Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

Abstract

BACKGROUNDThe cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear. METHODSWe evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited. RESULTSIn 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases. CONCLUSIONSIn this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases.

Value of Exome Sequencing in Diagnosis and Management of Recurrent Non-immune Hydrops Fetalis: A Retrospective Analysis

“…A higher diagnostic rate (36%) was noticed in our study compared with other studies (Moreno et al, 2013;Sheth et al, 2017;Sudrie-Arnaud et al, 2018;Lord et al, 2019;Sparks et al, 2019Sparks et al, , 2020. One reason was that recurrent fetal hydrops in the study represented a highly selected study group, which indicated that a higher incidence of single-gene disorders and non-genetic reasons contributing to NIHF has been ruled out as much as possible in the study following systematic work-up for NIHF.…”

“…One was autosomal dominant. Those major causes of fetal hydrops such as RASopathies, which composed the largest proportion in the recent publication (Sparks et al, 2020), are likely to be de novo and therefore would not have been identified in our recurrent cohort, which might skew results toward the autosome recessive inherited disorders. The results also indicated that inborn errors of metabolism accounted for 50% of the singlegene disorders for NIHF detected by ES, and they all confirmed to diagnosed with lysosomal storage disorders (LSD).…”

“…For example, lysosomal storage disorders (LSDs) have been reported to contribute to approximately 1% of non-immune hydrops cases by specific enzymatic analyses according to previous studies from 1979 to 2013 (Burin et al, 2004;Bellini et al, 2015). With exome sequencing (ES) widely used in recent years, more rare genetic diseases related to NIHF, such as generalized lymphatic dysplasia, Cornelia de Lange syndrome, Kabuki syndrome, and RASopathies, can also be identified with diagnostic yield of 9% and 29% for NIHF with normal karyotyping and CMA given the results from the PAGE study and the recent publication (Fotiou et al, 2015;Datkhaeva et al, 2018;Lord et al, 2019;Sparks et al, 2020). However, the PAGE study was not designed specific for NIHF cases, and the population studied in the recent publication was of different racial or ethnic backgrounds.…”

First prenatal case of Noonan syndrome with SOS2 mutation: Implications of early diagnosis for genetic counseling

“…Considering previous findings (Croonen et al, 2013; Leach et al, 2019; Sinajon et al, 2020; Stuurman et al, 2019), in euploid fetuses, targeted NGS RD testing should be proposed in all pregnancies with severely increased NT (> 5 mm) or NT ≥3.5 mm (99th centile) associated with other signs. RASopathies were also the most common genetic diseases (30% of the genetic diagnosis) among fetuses with unexplained nonimmune hydrops fetalis (Sparks et al, 2020).…”

Prenatal cases with rare RIT1 variants causing severe fetal hydrops and death

“…A very recently published study, learning the genetic causes of non-immune hydrops fetalis, showed that 29% of the cases were solely due to gene variants in MAPK-dependent signaling pathways [14]. All of them were de novo variants, including a RIT1 variant.…”