Cardiac Ion Channelopathies and Stillbirth

tillbirth, defined as the intrauterine demise of a fetus during the second half of pregnancy, represents a profoundly traumatic experience for parents and remains a major, global public health burden.Although stillbirth rates have decreased by ≈20% since 2000, there are an estimated 2.6 million stillbirths globally, with low-and middle-income countries disproportionately affected.1 In a recent report from the US-based Stillbirth Collaborative Research Network, the most common causes of stillbirth were obstetric conditions such as cervical insufficiency, followed by placental abnormalities, and fetal structural abnormalities. 2 Importantly, ≈25% to 30% of deaths remained unexplained after systematic examination.In this context, attention has turned to the role of additional mechanisms of stillbirth, including genetic abnormalities, that may explain sudden fetal death.Given the established association between cardiac ion channelopathies and sudden death syndromes (eg, long-QT, short-QT, and Brugada syndromes), initial efforts have focused on the relationship between mutations underlying these conditions and the risk of stillbirth.3 The rationale behind this approach includes the suggested continuum between stillbirth and sudden infant death syndrome, 4 coupled with the clinical observation of fatal ventricular arrhythmias in neonates with a genetic predisposition to sudden death.5 In sudden infant death syndrome, case-control studies have identified mutations associated with long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and hypertrophic cardiomyopathy, 6 with observed frequency rates of 0.3% to 10%.7,8 Fewer data are available in stillbirth, including a case-control study of 91 stillbirths in which long-QT susceptibility mutations in KCNQ1 and KCNH2 were identified in 3 cases.3 In this issue of Circulation: Genomic and Precision Medicine, Munroe et al 9 examine the relationship between ion channel mutations and stillbirth using 70 stillbirth cases from 4 hospitals in the United Kingdom and 563 control samples selected to reflect the ethnic distribution of the cases.In addition to stillbirths without explanation, the study included stillbirths with incompletely explained intrauterine demise including the presence of placental lesions and vasculopathy.Channelopathy mutations were identified using a custom panel of 35 genes associated with QT syndromes (short and long), catecholaminergic polymorphic ventricular tachycardia, and sudden death.Potentially damaging nonsynonymous variants were found in ≈60% of stillbirths (41 of 70) including 4 cases that were putatively pathogenic (≈6% of cases) with the remainder of uncertain clinical significance.The putatively pathogenic variants included mutations in KCNE1/KCNE2, SCN5A, and KCNJ2.Using whole-cell patch clamping, the authors show that the identified KCNJ2 variant was associated with a reduction in inward current in vitro.