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Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths

Research output: Contribution to journalArticle

  • Patricia B Munroe
  • Shea Addison
  • Dominic J Abrams
  • Neil J Sebire
  • James Cartwright
  • Ian Donaldson
  • Marta M Cohen
  • Charles Mein
  • Andrew Tinker
  • Stephen C Harmerhttp://orcid.org/0000-0003-3909-6698
  • Qadeer Aziz
  • Anna Terry
  • Monika Struebig
  • Helen R Warren
  • Bhumita Vadgama
  • Darren J Fowler
  • Donald Peebles
  • Andrew M Taylor
  • Peter J Lally
  • Sudhin Thayyil
Original languageEnglish
Article numbere001817
Number of pages10
JournalCirculation: Genomic and Precision Medicine
Volume11
Issue number1
Early online date7 Nov 2017
DOIs
DateAccepted/In press - 7 Nov 2017
DateE-pub ahead of print - 7 Nov 2017
DatePublished (current) - 11 Jan 2018

Abstract

BACKGROUND: Although stillbirth is a significant health problem worldwide, the definitive cause of death remains elusive in many cases, despite detailed autopsy. In this study of partly explained and unexplained stillbirths, we used next-generation sequencing to examine an extended panel of 35 candidate genes known to be associated with ion channel disorders and sudden cardiac death.

METHODS AND RESULTS: We examined tissue from 242 stillbirths (≥22 weeks), including those where no definite cause of death could be confirmed after a full autopsy. We obtained high-quality DNA from 70 cases, which were then sequenced for a custom panel of 35 genes, 12 for inherited long- and short-QT syndrome genes (LQT1-LQT12 and SQT1-3), and 23 additional candidate genes derived from genome-wide association studies. We examined the functional significance of a selected variant by patch-clamp electrophysiological recording. No predicted damaging variants were identified in KCNQ1 (LQT1) or KCNH2 (LQT2). A rare putative pathogenic variant was found in KCNJ2(LQT7) in 1 case, and several novel variants of uncertain significance were observed. The KCNJ2 variant (p. R40Q), when assessed by whole-cell patch clamp, affected the function of the channel. There was no significant evidence of enrichment of rare predicted damaging variants within any of the candidate genes.

CONCLUSIONS: Although a causative link is unclear, 1 putative pathogenic and variants of uncertain significance variant resulting in cardiac channelopathies was identified in some cases of otherwise unexplained stillbirth, and these variants may have a role in fetal demise.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01120886.

Additional information

© 2018 American Heart Association, Inc.

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