A MILD PHENOTYPE ASSOCIATED WITH KCNQ1 P.V205M MEDIATED LONG QT SYNDROME IN FIRST NATIONS CHILDREN OF NORTHERN BRITISH COLUMBIA: EFFECT OF ADDITIONAL VARIANTS AND CONSIDERATIONS FOR MANAGEMENT (CCC-170)

Background: Congenital Long QT Syndrome (LQTS) is common in a First Nations community in Northern British Columbia due to the founder variant KCNQ1 p.V205M. Although well characterized molecularly and clinically in adults, no data have been previously reported on children. Sex differences in cardiac events have been shown in adults, with women of childbearing years demonstrating the highest risk. Furthermore, the electrical phenotype in adult males is modified by a splice site variant in KCNQ1 (p.L353L). Another genetic variant, the CPT1A p.P479L metabolic variant, is common in Northern Indigenous populations, and is associated with hypoglycemia and infant death. Since hypoglycemia can affect the QT interval corrected for rate (QTc) and may confer risk for seizures (also associated with LQTS), we sought to determine the effect of the KCNQ1 p.V205M, p.L353L and the CPT1A p.P479L variants on the LQTS phenotype in children within our First Nations cohort.

METHODS AND RESULTS: As part of a longstanding community based study assessing those with LQTS and their relatives in a Northern BC First Nations, we assessed those entering the study from birth to age 18 years. We assessed the QTc and potential cardiac events (syncope/seizures) of 190 children from birth to 18 years, with and without the KCNQ1 (p.V205M and p.L353L) and CPT1A variants, alone and in combination. Linear and logistic regression, and student t tests were applied as indicated.

Of the 42 individuals identified with the p.V205M variant, 4 presented symptomatically, and 38 underwent family cascade testing with management was initiated for all. Of the three variants assessed, only the KCNQ1 p.V205M variant conferred a significant increase in peak QTc (23.8ms;p < 0.001) above baseline with females increased by 30.1ms (p < 0.001) and males by 18.9ms (p < 0.01). There was no evidence of interaction effects with other two variants studied. One cardiac arrest was documented with exposure to an overdose of a QT prolonging medication. Although the p.V205M variant was not significantly associated with syncope/seizures, the odds of having seizure/syncope were significantly increased for those homozygous for CPT1A p.P479L compared to non-carriers (OR=3.2 (95% CI 1.3-8.2); p=0.013).


Conclusion: While the KCNQ1 p.V205M variant prolongs the peak QTc, in pediatric participants, the electrical phenotype was considered mild. The common CPT1A variant, possibly conferring risk for hypoglycemia, is more strongly associated with loss of consciousness events which may mimic a long QT phenotype. These findings may have implications for standard management such as for the initiation of beta-blockers.