Long QT syndrome mutations and intrauterine fetal death

Intrauterine fetal death occurs in approximately 1 in every 160 pregnancies; postmortem evaluation often fails to find an underlying cause. The objective of this paper was to determine the spectrum and prevalence of mutations in the three most common Long QT syndrome (LQTS) susceptible genes in a cohort of cases of unexplained intrauterine death.

Retrospective post-mortem genetic testing was carried out on 91 unexplained intrauterine fetal deaths collected between 2006 and 2012. Publically available exome databases were assessed for the general population frequency of identified genetic variants. Mutations analysis was performed by liquid chromatography and DNA sequencing. Functional analysis of novel mutations was performed using heterologous expression and patch-clamp recording.

The three LQTS missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W) were discovered in three intrauterine fetal deaths. 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, while the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. Furthermore, five intrauterine fetal deaths hosted SCN5A rare nonsynonymous …