Table 2.
Paroxysmal nuclear gene variants in our participants.
| Gene | Key variantsa | Other qualifying variants | Points by our studyb |
|---|---|---|---|
| ATP1A2 | (p.Glu492Lys: #1) | 1 | |
| ATP1A3 | 0 | ||
| CACNA1A | (p.Ala454Thr [x2]: #1, 11), (p.Arg68Gln: #76), (p.Arg2294Pro: #74), (p.Arg2298Pro [x2]: #43, 75), (CAG 7 [X9]: #5, 8, 27, 30, 52[HOM], 55, 67, 76, 80[HOM]), (CAG 4 [x2]: #31, 70), (p.Tyr2228Asn: #50), (p.Arg2135His: #46) | 19 | |
| CACNA1S | (p.Ser516Leu: #30, CC: ataxia, PP), (p.Thr1335Ser: #72, CC: episodes of profound fatigue, ptosis), (p.Thr1354Ser: #16, CC: PP, hand weakness asymmetrical during migraine/CVS, frequent twitches), (p.Val1253Ala: #23, CC: PP) | (p.Ala814Thr, p.Tyr299His: #69), (p.Cys288Gly: #32), (p.Pro1839Ser: #14), (p.Ser1857Asn: #43) | 17 |
| CDK8 | 0 | ||
| CHAMP1 | (p.Pro406Ser: #25) | 1 | |
| CLCN1 | (p.Thr736Ile: #68, CC: myalgia, muscle tightness, episodes of ptosis and muscle weakness) | 3 | |
| CNR1 | 0 | ||
| GFAP | (p.Asp157Asn: #48), (p.Pro47Leu[x2]: #35, 76) | 3 | |
| HMBS | 0 | ||
| KCNA1 | 0 | ||
| KCNJ2 | 0 | ||
| KCNJ18 | (p.Gln407*: #37, CC: PP) | 3 | |
| MEFV | (p.Ala744Ser: #53), (p.Ile591Thr: #65, CC: paroxysmal abdominal pain, eye pain as main prodrome of vomiting episodes), (p.Val726Ala, c.*381 T > C: #5, CC: paroxysmal severe neuropathic pain in four extremities, joint and muscle pain, migraine, abdominal pain during episodes, hives) | (p.Pro369Ser: #36, 66), (p.Arg408Gln: #66) | 12 |
| OPRM1 | (p.Cys192Phe [x3]: #2, 34, 73), (p.Ser147Cys: #53), (p.Ser451Phe: #11) | 5 | |
| OTC | 0 | ||
| PDHA1 | (p.Met320Leu: #28) | 1 | |
| PNKD | (p.Glu307Lys: #43) | 1 | |
| POGZ | (p.Cys652Arg, de novo: #18, CC: NDD), (p.Phe806Leu, de novo: #77, CC: ASD, microcephaly, ID) | (p.Lys871Asn: #27) | 7 |
| POLG | (p.Lys460_Leu463del: #74) | (p.Arg42_Gln43insGln: #38), (p.Gly268Ala [x2]: #9, 18), (p.Gly517Val [x3]: #38, 52, 58) | 9 |
| PPM1D | (p.Tyr401fs, de novo: #56, CC: dysmorphic features, NDD) | 3 | |
| PRRT2 | (p.Pro216Leu [x3]: #41, 42, 54) | 3 | |
| RYR2 | (p.Tyr3459*: #54), (p.Glu4431Lys: #44, CC: chronic pain, GI dysmotility, fatigue; severe abdominal pain and fatigue during episodes), (p.Gly2094Ser: #53, CC: panic disorder, idiopathic urticaria) | (p.Arg3567Cys: #9), (p.Arg4573His: #35), (p.Asn4736Asp: #34), (p.Gly1885Glu: #4), (p.Ser2829Gly: #75), (p.Thr1107Met: #15) | 15 |
| SCN1A | (p.Arg1928Gly: #80, CC: ice pick migraine with muscle weakness) | (p.Ile1437Val, p.Ile1452Val, p.Ile1465Val: #29)c | 4 |
| SCN2A | (p.Ile403Thr, p.Thr674Ala: #58) | 2 | |
| SCN4A | (p.Ala488Thr: #68, CC: myalgia, muscle tightness, episodes of ptosis and muscle weakness), (p.His599Arg [x2]: #61, 76, CC: PP), (p.Ser906Thr: #63, CC: PP, tremor, strabismus) | (p.Arg1408Cys: #45), (p.Lys477Arg: #49), (p.Thr323Met: #50), (p.Ser906Thr[x5]: #15, 25, 52, 73, 78) | 20 |
| SCN9A | (p.Asn1256Ser: #9, CC: myalgia, migraine with aura, abdominal pain, chronic daily headache), (p.Ser802Gly: #27, CC: severe migraine with aura) | (p.Val1726Phe: #7), (p.Val1715Phe: #9) | 8 |
| SCN10A | (p.Ala123Val: #64, CC: CRPS), (p.Arg14Leu: #47, CC: widespread pain), (p.Val1697Ile: #27, CC: severe migraine with aura) | 9 | |
| SCN11A | (p.Gly1736Val: #50) | 1 | |
| SLC1A3 | (p.Arg47Gln: #77) | 1 | |
| SLC2A1 | 0 | ||
| TNFRSF1A | (p.Arg121Gln [x3]: #14, 60, 68) | (p.Pro75Leu: #69) | 10 |
| TRAP1 | (p.Ile253Val: #18), (p.Arg128His: #60, CC: fatigue, pain, GI issues) | (p.Arg469Cys: #7), (p.Asp685Asn, p.Arg469His: #39), (p.Gln165Glu: #14), (p.Gly445Ser: #3), (p.Ser477_Gly478insAla [x2]: #3, 76), (p.Tyr444Asn: #51) | 14 |
| TRPA1 | (p.Ala138Ser: #49, CC: mild NDD, chronic pain syndrome, main symptom during episodes is severe diaphragmatic pain requiring hydromorphone), (p.Met214Thr: #52, CC: episodic pain syndrome) | (p.Asn109Lys: #2) | 7 |
| TUBB3 | 0 |
a
“Key Qualifying” variants include “P/LP” (Pathogenic or Likely Pathogenic, in red font) and “Clinical” (in purple font). “Qualifying” variants were defined as being rare and highly conserved, see Methods. Variants that were both P/LP and Clinical are colored in red.
b
Per our scoring algorithm in Methods, which gave higher weight (3 points) to Key Qualifying variants versus “Other Qualifying” variants (1 point). Literature points were awarded as one per family with reported paroxysmal nausea and vomiting (CVS). Composite refers to the highest color designation of the two previous columns.
c
Three closely-spaced variants with identical prevalence data and thus co-segregate.