Recurrent Pregnancy Loss and Concealed Long‐QT Syndrome

BACKGROUND: Recurrent pregnancy loss affects 1% to 2% of couples attempting childbirth. A large fraction of all cases remains idiopathic, which warrants research into monogenic causes of this distressing disorder. METHODS AND RESULTS: We investigated a nonconsanguineous Estonian family who had experienced 5 live births, intersected by 3 early pregnancy losses, and 6 fetal deaths, 3 of which occurred during the second trimester. No fetal malformations were described at the autopsies performed in 3 of 6 cases of fetal death. Parental and fetal chromosomal abnormalities (including submicroscopic) and maternal risk factors were excluded. Material for genetic testing was available from 4 miscarried cases (gestational weeks 11, 14, 17, and 18). Exome sequencing in 3 pregnancy losses and the mother identified no rare variants explicitly shared by the miscarried conceptuses. However, the mother and 2 pregnancy losses carried a heterozygous nonsynonymous variant, resulting in p.Val173Asp (rs199472695) in the ion channel gene KCNQ1. It is expressed not only in heart, where mutations cause type 1 long‐QT syndrome, but also in other tissues, including uterus. The p.Val173Asp variant has been previously identified in a patient with type 1 long‐QT syndrome, but not reported in the Genome Aggregation Database. With heterologous expression in CHO cells, our in vitro electrophysiologic studies indicated that the mutant slowly activating voltage‐gated K+ channel (I (Ks)) is dysfunctional. It showed reduced total activating and deactivating currents (P<0.01), with dramatically positive shift of voltage dependence of activation by ≈10 mV (P<0.05). CONCLUSIONS: The current study uncovered concealed maternal type 1 long‐QT syndrome as a potential novel cause behind recurrent fetal loss.