Whole genome sequencing identifies etiology of recurrent male intrauterine fetal death

• Published in: Prenatal diagnosis 2017-10, Vol.37 (10), p.1040-1045
• Main Authors: Shehab, Omar, Tester, David J., Ackerman, Nicholas C., Cowchock, F. Susan, Ackerman, Michael J.
• Format: Article
• Language: English
• Subjects: Children; Death; Deoxyribonucleic acid; Diabetes Mellitus, Type 1 - congenital; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - pathology; Diarrhea - genetics; Diarrhea - pathology; DNA; DNA - analysis; DNA microarrays; DNA sequencing; Edema; Etiology; Female; Females; Fetal Death - etiology; Fetuses; Filtration; Forkhead Transcription Factors - genetics; Foxp3 protein; Frameshift mutation; Frameshift Mutation - genetics; Genes, X-Linked; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - pathology; Genomes; Gestation; Gestational Age; Heredity; Humans; Hydrops fetalis; Hydrops Fetalis - genetics; Immune System Diseases - congenital; Immune System Diseases - genetics; Immune System Diseases - pathology; Immunoregulation; Lymphocytes; Lymphocytes T; Male; Males; Mortality; Mutation; Offspring; Pedigree; Pregnancy; Pregnancy Trimester, Second; Public health; Transcription; Whole Genome Sequencing
• ISSN: 0197-3851; 1097-0223
• DOI: 10.1002/pd.5142

Objective To identify the underlying genetic cause for recurrent intrauterine fetal death (IUFD) of males. Methods Whole 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. Results Following 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. Conclusions Here, 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. What's Already Known About This Topic? Intrauterine fetal death continues to be a major public health problem. It is estimated that 25% of stillbirths are attributed to genetic etiologies. What Does this Study Add? The use of whole genome sequencing to characterize a monogenic cause of recurrent male intrauterine fetal demise after karyotype and microarrays was negative. Discovery of a novel, ultra‐rare FOXP3 frameshift mutation (c.906delT; p.D303fs*87) responsible for recurrent male intrauterine fetal death in a large multigenerational pedigree.