Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths

Patricia B Munroe, Shea Addison, Dominic J Abrams, Neil J Sebire, James Cartwright, Ian Donaldson, Marta M Cohen, Charles Mein, Andrew Tinker, Stephen C Harmer, Qadeer Aziz, Anna Terry, Monika Struebig, Helen R Warren, Bhumita Vadgama, Darren J Fowler, Donald Peebles, Andrew M Taylor, Peter J Lally, Sudhin Thayyil

Research output: Contribution to journalArticle (Academic Journal)peer-review

17 Citations (Scopus)


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: Unique identifier: NCT01120886.

Original languageEnglish
Article numbere001817
Number of pages10
JournalCirculation: Genomic and Precision Medicine
Issue number1
Early online date7 Nov 2017
Publication statusPublished - 11 Jan 2018

Bibliographical note

© 2018 American Heart Association, Inc.


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