Recurrent Pregnancy Loss and Concealed Long-QT Syndrome

Abstract

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.

Keywords: KCNQ1; exome; long‐QT syndrome; miscarriage; recurrent pregnancy loss.

Figure 1. Identification of the KCNQ1 variant.

A, Pedigree of the family. Circles denote female family members, squares denote male members, and triangles indicate spontaneous pregnancy losses. The proband is indicated with an arrow. Solid symbols indicate pedigree members, whose genomic DNA was subjected to exome sequencing. B, Sanger sequencing confirmation of the KCNQ1 p.V173D variant (rs199472695) in the family. C, Molecular position of the K_V7.1 variant p.V173D in the first C‐loop. D, The conservation of the amino acid residue affected by the KCNQ1 variant in different species. d, death; ECT indicates ectopic pregnancy; trim, trimester; wks, gestational weeks; WT, wild type and yrs, years.

Figure 2. KCNQ1 mutation p.V173D caused a loss of cardiac I _Ks function.

A and B, Typical I _Ks traces recorded in CHO cells in which either wild‐type (WT) KCNQ1 or V173D were coexpressed with WT KCNE1. C and D, I _Ks steady‐state and tail current densities in the 2 groups of cells (n=10 each). The mutant channel p.V173D significantly reduced total I _Ks steady‐state and tail currents with a dramatic positive shift of the voltage dependence of activation, by ≈10 mV (P<0.05). Current densities were expressed in pA/pF after normalization of current amplitude to cell capacitance. The voltage clamp protocol is shown in the insert.