Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome

作     者：Faridi, Rabia Tona, Risa Brofferio, Alessandra Hoa, Michael Olszewski, Rafal Schrauwen, Isabelle Assir, Muhammad Z. K. Bandesha, Akhtar A. Khan, Asma A. Rehman, Atteeq U. Brewer, Carmen Ahmed, Wasim Leal, Suzanne M. Riazuddin, Sheikh Boyden, Steven E. Friedman, Thomas B. 

作者机构：Natl Inst Deafness & Other Commun Disorders Lab Mol Genet NIH Bethesda MD USA Univ Punjab Natl Ctr Excellence Mol Biol Lahore Pakistan NHLBI Cardiol Branch NIH Clin Ctr Bldg 10 Bethesda MD 20892 USA Natl Inst Deafness & Other Commun Disorders Auditory Dev & Restorat Program NIH Bethesda MD USA Baylor Coll Med Dept Mol & Human Genet Ctr Stat Genet Houston TX 77030 USA Jinnah Hosp Complex Allama Iqbal Med Res Ctr Lahore Pakistan Pakistan Inst Med Sci Cardiol Dept Islamabad Pakistan Natl Inst Deafness & Other Commun Disorders NIDCD Audiol Unit NIH Bethesda MD USA Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Natl Inst Deafness & Other Commun Disorders Sect Genet Commun Disorders NIH Bethesda MD USA New York Genome Ctr Clin Lab New York NY USA Univ Utah Dept Human Genet USTAR Ctr Genet Discovery Salt Lake City UT USA 

出 版 物：《HUMAN MUTATION》 (人类突变)

年 卷 期：2019年第40卷第2期

页      面：162-176页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：National Institute on Deafness and Other Communication Disorders [R01 DC011651, R01 DC003594] NIH Intramural Research Program [DC000048, Z1A-000046, DC000088] Higher Education Commission of Pakistan 

主　　题：deafness Jervell and Lange-Nielson syndrome KCNE1 KCNQ1 prolonged-QT Romano-Ward syndrome 

摘      要：KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50GA (***17*), c.51GA (***17*), and c.138CA (***46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants.