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Original Contribution
April 10, 2013

Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death

Author Affiliations

Author Affiliations: Department of Molecular Medicine, University of Pavia, and Molecular Cardiology Laboratory, Fondazione IRRCCS Policlinico S Matteo (Drs Crotti, Insolia, and Schwartz and Ms Ghidoni), Pavia, Italy; Institute of Human Genetics Helmholtz Center, Munich, Germany (Dr Crotti); Department of Medicine, Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (Mr Tester, Ms Will, and Dr Ackerman), Division of Cardiovascular Disease (Mr Tester, Ms Will, and Dr Ackerman), and Division of Maternal Fetal Medicine (Drs White, Wick, and Brost), Department of Pediatrics, Division of Pediatric Cardiology (Dr Ackerman), and Department of Laboratory Medicine and Pathology (Ms Blair and Dr Van Dyke), Mayo Clinic, Rochester, Minnesota; Department of Physiology, University of Kentucky, Lexington (Mr Bartos, Ms Velasco, and Dr Delisle); Laboratory of Cardiovascular Genetics, IRCCS Insituto Auxologico Italiano, Milan, Italy (Dr Besana); Departments of Medicine (Ms Kunic and Dr George), Pharmacology and Institute for Integrative Genomics (Dr George), Vanderbilt University, Nashville, Tennessee; Department of Clinical Sciences Luigi Sacco, University of Milan, Italy (Dr Cetin); Department of Obstetrics and Gynaecology, University of Modena and Reggio Emilia, Italy (Dr Facchinetti); Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research Department of Medicine, University of Cape Town and Department of Medicine, University of Stellenbosch (Dr Schwartz), South Africa; and Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia (Dr Schwartz).

JAMA. 2013;309(14):1473-1482. doi:10.1001/jama.2013.3219

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.