scholarly journals Discovery of Digenic Mutation, KCNH2 c.1898A >C and JUP c.916dupA, in a Chinese Family with Long QT Syndrome via Whole-Exome Sequencing

2020 ◽  
Vol 4 (4) ◽  
pp. 257-267
Author(s):  
Yafei Zhai ◽  
Jinxin Miao ◽  
Ying Peng ◽  
Guangming Fang ◽  
Chuchu Wang ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Long Qt Syndrome ◽  
Cardiac Death ◽  
Chinese Family ◽  
Long Qt ◽  
Double Mutation ◽  
Whole Exome ◽  
Qt Syndrome

Long QT syndrome (LQTS), which is caused by an ion channel‐related gene mutation, is a malignant heart disease with a clinical course of a high incidence of ventricular fibrillation and sudden cardiac death in the young. Mutations in KCNH2 (which encodes potassium voltage-gated channel subfamily H member 2) are responsible for LQTS in many patients. Here we report the novel mutation c.1898A>C in KCNH2 in a Chinese family with LQTS through whole-exome sequencing. The c.916dupA mutation in JUP (which encodes junction plakoglobin) is also discovered. Mutations in JUP were found to be associated with arrhythmogenic right ventricular cardiomyopathy. The double mutation in the proband may help explain his severe clinical manifestations, such as sudden cardiac death at an early age. Sequencing for the proband’s family members revealed that the KCNH2 mutation descends from his paternal line, while the mutation in JUP came from his maternal line. The data provided in this study may help expand the spectrum of LQTS-related KCNH2 mutations and add support to the genetic diagnosis and counseling of families affected by malignant arrhythmias.

scholarly journals KCNQ1 and Long QT Syndrome in 1/45 Amish

2020 ◽  
Vol 13 (6) ◽  
Author(s):  
Elizabeth A. Streeten ◽  
Vincent Y. See ◽  
Linda B.J. Jeng ◽  
Kristin A. Maloney ◽  
Megan Lynch ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Exome Sequencing ◽  
Long Qt Syndrome ◽  
Cardiac Death ◽  
Chinese Hamster Ovary Cells ◽  
Population Based ◽  
Long Qt ◽  
Variant Of Unknown Significance ◽  
Unknown Significance ◽  
Qt Syndrome

Background: In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health. Methods: Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a KCNQ1 variant from variant of unknown significance to pathogenic. Results were returned to participants in a community setting. Results: A missense variant was identified in KCNQ1 (c.671C>T, p.T224M), a gene associated with long QT syndrome type 1, which can cause syncope and sudden cardiac death. The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248 566 in gnomAD) and was highly associated with QTc on electro-cardiogram ( P =5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 noncarriers. There was stronger clinical evidence of long QT syndrome in carriers (38.6% versus 5.5%, P =0.0006), greater history of syncope (32% versus 17%, P =0.020), and higher rate of sudden cardiac death in first degree relatives<age 30 (4.5% versus 0%, P =0.026). Expression of p.T224M KCNQ1 in Chinese hamster ovary cells showed near complete loss of protein function. Our clinical and functional data enabled reclassification of p.T224M from a variant of unknown significance to pathogenic. Of the 88 carriers, 93% met criteria for beta-blocker treatment and 5/88 (5.7%) were on medications that may further prolong QTc. Carriers were provided a Clinical Laboratory Improvement Amendments confirmed report, genetic counseling, and treatment recommendations. Follow-up care was coordinated with local physicians. Conclusions: This work provides a framework by which research exome sequencing can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.

scholarly journals A novel KCNH2 frameshift mutation (c.46delG) associated with high risk of sudden death in a family with congenital long QT syndrome type 2

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hyun Sok Yoo ◽  
Nancy Medina ◽  
María Alejandra von Wulffen ◽  
Natalia Ciampi ◽  
Analia Paolucci ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Long Qt Syndrome ◽  
Cardiac Death ◽  
Frameshift Mutation ◽  
Alpha Subunit ◽  
Syndrome Type ◽  
Long Qt ◽  
Qt Syndrome ◽  
Congenital Long Qt Syndrome

Abstract Background The congenital long QT syndrome type 2 is caused by mutations in KCNH2 gene that encodes the alpha subunit of potassium channel Kv11.1. The carriers of the pathogenic variant of KCNH2 gene manifest a phenotype characterized by prolongation of QT interval and increased risk of sudden cardiac death due to life-threatening ventricular tachyarrhythmias. Results A family composed of 17 members with a family history of sudden death and recurrent syncopes was studied. The DNA of proband with clinical manifestations of long QT syndrome was analyzed using a massive DNA sequencer that included the following genes: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, ANK2, KCNJ2, CACNA1, CAV3, SCN1B, SCN4B, AKAP9, SNTA1, CALM1, KCNJ5, RYR2 and TRDN. DNA sequencing of proband identified a novel pathogenic variant of KCNH2 gene produced by a heterozygous frameshift mutation c.46delG, pAsp16Thrfs*44 resulting in the synthesis of a truncated alpha subunit of the Kv11.1 ion channel. Eight family members manifested the phenotype of long QT syndrome. The study of family segregation using Sanger sequencing revealed the identical variant in several members of the family with a positive phenotype. Conclusions The clinical and genetic findings of this family demonstrate that the novel frameshift mutation causing haploinsufficiency can result in a congenital long QT syndrome with a severe phenotypic manifestation and an elevated risk of sudden cardiac death.

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