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.

Increased nuchal translucency after low‐risk noninvasive prenatal testing: What should we tell prospective parents?

“…However, among the cases with isolated increased NT or cystic hygroma, the diagnostic yield was 7% (1/15). Not surprisingly, the presence of hydrops, effusions, or other lymphatic system anomalies increased the yield of pathogenic variants up to 24%–34% 42,44 . When combining all the apparently isolated NT ≥3.5 mm from these studies, the weighted average diagnostic yield was 3.7%, including RASopathy conditions (Table 5).…”

“…Since then, larger cohorts of fetuses with isolated and non‐isolated increased NT have been studied with sequencing after normal microarray (Table 5). 42–48 Yang et al. performed trio exome sequencing on 73 fetuses with isolated first trimester increased NT ≥3.5 mm and normal CMA 45 .…”

“…Sparks et al. performed exome sequencing on 127 second trimester fetuses with nonimmune hydrops, defined as the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased NT, or a combination of these conditions 44 . The median gestation at diagnosis was 20 weeks (range 13.4–24.6).…”

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

“…H, Enlarged abdominal circumference with ascites at GA 28 weeks +2 days signaling pathways. 15 All of them were de novo variants, including a RIT1 variant. It indicates that Noonan-associated gene variants are a rather frequent finding in cases with hydrops fetalis.…”

“…A 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 15 . All of them were de novo variants, including a RIT1 variant.…”