Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity

John R. Giudicessi, Michael John Ackerman

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background-Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome, a rare, autosomal-recessive form of long-QT syndrome characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. In this study, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of patients with long-QT syndrome. Methods and Results-A retrospective analysis of all patients with long-QT syndrome evaluated from July 1998 to April 2012 was used to identify those with ≥1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 (6.0%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 of these patients (73%) presented without the sensorineural deafness associated with Jervell and Lange-Nielsen syndrome. The degree of QT-interval prolongation and the number of breakthrough cardiac events were similar between patients with and without deafness. Interestingly, truncating mutations were more prevalent in patients with Jervell and Lange-Nielsen syndrome (79%) than in nondeaf patients (36%; P<0.001) derived from this study and those in the literature. Conclusions-In this study, we provide evidence that the recessive inheritance of a severe long-QT syndrome type 1 phenotype in the absence of an auditory phenotype may represent a more common pattern of long-QT syndrome inheritance than previously anticipated and that these cases should be treated as a higher-risk long-QT syndrome subset similar to their Jervell and Lange-Nielsen syndrome counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ≥1 KCNQ1 mutation on each allele.

Original languageEnglish (US)
Pages (from-to)193-200
Number of pages8
JournalCirculation: Cardiovascular Genetics
Volume6
Issue number2
DOIs
StatePublished - Apr 2013

Fingerprint

Deafness
Jervell-Lange Nielsen Syndrome
Long QT Syndrome
Mutation
Alleles
Romano-Ward Syndrome
Genetic Phenomena
Phenotype
Sudden Death
Referral and Consultation
Population

Keywords

  • Genetics
  • Ion channels
  • Long QT syndrome
  • Pediatrics
  • Sudden cardiac death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

@article{b583c7ddaf0b4cdebf5242a035540aef,
title = "Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity",
abstract = "Background-Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome, a rare, autosomal-recessive form of long-QT syndrome characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. In this study, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of patients with long-QT syndrome. Methods and Results-A retrospective analysis of all patients with long-QT syndrome evaluated from July 1998 to April 2012 was used to identify those with ≥1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 (6.0{\%}) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 of these patients (73{\%}) presented without the sensorineural deafness associated with Jervell and Lange-Nielsen syndrome. The degree of QT-interval prolongation and the number of breakthrough cardiac events were similar between patients with and without deafness. Interestingly, truncating mutations were more prevalent in patients with Jervell and Lange-Nielsen syndrome (79{\%}) than in nondeaf patients (36{\%}; P<0.001) derived from this study and those in the literature. Conclusions-In this study, we provide evidence that the recessive inheritance of a severe long-QT syndrome type 1 phenotype in the absence of an auditory phenotype may represent a more common pattern of long-QT syndrome inheritance than previously anticipated and that these cases should be treated as a higher-risk long-QT syndrome subset similar to their Jervell and Lange-Nielsen syndrome counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ≥1 KCNQ1 mutation on each allele.",
keywords = "Genetics, Ion channels, Long QT syndrome, Pediatrics, Sudden cardiac death",
author = "Giudicessi, {John R.} and Ackerman, {Michael John}",
year = "2013",
month = "4",
doi = "10.1161/CIRCGENETICS.112.964684",
language = "English (US)",
volume = "6",
pages = "193--200",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "2",

}

TY - JOUR

T1 - Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity

AU - Giudicessi, John R.

AU - Ackerman, Michael John

PY - 2013/4

Y1 - 2013/4

N2 - Background-Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome, a rare, autosomal-recessive form of long-QT syndrome characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. In this study, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of patients with long-QT syndrome. Methods and Results-A retrospective analysis of all patients with long-QT syndrome evaluated from July 1998 to April 2012 was used to identify those with ≥1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 (6.0%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 of these patients (73%) presented without the sensorineural deafness associated with Jervell and Lange-Nielsen syndrome. The degree of QT-interval prolongation and the number of breakthrough cardiac events were similar between patients with and without deafness. Interestingly, truncating mutations were more prevalent in patients with Jervell and Lange-Nielsen syndrome (79%) than in nondeaf patients (36%; P<0.001) derived from this study and those in the literature. Conclusions-In this study, we provide evidence that the recessive inheritance of a severe long-QT syndrome type 1 phenotype in the absence of an auditory phenotype may represent a more common pattern of long-QT syndrome inheritance than previously anticipated and that these cases should be treated as a higher-risk long-QT syndrome subset similar to their Jervell and Lange-Nielsen syndrome counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ≥1 KCNQ1 mutation on each allele.

AB - Background-Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome, a rare, autosomal-recessive form of long-QT syndrome characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. In this study, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of patients with long-QT syndrome. Methods and Results-A retrospective analysis of all patients with long-QT syndrome evaluated from July 1998 to April 2012 was used to identify those with ≥1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 (6.0%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 of these patients (73%) presented without the sensorineural deafness associated with Jervell and Lange-Nielsen syndrome. The degree of QT-interval prolongation and the number of breakthrough cardiac events were similar between patients with and without deafness. Interestingly, truncating mutations were more prevalent in patients with Jervell and Lange-Nielsen syndrome (79%) than in nondeaf patients (36%; P<0.001) derived from this study and those in the literature. Conclusions-In this study, we provide evidence that the recessive inheritance of a severe long-QT syndrome type 1 phenotype in the absence of an auditory phenotype may represent a more common pattern of long-QT syndrome inheritance than previously anticipated and that these cases should be treated as a higher-risk long-QT syndrome subset similar to their Jervell and Lange-Nielsen syndrome counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ≥1 KCNQ1 mutation on each allele.

KW - Genetics

KW - Ion channels

KW - Long QT syndrome

KW - Pediatrics

KW - Sudden cardiac death

UR - http://www.scopus.com/inward/record.url?scp=84878031767&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878031767&partnerID=8YFLogxK

U2 - 10.1161/CIRCGENETICS.112.964684

DO - 10.1161/CIRCGENETICS.112.964684

M3 - Article

C2 - 23392653

AN - SCOPUS:84878031767

VL - 6

SP - 193

EP - 200

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 2

ER -