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Journal of the American Medical Association

Clinical Articles, News & Views

Genetic variants of LQTS linked to unexplained stillbirths

A proportion of unexplained foetal deaths may be linked to mutations associated with susceptibility to long QT syndrome (LQTS), according to a study1 published recently in the Journal of the American Medical Association.

Researchers led by Drs Lia Crotti (University of Pavia, Italy) and Michael J Ackerman (Mayo Clinic, Rochester, USA) conducted a study to determine the spectrum and prevalence of mutations in the three most common LQTS-susceptible genes (KCNQ1, KCNH2, and SCN5A) for a group of unexplained foetal death cases. In this case series, retrospective postmortem genetic testing was conducted on a sample of 91 unexplained intrauterine foetal deaths that were collected from 2006–2012 (average estimated gestational age at foetal death, 26.3 weeks; 51 females, 40 males).

More than 1,300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants.

Excluding two very common genetic variants, the researchers identified 14 genetic variants in 18 intrauterine foetal deaths (19.8%) of 91 including three of 30 late abortion or miscarriages (10%) and 15 of 61 stillbirths (24.6%). “Three variants found in three intrauterine foetal death cases (3.3%) of 91 were considered putative pathogenic mutations based on their absence in more than 1,000 ethnically similar controls, a heterozygote frequency below the prevalence of LQTS in the general population (0.05%) as determined by analysis of more than 10,000 publicly available exomes, and an abnormal functional electrophysiological profile.”

In addition, five intrauterine foetal deaths hosted SCN5A rare non-synonymous genetic variants (a polymorphism that results in a change in the amino acid sequence of a protein) that conferred in vitro electrophysiological characteristics consistent with potentially pro-arrhythmic phenotypes.

Overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in 8 cases (8.8%).

Postmortem evaluations fail to identify a cause of death in approximately 25–40% of foetal deaths, according to the authors. However, “LQTS has been shown to be a major determinant in young sudden death individuals for which an autopsy was performed but had remained inconclusive and a determinant for as much as 10% of sudden infant death syndrome (SIDS),” they add, speculating that long QT syndrome may also contribute to sudden unexpected foetal mortality.

“To our knowledge, this represents the first demonstration of such findings. This preliminary evidence suggests LQTS is one plausible cause of intrauterine fetal death; supports the previously proposed mechanistic link between some cases of intrauterine fetal death, SIDS, and LQTS; and provides precedence for further large-scale investigations into the extent and role of cardiac channelopathies in stillbirth,” the authors conclude.

In an accompanying editorial2, Dr Alan Guttmacher (National Institutes of Health, Bethesda, USA) and colleagues say:”Understanding the etiology of stillbirth is essential not just for crafting effective prevention strategies but also for providing families and clinicians with counseling information and the opportunity for a greater sense of closure”.

“Recent efforts to fully characterize stillbirths have provided a foundation for identifying the causal factors and include novel technologies to evaluate the genomic alterations in stillbirth. The findings of Crotti and colleagues add another piece to solving this puzzle. If confirmed in well-characterized cohorts and amplified by broader genomic approaches, such work may provide an explanation for many cases of late miscarriage and stillbirth previously labeled as ‘unknown,’” they conclude.


1. Crotti L, Tester DJ, White WM, et al. Long QT syndrome–associated mutations in intrauterine fetal death. J Am Med Assoc 2013;309:1473–82.

2. Guttmacher AE, Spong CY, Willinger M. Long QT syndrome susceptibility mutations and pregnancy loss another piece of a still unfinished puzzle? J Am Med Assoc 2013;309:1525–6.

Published on: May 22, 2013

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