Long QT Syndrome Susceptibility Mutations and Pregnancy Loss Another Piece of a Still Unfinished Puzzle? Long QT Syndrome Mutations

Guttmacher AE, Spong CY, Willinger M. — Wed, 10 Apr 2013 00:00:00 GMT

Loss of a pregnancy is a lifelong trauma for a family. Among the 6 632 000 pregnancies in the United States in 2006, an estimated 1 124 000 spontaneous fetal losses occurred, including miscarriages (losses before the 20th week of gestation) and stillbirths (losses at 20 weeks or later), as extrapolated from reports of recognized pregnancies in the National Survey of Family Growth. In the same year, 25 972 stillbirths were reported through a different mechanism, the national vital statistics system. But regardless of reporting methods, the scope of the problem is large.

Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death Long QT Syndrome and Intrauterine Fetal Death

Crotti L, Tester DJ, White WM, et al. — Wed, 10 Apr 2013 00:00:00 GMT

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 (K_V7.1, LQTS type 1), KCNH2 (HERG/K_V11.1, LQTS type 2), and SCN5A (Na_V1.5, 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 K_V7.1-A283T (16-week male) and K_V7.1-R397W (16-week female) mutations were associated with marked K_V7.1 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.

AMA Publishing Group: Ventricular Arrhythmias Topic Collection

Long QT Syndrome Susceptibility Mutations and Pregnancy Loss Another Piece of a Still Unfinished Puzzle? Long QT Syndrome Mutations

Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death Long QT Syndrome and Intrauterine Fetal Death