Abstract 2927: Long QT Syndrome as a Cause of Stillbirths
Background: Stillbirths (intrauterine fetal deaths occurring after the 22th week of gestation) notably contribute to perinatal mortality. Among them, 25–50% of cases remain unexplained after thorough investigation. We recently demonstrated that 10% of Sudden Infant Death Syndrome (SIDS) cases carry functionally relevant genetic variants in Long QT Syndrome (LQTS) genes. We previously hypothesized that severe forms of LQTS could contribute to mortality not only shortly after birth but also before. Accordingly, we are now screening LQTS genes in unexplained stillbirths.
Materials and Methods: We receive DNA from an ongoing Italian multicenter study on rigorously defined ``unexplained stillbirths”. DNA is extracted from placenta or umbilical cord. Through DHPLC and sequence analysis we screen the main LQTS genes: KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2. Any amino-acid substitution identified in the samples is checked in a control population of 122 Caucasian controls. Here, we report the preliminary data on the first 17 cases (gestational age of death: 23–38 weeks).
Results: A total of 3 missense mutations have been identified in 3 of 17 stillbirths (18%). Two were on SCN5A and one on KCNH2. The two mutations on SCN5A (V1951L; P2006A) have been previously associated to SIDS and shown to increase the late sodium current. The mutation on KCNH2 is a novel genetic variant absent in 244 reference alleles and never described in any control populations. We are currently performing the electrophysiological cellular studies to define its functional effect.
Conclusions: The initial data from this ongoing study already indicate that a yet to be defined but potentially significant number of currently unexplained intrauterine fetal deaths might be caused by ion channel diseases such as LQTS. The completion of our study will soon provide a reliable quantification of this contribution. There are potentially important implications for the affected families, ranging from prevention of recurrences to identification of other affected family members and to possible prevention of SIDS or later sudden deaths in subsequent siblings.