PurposeThe aim of this study was to determine the diagnostic yield of whole-exome sequencing (WES) in fetuses with ultrasound anomalies that resulted in fetal demise or pregnancy termination. The results were also utilized to aid in the identification of candidate genes for fetal development and to expand the clinical phenotype of known genetic conditions.MethodsWES was performed on specimens from 84 deceased fetuses. Data were analyzed and final results were classified into one of four categories: positive, possible, negative, and candidate gene only. WES analysis was predominantly performed in fetus-parent trios or quads (61%, n=52).ResultsOverall, 20% (n = 17) of cases were positive, 45% (n=38) were possible, 9% (n=7) had only candidate gene variants and 26% (n = 22) tested negative. The diagnostic yield for definitive findings for trio analysis was 24% (n = 11) compared to 14% (n = 4) for singletons. The most frequently reported ultrasound anomalies were central nervous system (37%, n = 31), hydrops/edema (36%, n = 30), and cardiovascular anomalies (31%, n = 26).ConclusionOur experience supports the use of WES to identify the molecular etiology of fetal ultrasound anomalies, to identify candidate genes involved in fetal development, and to expand our knowledge of the clinical phenotype of known genetic conditions.

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Bohring-Opitz syndrome (BOS) is characterized clinically by severe developmental delays, microcephaly, failure to thrive, and characteristic facial features (prominent eyes, facial nevus simplex [flammeus], and others). Most patients meeting the clinical criteria for BOS (MIM: 605039) have a de novo nonsense or frameshift variant in ASXL1. We report a case of BOS caused by a pathogenic ASXL1 variant inherited from a germline mosaic mother. The ASXL1 mutation was detected via trio exome sequencing. The sequencing data demonstrated that the variant was inherited maternally but that the maternal variant was underrepresented in comparison to the normal allele. These results suggested maternal mosaicism for the variant. Additional testing on the mother was performed on buccal cell DNA, which was also consistent with mosaicism. The mother had been reported to be healthy and the family history is unremarkable. This is the first report of BOS caused by a mutation inherited from an unaffected, presumed germline mosaic parent. This phenomenon has been reported for other traditionally de novo dominant disorders like CHARGE syndrome and Cornelia de Lange syndrome. This case emphasizes the need for accurate low but non-negative recurrence risk counseling for families with children with BOS and it impacts exome interpretation strategy.

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