Table 5.

Non-paroxysmal gene list key qualifying variants in our participants.

	Ion transport: KCNK18 {3 points} (p.Tyr121fs: #27; migraine with aura)
	Energy metabolism: GLS2b {3 points} (in trans p.Arg149Gln & p.Arg107Trp: #40, mitochondrial dysfunction on biochemical testing); COQ2c (p.Arg22*: #1);
On target: Likely to be related to patient’s CVS	Peripheral neuropathy: INF2 {5 pointsa, including from row below} (p.Leu480Gln: #4, CC: myalgia, pruritus, GERD, constipation, urinary incontinence); Multiple genes including PMP22 {3 points} (chr17p12p12×1 [14,186,500-15,584,000], 1.4 Mb, inheritance unknown: #75); SH3TC2 {3 points} (homozygous deletiond: #9, CC: CMT neuropathy and IBS); GLA {3 points} (p.Ala143Thr: #8, CC: peripheral/enteric neuropathy with an emphasis on pain); KIF1B {7 points} (p.Val1600Met: #22, CC: longstanding ankle braces for pain; p.Thr827Ile: #38; p.Ser1327Arg & p.Gly545Arg: #43; p.Val1600Met: #79)
On target: Unclear relationship to patient’s CVS	COQ2b (p.Met128Lys: #10); INF2 (p.Leu480Gln: #4; p.Arg478His: #27);
On or off target	MEF2De (p.Arg177Trp, de novo: #56); ADAMTS2 (homozygous 41-bp deletion: #9)
Off target: Patient has condition, previously known to have variant	CFTR (p.Phe508del, homozygous: #49, CC: cystic fibrosis); PORCN (p.Arg232*: #6, CC: focal dermal hypoplasia)
Off target: Patient has condition, previously not known to have variant	TNFRS13B (p.Ala181Glu: #35, CC: common variable immunodeficiency); CSNK2B (p.Arg47*: #39, CC: neurodevelopmental disease), ASMT (chrXp22.33p22.33×1 [1,529,000-1,644,000], 115-kb pseudo autosomal region deletion: #31); Multiple genes including IgG2 (chr14q32.33q32.33×1 [105,613,590-105,729,866], 115 kb that crosses 10 genes: #20, CC: frequent infections, resolved on IVIg); Multiple genes (15q11.2×1 [22,815,306-23,217,514], 42 kb: #6, CC: intellectual disability, but also can be explained by other variants)
Off target: P/LP variants conferring risk for conditions not seen in patient or family	CTNNA3 (chr10q21.3q21.3×1 [66,195,323-66,324,900], 130 kb: #41; risk for cardiac arrhythmia); Multiple genes (15q11.2q11.2×1, 520 kb, maternally inherited: #26, risk for neurodevelopmental disease)

Definition of variants (e.g., font color) as per Table 4 and Methods. CC: clinical correlation.

^aPoints are added including additional variants shown in subsequent rows.

^bThis was the only gene identified in our analysis for metabolic disorders. The variants are considered as Key by virtue of having two in trans Qualifying variants in the same gene.

^cThe literature reports this gene as autosomal recessive, and thus the variants in this gene likely represent carrier status at most. However, COQ4 has a dominant form, thus the inclusion of these variants in this table.

^dThis homozygous 144-base-pair deletion in the SH3TC2 gene removes almost the entire intron, right up to the intron-exon border on the 3′ end. This should affect splicing, and thus is a good candidate for disease association via loss-of-function.

^eA second de novo variant of uncertain significance was identified in the same patient with PPM1D-related disease: MEF2D c.529C > T, p.Arg177Trp. This gene encodes a transcription factor affecting dendritic spine density in a rat model (32), thus this may be incidental to her CVS.