Objective:

To utilize whole exome or genome sequencing (WES/WGS) and the literature to improve understanding of cyclic vomiting syndrome (CVS).

Background:

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.

Design/Methods:

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.

Results:

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 (< 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.

Conclusions:

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 hyperexcitability. 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.