PDF(Pubmed)
Abstract：
UNASSIGNED: 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 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.
UNASSIGNED: As 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.
UNASSIGNED: Only 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).
UNASSIGNED: While 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.
UNASSIGNED: As 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.
UNASSIGNED: Only 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).
UNASSIGNED: While 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.
摘要：
■先天性长QT综合征（LQTS）在不列颠哥伦比亚省北部的原住民社区中很常见，原因是其创始人KCNQ1p.V205M。尽管在成人中具有良好的分子和临床特征，以前没有关于儿科人群的数据报道.成人的表型已被KCNQ1中的剪接位点变体修饰（p。L353L)。CPT1Ap.P479L代谢变体，在北方土著居民中也很常见，与低血糖和婴儿死亡有关。由于低血糖会影响校正的QT间期（QTc），并可能导致癫痫发作的风险（也与LQTS相关），我们试图在原住民队列中确定所有三种变异体对儿童LQTS表型的影响.
■作为一项大型研究的一部分，该研究评估了在北不列颠哥伦比亚省第一民族中患有LQTS及其亲属的人，我们评估了从出生到18岁进入研究的人群.我们比较了从出生到18岁的186名儿童的校正峰值QTc和潜在的心脏事件（晕厥/癫痫发作），有和没有KCNQ1（p。V205M和p.L353L)和CPT1A变体，单独和组合。适当时应用线性和逻辑回归和学生t检验。
■只有KCNQ1p.V205M变体使QTc峰值比基线显著增加23.8ms（p<0.001），女性增加30.1ms（p<0.001），男性增加18.9ms（p<0.01）。没有证据表明与所研究的其他两种变体具有相互作用作用。尽管p.V205M变异与晕厥/癫痫发作没有显著相关，与纯合野生型相比,CPT1Ap.P479L纯合型患者发生癫痫发作/晕厥的几率显著增加(几率[OR]3.0[95%置信区间(CI)1.2-7.7];p=0.019).
■虽然KCNQ1p.V205M变体延长了QTc的峰值，尤其是女性，CPT1Ap.P479L变异与意识丧失事件的相关性更强。这些发现表明，KCNQ1p.V205M变体的影响在该队列中是温和的，这可能会对标准管理产生影响。我们的发现还表明CPT1Ap.P479L变异体是癫痫发作和可能晕厥的危险因素。这可能模拟长QT表型。
■作为一项大型研究的一部分，该研究评估了在北不列颠哥伦比亚省第一民族中患有LQTS及其亲属的人，我们评估了从出生到18岁进入研究的人群.我们比较了从出生到18岁的186名儿童的校正峰值QTc和潜在的心脏事件（晕厥/癫痫发作），有和没有KCNQ1（p。V205M和p.L353L)和CPT1A变体，单独和组合。适当时应用线性和逻辑回归和学生t检验。
■只有KCNQ1p.V205M变体使QTc峰值比基线显著增加23.8ms（p<0.001），女性增加30.1ms（p<0.001），男性增加18.9ms（p<0.01）。没有证据表明与所研究的其他两种变体具有相互作用作用。尽管p.V205M变异与晕厥/癫痫发作没有显著相关，与纯合野生型相比,CPT1Ap.P479L纯合型患者发生癫痫发作/晕厥的几率显著增加(几率[OR]3.0[95%置信区间(CI)1.2-7.7];p=0.019).
■虽然KCNQ1p.V205M变体延长了QTc的峰值，尤其是女性，CPT1Ap.P479L变异与意识丧失事件的相关性更强。这些发现表明，KCNQ1p.V205M变体的影响在该队列中是温和的，这可能会对标准管理产生影响。我们的发现还表明CPT1Ap.P479L变异体是癫痫发作和可能晕厥的危险因素。这可能模拟长QT表型。
