International research finds heart disorder genetic variants in stillbirth cases

April 9, 2013, Mayo Clinic

In a molecular genetic evaluation involving 91 cases of intrauterine fetal death, mutations associated with susceptibility to long QT syndrome (LQTS; a heart disorder that increases the risk for an irregular heartbeat and other adverse events) were discovered in a small number of these cases, preliminary evidence that may provide insights into the mechanism of some intrauterine fetal deaths, according to a study in the April 10 issue of JAMA, a Genomics theme issue.

"Intrauterine fetal death is a major public health problem. About 1 million fetal deaths occur in the United States annually, with the vast majority occurring prior to 20 weeks' estimated gestational age," according to background information in the article. Fetal death occurring after 20 weeks is defined as stillbirth, and in 2009, an estimated 2.64 million stillbirths occurred worldwide. Postmortem evaluations fail to identify a cause of death in approximately 25 percent to 40 percent of fetal deaths. "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 percent of sudden infant death syndrome (SIDS). Long QT syndrome may also contribute to sudden unexpected fetal mortality."

Lia Crotti, M.D., Ph.D., of the University of Pavia, Italy, and Michael J. Ackerman, M.D., Ph.D., of Mayo Clinic, Rochester, Minn., and colleagues conducted a study to determine the spectrum and prevalence of mutations in the 3 most common LQTS-susceptible genes (KCNQ1, KCNH2, and SCN5A) for a group of unexplained fetal death cases. In this case series, retrospective postmortem genetic testing was conducted on a sample of 91 unexplained intrauterine fetal deaths that were collected from 2006-2012 (average estimated gestational age at fetal death, 26.3 weeks; 51 females, 40 males). More than 1,300 ostensibly healthy individuals served as controls. In addition, publicly available exome (the entire portion of the genome consisting of protein-coding sequences) databases were assessed for the general population frequency of identified genetic variants.

Excluding 2 very common genetic variants, the researchers identified 14 genetic variants in 18 intrauterine fetal deaths (19.8 percent) of 91 including 3 of 30 late abortion or miscarriages (10 percent) and 15 of 61 stillbirths (24.6 percent). "Three variants found in 3 intrauterine fetal death cases (3.3 percent) of 91 were considered putative [supposed] pathogenic mutations based on their absence in more than 1,000 ethnically similar controls, a heterozygote [a person possessing two different forms of a particular gene] frequency below the prevalence of LQTS in the general population (0.05 percent) as determined by analysis of more than 10,000 publicly available exomes, and an abnormal functional electrophysiological profile."

In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (a polymorphism that results in a change in the amino acid sequence of a protein [and therefore may affect the function of the protein]) that conferred in vitro electrophysiological characteristics consistent with potentially pro-arrhythmic phenotypes.

Overall, genetic variants leading to dysfunctional LQTS-associated ion channels (a protein that acts as a pore in a cell membrane and permits the selective passage of ions by means of which electrical current passes in and out of the cell) in vitro were discovered in 8 cases (8.8 percent).

"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 [a disease involving dysfunction of an ion channel] in stillbirth," the authors write.

"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," writes Alan E. Guttmacher, M.D., of the National Institutes of Health, Bethesda, Md., and colleagues in an accompanying editorial.

"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.'"

Explore further: Sports guidelines for long QT syndrome patients may be too strict, study finds

More information: JAMA. 2013;309(14):1473-1482
JAMA. 2013;309(14):1525-1526

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