Whole Exome/Genome Sequencing in Cyclic Vomiting Syndrome, a Migraine Variant, Reveals Multiple Candidate Genes, Especially in Cation Channels, Suggesting a Mechanism of Cellular Overexcitation (S41.007)

Abstract

<h3>Objective:</h3> To utilize whole exome or genome sequencing (WES/WGS) and the literature to improve understanding of cyclic vomiting syndrome (CVS). <h3>Background:</h3> CVS is a frequently disabling condition defined by severe, discrete, stereotypical episodes of nausea and vomiting, with the essential absence of these manifestations between episodes. Considered a migraine variant, its etiology remains unclear. Two fundamental aspects of CVS are its highly paroxysmal nature, and the presence of episodic discomfort and disability. <h3>Design/Methods:</h3> A retrospective chart review of 80 unrelated participants was conducted. To develop a candidate gene list for detailed molecular investigation, the literature was queried for genes associated with dominant cases of paroxysmal vomiting or both discomfort and disability. <h3>Results:</h3> 35 candidate genes were identified. Based on variants identified in our participants, 9 candidate genes were determined “highly likely” to be CVS related (SCN4A, CACNA1A, CACNA1S, SCN9A, RYR2, POGZ, MEFV, TRAP1, POLG), while 5 others were “likely” related (SCN10A, OPRM1, TNFRSF1A, TRPA1, GFAP). A rare (&lt; 2% prevalence) and highly evolutionarily-conserved (“qualifying”) variant among those 14 genes was identified in 65 participants, with a qualifying mtDNA variant identified in 14 participants. Altogether, a qualifying variant was present in 70/80 (88%) of participants. <h3>Conclusions:</h3> Our data reveals 14 genes as likely related to CVS; 7 of which encode cation channels. Our literature search revealed paroxysmal nausea/vomiting cases in 8 other genes (ATP1A3, ATP1A2, SLC2A1, TUBB3, PPM1D, CHAMP1, CNR1, HMBS) despite a lack of evidence from our study; 2 of which encode cation pumps. Cation channel pathology is generally attributed to a gain-of-function with resultant cellular hyper excitability. Our findings suggest a model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle. While cellular hyperactivity likely refers to neurons, including central or peripheral/autonomic, it may also refer to muscle, including smooth or skeletal. <b>Disclosure:</b> Mr. Bar has nothing to disclose. Miss Ebenau has nothing to disclose. Miss Weiner has nothing to disclose. The institution of Dr. Mintz has received research support from Curemark. The institution of Dr. Mintz has received research support from Otsuka. Dr. Boles has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for NeuroNeeds . Dr. Boles has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Mitochondrial and Molecular Medicine. Dr. Boles has stock in NeuroNeeds.