Ackerman, Nicholas C.

AbstractObjectiveTo identify the underlying genetic cause for recurrent intrauterine fetal death (IUFD) of males.MethodsWhole genome sequencing was performed on DNA from five healthy obligatory carrier females and an unaffected male offspring of a multigenerational pedigree with recurrent second‐trimester IUFD of males (n = 19). When documented, all deaths occurred at ≤20 weeks of gestation. Hydrops fetalis was diagnosed at death in the most recent case.ResultsFollowing variant filtering based on a recessive X‐linked inheritance pattern, a rare FOXP3 frameshift mutation (p.D303fs*87) that results in a premature truncation of the protein was discovered. Sanger sequencing confirmed the mutation in the affected fetus. The FOXP3 gene encodes for a transcriptional regulator critical to the function of regulatory T cells. FOXP3 mutations are associated with immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome which exclusively affects males and may present with a potentially life‐threatening complex autoimmune disorder in early childhood.ConclusionsHere, we demonstrate the utility of whole genome sequencing‐based pedigree analysis to identify the genetic cause for recurrent IUFD when chromosome studies, including microarray analysis, are normal. Further studies are needed to determine the prevalence of FOXP3‐mediated IUFD in males. © 2017 John Wiley & Sons, Ltd.