Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths

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.clinical trials.gov . Unique identifier: NCT01120886.

Cardio-pathogenic variants in unexplained intrauterine fetal death: a retrospective pilot study

“…A recent exome sequencing analysis in 246 unexplained stillborn fetuses revealed an underlying monogenetic cause in approximately 8.5% phenotypically normal fetuses. 14 Also studies regarding cardio-pathogenic findings in otherwise unexplained stillbirths detected putative variants in 5.7% to 12.1% of cases 7,8 . In contrast to other authors, we found an incidence of 15.5% of variants of uncertain significance in genes contributing to LQTS, compared to the reported prevalence of over 50% of putative variants in previous investigations [15][16][17] .…”

“…Previous studies have suggested the influence of cardiac arrhythmias as a possible cause for fetal death in phenotypically normal fetuses and without detectable myocardial or brain lesions in autopsy 7,8 . To date, long-QT syndrome (LQTS) is one of the most investigated genetic cardiac disorders that has been associated with arrhythmias as early as in the fetal period and has been previously found in up to 10% of otherwise unexplained stillbirths 9,10 .…”

Genetic variants in TRPM7 associated with unexplained stillbirth modify ion channel function

“…Almost half of stillbirths go unexplained, despite extensive post-mortem analysis. In this study, we present data from previously sequenced and predicted damaging TRPM7 genetic variants found in unexplained stillbirth cases ( 5 ). There is extensive research studying ion channelopathies that cause sudden cardiac death in young adults; however, there is little evidence of harmful ion channel variants in stillbirth ( 21 ).…”

“…The cause of death is usually found after a negative post-mortem. We recently sequenced a custom panel of 35 arrhythmia-associated genes in 70 unexplained stillbirth cases from the Cardiac Ion Channelopathies in Stillbirth study ( 5 ). We found four cases to have putative pathogenic variants in four long QT syndrome genes, KCNE1, KCNE2, SCN5A and KCNJ2 .…”

Whole-exome sequencing analysis on products of conception: A cohort study to evaluate clinical utility and genetic etiology for pregnancy loss

“…Furthermore, a list of reference genes and variants was generated to include 147 genes reported in cases of fetal death throughout gestation from a literature search ( Supplementary Table S2). [6][7][8][9]11,[17][18][19][20][21][22][23][24] Variants of diagnostic value in this study were compared to the list of reference genes to assess recurrence at either gene level or variant level.…”