Table1_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.docx

IntroductionCongenital 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 the pediatric population. The phenotype in adults has been shown to be modified by a splice site variant in KCNQ1 (p.L353L). The CPT1A p.P479L metabolic variant, also common in Northern Indigenous populations, is associated with hypoglycemia and infant death. Since hypoglycemia can affect the corrected QT interval (QTc) and may confer risk for seizures (also associated with LQTS), we sought to determine the effect of all three variants on the LQTS phenotype in children within our First Nations cohort.
MethodsAs part of a larger study assessing those with LQTS and their relatives in a Northern BC First Nation, we assessed those entering the study from birth to age 18 years. We compared the corrected peak QTc and potential cardiac events (syncope/seizures) of 186 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 appropriate.
ResultsOnly the KCNQ1 p.V205M variant conferred a significant increase in peak QTc 23.8 ms (p < 0.001) above baseline, with females increased by 30.1 ms (p < 0.001) and males by 18.9 ms (p < 0.01). There was no evidence of interaction effects with the other two variants studied. Although the p.V205M variant was not significantly associated with syncope/seizures, the odds of having a seizure/syncope were significantly increased for those homozygous for CPT1A p.P479L compared to homozygous wild type (Odds Ratio [OR]3.0 [95% confidence interval (CI) 1.2–7.7]; p = 0.019).
ConclusionWhile the KCNQ1 p.V205M variant prolongs the peak QTc, especially in females, the CPT1A p.P479L variant is more strongly associated with loss of consciousness events. These findings suggest that effect of the KCNQ1 p.V205M variant is mild in this cohort, which may have implications for standard management. Our findings also suggest the CPT1A p.P479L variant is a risk factor for seizures and possibly syncope, which may mimic a long QT phenotype.

引言
先天性长QT综合征（Congenital Long QT Syndrome, LQTS）在不列颠哥伦比亚省北部的第一民族社区中高发，其致病根源为奠基者突变KCNQ1 p.V205M。尽管成人患者的分子与临床特征已得到充分阐明，但此前尚无针对该群体儿童的相关研究数据。已有研究证实，成人患者的表型可被KCNQ1基因的剪接位点突变p.L353L所修饰。同样在北部原住民群体中高发的CPT1A p.P479L代谢突变，与低血糖症及婴儿死亡风险存在显著关联。由于低血糖可影响校正QT间期（corrected QT interval, QTc），且可能增加癫痫发作风险（该风险同样与LQTS相关），本研究旨在明确本第一民族队列中三类突变对儿童LQTS表型的影响。

方法
作为一项评估不列颠哥伦比亚省北部第一民族LQTS患者及其亲属的大型研究的子课题，我们纳入了自出生至18岁的所有入组受试者。我们对比了186名0~18岁儿童的校正峰值QT间期与潜在心脏不良事件（晕厥/癫痫发作）发生情况，这些儿童分别携带或不携带KCNQ1（p.V205M与p.L353L）及CPT1A突变，并单独或联合分析各类突变的效应。研究根据数据分析需求，分别采用线性回归、logistic回归及Student t检验进行统计分析。

结果
仅KCNQ1 p.V205M突变可使峰值QT间期较基线水平显著延长23.8ms（p<0.001），其中女性受试者的QT间期延长幅度达30.1ms（p<0.001），男性受试者为18.9ms（p<0.01）。未观察到本研究涉及的另外两类突变存在交互效应。尽管p.V205M突变与晕厥/癫痫发作无显著关联，但与纯合野生型受试者相比，携带CPT1A p.P479L纯合突变的受试者出现癫痫或晕厥的概率显著升高（比值比[OR]=3.0，95%置信区间[CI] 1.2~7.7；p=0.019）。

结论
尽管KCNQ1 p.V205M突变可延长峰值QT间期，尤其在女性群体中表现更为显著，但CPT1A p.P479L突变与意识丧失事件的关联更为紧密。本研究结果提示，KCNQ1 p.V205M突变在该队列中的致病效应较为温和，这一发现或对临床标准诊疗方案的制定具有参考价值。同时本研究还表明，CPT1A p.P479L突变是癫痫发作乃至晕厥的风险因素，其临床表现可能模仿长QT综合征的表型。