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Original Article

Array Comparative Genomic Hybridization Identifies a Heterozygous Deletion of the Entire KCNJ2 Gene as a Cause of Sudden Cardiac Death

Renate Marquis-Nicholson, Debra O. Prosser, Jennifer M. Love, Liangtao Zhang, Ian Hayes, Alice M. George, Jackie R. Crawford, Jonathan R. Skinner, Donald R. Love
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https://doi.org/10.1161/CIRCGENETICS.113.000415
Circulation: Genomic and Precision Medicine. 2014;CIRCGENETICS.113.000415
Originally published January 6, 2014
Renate Marquis-Nicholson
Diagnostic Genetics, LabPlus, Auckland City Hospital, Auckland, New Zealand / Current Address: Centre for Translational Pathology, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
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Debra O. Prosser
Diagnostic Genetics, LabPlus, Auckland City Hospital, Auckland, New Zealand
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Jennifer M. Love
Diagnostic Genetics, LabPlus, Auckland City Hospital, Auckland, New Zealand
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Liangtao Zhang
Diagnostic Genetics, LabPlus, Auckland City Hospital, Auckland, New Zealand
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Ian Hayes
Genetic Health Service of New Zealand - Northern Hub & Cardiac Inherited Disease Group, Auckland City Hospital, Auckland, New Zealand
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Alice M. George
Diagnostic Genetics, LabPlus, Auckland City Hospital, Auckland, New Zealand
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Jackie R. Crawford
Cardiac Inherited Disease Group, Auckland City Hospital & Green Lane Paediatric and Congenital Cardiac Services, Starship Children's' Hospital, Auckland, New Zealand
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Jonathan R. Skinner
Cardiac Inherited Disease Group, Auckland City Hospital & Green Lane Paediatric and Congenital Cardiac Services, Starship Children's' Hospital, Auckland, New Zealand
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  • For correspondence: jskinner@adhb.govt.nz
Donald R. Love
Diagnostic Genetics, LabPlus & Cardiac Inherited Disease Group, Auckland City Hospital & School of Biological Sciences, University of Auckland, Auckland, New Zealand
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Abstract

Background—Large gene re-arrangements, not detectable by standard molecular genetic sequencing techniques, are present in a minority of patients with long QT syndrome (LQTS). We aimed to screen for large rearrangements in genes responsible for LQTS as part of the molecular autopsy of a 36 year old woman who died suddenly and had a negative autopsy. A retrospective analysis of an ECG identified a long QT interval, but sequencing of known LQT genes was uninformative.

Methods and Results—Array comparative genomic hybridization (aCGH) was used to screen for deletions and duplications in 101 genes implicated in cardiac disorders and sudden death using a post-mortem blood sample. A 542kb deletion encompassing the entire KCNJ2 gene was identified in the decedent. The mother had electrocardiographic U wave changes consistent with Andersen-Tawil Syndrome (ATS) and exaggerated by exercise, but none of the characteristic non-cardiac features. Fluorescence in situ hybridization (FISH) confirmed the deletion in the decedent and established its presence in the mother.

Conclusions—A novel application of aCGH and FISH has identified that LQTS and sudden cardiac death may occur as a result of a deletion of an entire gene. The case also supports recent research suggesting that non cardiac features of ATS occur only with missense or minor gene rearrangements in KCNJ2 resulting in a dominant negative effect on Kir2.x channels.

  • comparative genomic hybridization
  • molecular diangostic techniques
  • sudden cardiac death
  • long QT syndrome
  • cardiac arrhythmia
  • Andersen-Tawil syndrome
  • Received September 8, 2013.
  • Accepted December 11, 2013.
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    Array Comparative Genomic Hybridization Identifies a Heterozygous Deletion of the Entire KCNJ2 Gene as a Cause of Sudden Cardiac Death
    Renate Marquis-Nicholson, Debra O. Prosser, Jennifer M. Love, Liangtao Zhang, Ian Hayes, Alice M. George, Jackie R. Crawford, Jonathan R. Skinner and Donald R. Love
    Circulation: Genomic and Precision Medicine. 2014;CIRCGENETICS.113.000415, originally published January 6, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000415

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    Array Comparative Genomic Hybridization Identifies a Heterozygous Deletion of the Entire KCNJ2 Gene as a Cause of Sudden Cardiac Death
    Renate Marquis-Nicholson, Debra O. Prosser, Jennifer M. Love, Liangtao Zhang, Ian Hayes, Alice M. George, Jackie R. Crawford, Jonathan R. Skinner and Donald R. Love
    Circulation: Genomic and Precision Medicine. 2014;CIRCGENETICS.113.000415, originally published January 6, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000415
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