Postmortem genetic testing of 91 unexplained intrauterine fetal deaths identified missense mutations associated with long QT syndrome susceptibility in 3.3% of cases (95% CI, 0.68%-9.3%).
Observational (n=91)
Yes
Do mutations in Long QT Syndrome susceptibility genes contribute to unexplained intrauterine fetal deaths?
Genetic variants associated with Long QT syndrome were found in nearly 9% of unexplained intrauterine fetal deaths, suggesting a potential arrhythmogenic mechanism for some stillbirths.
Absolute Event Rate: 3.3% vs 0%
IMPORTANCE: Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. OBJECTIVE: To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. DESIGN, SETTING, AND PATIENTS: In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean SD estimated gestational age at fetal death, 26.3 8.7 weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. MAIN OUTCOMES AND MEASURES: Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. RESULTS: The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2 1b, p.R25W), with a heterozygous frequency of less than 0.05% in more than 10 000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% 95% CI, 0.68%-9.3%). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (p.T220I, p.R1193Q, involving 2 cases, and p.P2006A, involving 2 cases) that conferred in vitro electrophysiological characteristics consistent with potentially proarrhythmic phenotypes. CONCLUSIONS AND RELEVANCE: In this molecular genetic evaluation of 91 cases of intrauterine fetal death, missense mutations associated with LQTS susceptibility were discovered in 3 cases (3.3%) and overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in 8 cases (8.8%). These preliminary findings may provide insights into mechanisms of some cases of stillbirth.
Crotti et al. (Wed,) conducted a observational in Unexplained intrauterine fetal death (n=91). Postmortem genetic testing for KCNQ1, KCNH2, and SCN5A mutations vs. Healthy controls was evaluated on Prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) (95% CI 0.68%-9.3%). Postmortem genetic testing of 91 unexplained intrauterine fetal deaths identified missense mutations associated with long QT syndrome susceptibility in 3.3% of cases (95% CI, 0.68%-9.3%).