Clinical and molecular analysis of seventy-one fetal cases with RASopathies

To present the prenatal sonographic features and genetic characteristics of fetuses with RASopathies.

This was a retrospective study of seventy-one cases with RASopathies diagnosed by prenatal features and confirmed by the detection of a (likely) pathogenic variant. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, exome sequencing (ES) results, and pregnancy outcomes.

The median gestational age at which the first abnormal fetal ultrasound findings were detected was 13 weeks (ranges 11-34 weeks). Forty (56.3 %; n = 40/71) exhibited an abnormal first trimester ultrasound, characterized by increased nuchal translucency (NT) (≥3.0 mm) in 28 cases and cystic hygroma (CH) in twelve. For those with increased NT, the median NT value was 5.0 mm (range 3.1-11.4 mm), with 10 (35.7 %; 10/28) presenting with an NT value of ≥ 6 mm. Eighteen (25.4 %; n = 18/71) cases were identified during the second trimester, and 13 (18.3 %; n = 13/71) were recognized during the third trimester. Variants were detected across sixteen genes: BRAF, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, MRAS, NF1, NRAS, PPP1CB, PTPN11, RAF1, RASA1, RIT1, SHOC2, and SOS1. The most significant contributor among these variants was PTPN11 (43.7 %; 31/71), followed by RAF (8.5 %; 6/71).

More than half of the RASopathy cases identified in utero exhibited features during the first trimester, thereby providing an opportunity for early prenatal diagnosis. Utilizing a cutoff of NT ≥ 6 mm would result in missing approximately 45 % (18/40) of RASopathy cases during the first trimester.