Long QT Syndrome-Associated Mutations in Intrauterine Fetal Death

Study Questions:

What is the prevalence of mutations in the three most common long QT syndrome (LQTS) susceptible genes (KCNQ1, KCNH2, and SCN5A) in a cohort of unexplained cases of intrauterine fetal death?


A retrospective case series was performed at two centers. Postmortem genetic testing was performed on a sample 91 unexplained intrauterine fetal deaths at mean estimated gestational age of 26.3 ± 8.7 weeks. Approximately 1,300 healthy individuals served as controls. Publicly available exome databases were also assessed for the general population frequency of identified genetic variants. Comprehensive mutational analysis for mutations associated with LQTS 1 (KCNQ1 [KV7.1]), LQTS 2 (KCNH2 [HERG/KV11.1]), and LQTS 3 (SCN5A [NaV1.5]). Functional analyses of novel mutations were also performed.


Three cases of intrauterine fetal death (3.3%) were found to have missense mutations described in LQTS. Missense mutations associated with LQTS type 1 occurred in two patients, a 16-week-old male and a 16-week-old female. A missense mutation associated with LQTS type 2 occurred in one patient, a 33.2-week-old male. These mutations had a heterozygous frequency of <0.05% in 10,000 publicly available exomes and were absent in the 1,000 ethnically similar control patients. An additional five intrauterine fetal deaths hosted SCN5A (LQTS type 3) rare nonsynonymous genetic variants, which conferred in vitro eletrophysiological characteristics consistent with proarrhythmic phenotypes. In summary, genetic variants leading to LQTS-associated ion channels were present in 8.8% of cases of intrauterine fetal death.


Missense mutations associated with LQTS susceptibility were discovered in 3.3% of cases of intrauterine death, whereas in total, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were present in 8.8% of cases.


While many causes of fetal death can be attributed to such causes and chromosomal abnormalities, congenital anomalies, infection, or placental issues, approximately 50% are unexplained. As LQTS has been implicated as a contributor to sudden infant death syndrome, it has been theorized to contribute to sudden unexpected fetal mortality as well. Although preliminary, this study shows a disproportionately high rate of genetic variants known to be associated with channelopathies in cases of intrauterine fetal death. As minor LQTS-susceptibility genes were not assessed, this study may have underestimated the true prevalence of LQTS-associated mutations in intrauterine fetal death.

Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias

Keywords: Chromosome Aberrations, Gestational Age, Mutation, Missense, Sudden Infant Death, Fetal Death, Heart Defects, Congenital, Phenotype, Gene Frequency, Long QT Syndrome, Genetic Testing, Channelopathies, DNA Mutational Analysis

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