Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death

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 dete...

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Published in:	JAMA : the journal of the American Medical Association Vol. 309; no. 14; pp. 1473 - 1482
Main Authors:	Crotti, Lia, Tester, David J, White, Wendy M, Bartos, Daniel C, Insolia, Roberto, Besana, Alessandra, Kunic, Jennifer D, Will, Melissa L, Velasco, Ellyn J, Bair, Jennifer J, Ghidoni, Alice, Cetin, Irene, Van Dyke, Daniel L, Wick, Myra J, Brost, Brian, Delisle, Brian P, Facchinetti, Fabio, George, Alfred L, Schwartz, Peter J, Ackerman, Michael J
Format:	Journal Article
Language:	English
Published:	Chicago, IL American Medical Association 10-04-2013
Subjects:	Autopsy Biological and medical sciences Cardiac dysrhythmias Cardiology. Vascular system DNA Mutational Analysis ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels - genetics Ether-A-Go-Go Potassium Channels - metabolism Female Fetal Death - genetics Fetus - physiopathology Fetuses Gene Expression General aspects Genes Heart Humans Infant, Newborn KCNQ1 Potassium Channel - genetics KCNQ1 Potassium Channel - metabolism Long QT Syndrome - genetics Male Medical sciences Mortality Mutation Mutation, Missense Myocardium - metabolism NAV1.5 Voltage-Gated Sodium Channel - genetics NAV1.5 Voltage-Gated Sodium Channel - metabolism Retrospective Studies Stillbirth Medicine Arrhythmia Heart block Heart disease Prolonged QT interval Cardiovascular disease Genetics Mutation Conduction disorder Death in utero
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0098-7484 1538-3598
DOI:	10.1001/jama.2013.3219