Genetic mutations associated with LQTS discovered in small number of intrauterine fetal deaths

In a molecular genetic evaluation of 91 cases of intrauterine fetal death, mutations associated with susceptibility to long QT syndrome were discovered in a small number of cases. This finding demonstrates preliminary evidence that may provide insights into the mechanism of some intrauterine fetal deaths, researchers reported in JAMA.

Researchers conducted a study to determine the spectrum and prevalence of mutations in the three most common long QT syndrome (LQTS)-susceptible genes (KCNQ1, KCNH2 and SCN5A) for a group of unexplained fetal death cases. They performed retrospective molecular genetic evaluation of 91 unexplained intrauterine fetal deaths from 2006 to 2012 (average estimated gestational age at fetal death, 26.3 weeks; 51 girls). More than 1,000 healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population.

Discovery of the association

According to results, excluding two common genetic variants (KCNH2 and SCN5A), the researchers identified 14 genetic variants in 18 intrauterine fetal deaths (19.8%) of the 91. This included three of 30 late abortion or miscarriages (10%) and 15 of 61 stillbirths (24.6%).

“Three variants found in three intrauterine fetal death cases (3.3%) of 91 were considered putative pathogenic mutations based on their absence on 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,” the researchers wrote.

In addition, researchers identified five intrauterine fetal deaths that hosted SCN5A rare nonsynonumous genetic variants that conferred in vitro electrophysiological characteristics consistent with proarrhythmic phenotypes.

In other results, mutations associated with marked K_v7.1 loss of function in K_v7.1-A283T (16-week boy) and K_v7.1-R397W (16-week girl) were consistent with in utero LQTS type 1; the HERG1b-R25W mutation (33.2-week boy) were associated with loss of function consistent with in utero LQTS type 2.

“Missense mutations associated with LQTS susceptibility were discovered in three cases (3.3%) and, overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in eight cases (8.8%),” the researchers concluded. “These preliminary findings may provide insights into mechanisms of some cases of stillbirth.”

Potential role of LQTS in unexplained fetal death

The preliminary data “suggest that LQTS may be the cause for approximately 5% of otherwise unexplained stillbirths, and point to the need for further large-scale studies,” Michael J. Ackerman, MD, PhD, researcher and pediatric cardiologist at Mayo Clinic, stated in a release.

Michael J. Ackerman

In an accompanying editorial, Alan E. Guttmacher, MD, acknowledged that the cause of many stillbirths is still unknown.

“This study highlights the potential role of LQTS in unexplained fetal death, an intriguing concept given the known presence of mutations in channelopathy genes that predispose to sudden death in a subset of sudden infant death syndrome cases and the described continuum between stillbirths and SIDS. … The new identification of several genetic abnormalities in two channel genes among putative unexplained losses supports investigation of cardiac arrhythmias as a cause of fetal loss,” Guttmacher, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, wrote.

He added, “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.’”

For more information:

Crotti L. JAMA. 2013;309:1473-1482.

Guttmacher AE. JAMA. 2013;309:1525-1526.

Disclosure: See the full study and editorial for a list of relevant financial disclosures.