Inherited Genetic Risk in Stillbirth: A Shared Genomic Segments Analysis of High-Risk Pedigrees.

Background Stillbirth is a devastating adverse pregnancy outcome affecting 2 million pregnancies worldwide every year. Though an etiology may be found in some, one-third of stillbirth cases remain unexplained. Stillbirth clusters in families and, apart from infrequent aneuploidies and balanced translocations, few underlying inherited genes associated with stillbirth are known. Well-characterized family-based studies may aid in identifying genetic contributors to unexplained stillbirth. Methods Using the Utah Population Database, we defined pedigrees with high familial risk of stillbirth. Comprehensive phenotyping with review of primary medical records was conducted to identify stillbirth cases without identifiable causes. We generated whole-genome sequencing in seven stillborn placentas from three pedigrees, referred to hereafter as Pedigree A, Pedigree B, and Pedigree C. We performed shared genomic segments analysis to identify evidence for segregating haplotypes shared by the stillbirths to provide evidence for inherited risk. Results A region at 15q26.3 was identified in two independent pedigrees with genome-wide significance in both (a 1.2 Mb segment shared by two stillbirths in Pedigree A, and a 1.8 Mb segment shared by two stillbirths in pedigree B). Four other regions reached genome-wide significance in single pedigrees at 16p13.13-p13.12, 9p13.3-p13.1, and 6p22.2-p22.1 (shared by the same two stillbirths in Pedigree B), and 0.8 Mb segment at 14q.32.2 shared by three stillbirths in Pedigree C. The identified regions are implicated in in utero and postnatal development, pregnancy loss, and infertility. Conclusions We identified evidence for inherited risk loci in stillbirth placental genes are implicated in in utero and postnatal development, pregnancy loss, and infertility. Identification of inherited genes in stillbirth risk may provide novel therapeutic targets for prevention and treatment to improve pregnancy outcomes.