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Rabia Faridi - One of the best experts on this subject based on the ideXlab platform.
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mutational and phenotypic spectra of kcne1 deficiency in jervell and lange nielsen Syndrome and romano ward Syndrome
Human Mutation, 2018Co-Authors: Risa Tona, Rafal Olszewski, Akhtar A Bandesha, Isabelle Schrauwen, Muhammad Zaman Khan Assir, Rabia Faridi, Alessandra Brofferio, Asma A. Khan, Atteeq U. RehmanAbstract: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. Co-assembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This Mutation Update 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.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). 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.
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mutational and phenotypic spectra of kcne1 deficiency in jervell and lange nielsen Syndrome and romano ward Syndrome
Human Mutation, 2018Co-Authors: Risa Tona, Rafal Olszewski, Akhtar A Bandesha, Isabelle Schrauwen, Muhammad Zaman Khan Assir, Rabia Faridi, Alessandra Brofferio, Asma A. Khan, Atteeq U. RehmanAbstract: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. Co-assembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This Mutation Update 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.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). 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.
Atteeq U. Rehman - One of the best experts on this subject based on the ideXlab platform.
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mutational and phenotypic spectra of kcne1 deficiency in jervell and lange nielsen Syndrome and romano ward Syndrome
Human Mutation, 2018Co-Authors: Risa Tona, Rafal Olszewski, Akhtar A Bandesha, Isabelle Schrauwen, Muhammad Zaman Khan Assir, Rabia Faridi, Alessandra Brofferio, Asma A. Khan, Atteeq U. RehmanAbstract: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. Co-assembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This Mutation Update 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.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). 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.
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mutational and phenotypic spectra of kcne1 deficiency in jervell and lange nielsen Syndrome and romano ward Syndrome
Human Mutation, 2018Co-Authors: Risa Tona, Rafal Olszewski, Akhtar A Bandesha, Isabelle Schrauwen, Muhammad Zaman Khan Assir, Rabia Faridi, Alessandra Brofferio, Asma A. Khan, Atteeq U. RehmanAbstract: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. Co-assembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This Mutation Update 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.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). 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.
Amit Vora - One of the best experts on this subject based on the ideXlab platform.
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KCNQ1 mutations associated with Jervell and Lange–Nielsen Syndrome and autosomal recessive Romano–Ward Syndrome in India—expanding the spectrum of long QT Syndrome type 1
American journal of medical genetics. Part A, 2016Co-Authors: Bijal Vyas, Ratna Dua Puri, Narayanan Namboodiri, Mohan Nair, Deepak Sharma, Sireesha Movva, Renu Saxena, Shomu Bohora, Neeraj Aggarwal, Amit VoraAbstract:Long QT Syndrome type 1 (LQT1) is the most common type of all Long QT Syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen Syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward Syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 Syndrome. Forty patients with a clinical diagnosis of LQT1 Syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc.
Michael C. Sanguinetti - One of the best experts on this subject based on the ideXlab platform.
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Long QT Syndrome: ionic basis and arrhythmia mechanism in long QT Syndrome type 1.
Journal of cardiovascular electrophysiology, 2000Co-Authors: Michael C. SanguinettiAbstract:Long QT Syndrome type 1 (LQT1) causes torsades de pointes arrhythmia, ventricular fibrillation, and sudden death. It usually is inherited as an autosomal dominant trait (Romano-Ward Syndrome). The primary defect in LQT1 is a mutation in KVLQT1, a gene that encodes the pore-forming alpha-subunit of a K+ channel. KvLQT1 alpha-subunits coassemble with minK beta-subunits to form channels that conduct the slow delayed rectifier K+ current (I(Ks)) in the heart. Recessive mutations in KVLQT1 cause Jervell and Lange-Nielsen Syndrome, which is characterized by more severe arrhythmias and congenital neural deafness. Heterologous expression studies demonstrated that mutations in KVLQT1 reduce I(Ks) by causing loss of channel function, altered channel gating, and/or a dominant-negative effect. It remains to be proven that an understanding of the molecular basis of LQT1 will lead to more effective therapy.
Giorgio Casari - One of the best experts on this subject based on the ideXlab platform.
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A Recessive Variant of the Romano-Ward Long-QT Syndrome?
Circulation, 1998Co-Authors: Silvia G. Priori, Peter J. Schwartz, Carlo Napolitano, Laura Bianchi, Adrienne T. Dennis, Maurizio De Fusco, Arthur M. Brown, Giorgio CasariAbstract:Background—The congenital long-QT Syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged ventricular repolarization and life-threatening arrhythmias. Mutations of the KVLQT1 gene, a cardiac potassium channel, generate two allelic diseases: the Romano-Ward Syndrome, inherited as a dominant trait, and the Jervell and Lange-Nielsen Syndrome, inherited as an autosomal recessive trait. Methods and Results—A consanguineous family with the clinical phenotype of LQTS was screened for mutations in the KVLQT1 gene. Complementary RNAs for injection into Xenopus oocytes were prepared, and currents were recorded with the double microelectrode technique. A homozygous missense mutation, leading to an alanine-to-threonine substitution at the beginning of the pore domain of the KVLQT1 channel, was found in the proband, a 9-year-old boy with normal hearing, a prolonged QT interval, and syncopal episodes during physical exercise. The parents of the proband were heterozygous for the mutation and ha...
