</italic>, <italic>MEFV</italic>) or “Likely” (<italic>SCN9A</italic>, <italic>TNFRSF1A</italic>, <italic>POLG</italic>, <italic>SCN10A</italic>, <italic>POGZ, TRPA1</italic>) CVS related. Nine additional genes (<italic>OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3</italic>, <italic>PPM1D</italic>, <italic>CHAMP1</italic>, <italic>HMBS</italic>) 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 (<italic>p</italic> &lt; 0.0001, <italic>p</italic> = 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.</p></sec><sec><title>Conclusion</title><p>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.</p></sec>