Data_Sheet_1_Linkage Evidence for a Two-Locus Inheritance of LQT-Associated Seizures in a Multigenerational LQT Family With a Novel KCNQ1 Loss-of-Function Mutation.docx

Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Clinical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ1dup12; p.R360_Q361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LQT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ1dup12 mutation for the LQT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LQTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LQT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures.

数种编码离子通道的基因突变可导致长QT（LQT）综合症，伴随心脏节律失常、晕厥及猝死。近期，这些基因中的一些突变亦被识别为可引发患者癫痫发作，以及癫痫的突发不明原因死亡（SUDEP），被视为两种临床状况的病理学重叠。对于与LQT相关的KCNQ1基因突变，仅有少数研究报道了心脏功能障碍与癫痫发作的并发情况。对一大谱系（n=241家族成员）进行临床、电生理及遗传特征描述，该谱系因KCNQ1基因第8外显子12碱基对重复而导致LQT综合症，该重复在KCNQ1羧基末端结构域中重复了四个氨基酸（KCNQ1dup12；p.R360_Q361dupQKQR，NM_000218.2，hg19）。电生理记录显示无显著的KCNQ1样电流。该突变未表现出对野生型KCNQ1通道功能的显性负效应。最有可能的是，突变蛋白未功能性表达，因此未整合入异源四聚体通道。许多LQT家族成员遭受晕厥或发展为猝死，通常在体力活动后。在26名LQT家族成员中，14名（LQTplus癫痫特征）存在癫痫发作。分子遗传学分析证实了新型KCNQ1dup12突变在LQT特征中的致病作用，并揭示了与LQTplus癫痫特征的强烈联系。全基因组参数多点多点连锁分析在染色体区域10p14中确定了第二个强遗传修饰位点，与LQTplus癫痫特征的关联。连锁分析结果提示，LQTplus癫痫特征的遗传模式为双位点遗传，其中KCNQ1dup12突变和10p14风险单倍型均为LQT相关癫痫发作发生的必要条件。数据强烈支持新兴观点，即KCNQ1突变可能增加癫痫的风险，但临床癫痫发作的临床表现还需要额外的遗传修饰因子。