EP18.30: Enlarged yolk sac as a potential new phenotype of RAF1 Noonan syndrome

A yolk sac (YS) of >6mm is generally accepted as abnormal. It has long been associated with adverse pregnancy outcome, and historically, with aneuploidies, which can be found in most cases with enlarged YS. Here, we report an enlarged YS with an unexpected finding after whole exome sequencing (WES). A 33yo patient presented in 9 weeks of gestation of her second pregnancy. At a CRL of 17.8mm a yolk sac of 9mm was found. In the first trimester test NT was 1mm with a low risk for trisomy 21 and a combined T13/18 risk of 1:2. In CVS-material, a FISH for common trisomies and molecular karyotyping were both normal. A trio WES was initiated and revealed a maternally inherited variant of uncertain significance in the RAF1 gene (c.1450A>G p.(lle484Val)) in heterozygous state, leading to Noonan syndrome (NS). It was later also detected in the patient's father. Neither the father nor the patient showed clinical signs of NS. At 24 weeks of gestation, a detailed ultrasound scan was performed without further abnormalities detected. The course of the pregnancy was uneventful. The patient delivered at term per planned Caesarean, the child is healthy without visible or echocardiographic anomalies. NS is a clinically and genetically heterogeneous disorder. Several genes are currently being associated with NS: PTPN11 in half of cases, but also RAF1, LZTR1 or NRAS. The clinical appearance varies, depending on the gene involved and there is a high variability in expression. Characteristics can include short stature, characteristic facies, pectus, intellectual disability, cardiomyopathy and cardiac defects, bleeding diathesis and other. YS anomalies have been demonstrated in LZTR1-knock-out mice and NRAS-mutant zebra fish, but not yet in humans. The case shows that there might be more to YSA than aneuploidies. While earlier research showed chromosomal abnormalities in over 90% of cases of enlarged YS and an increased risk of pregnancy loss, there might be a subgroup of different etiology.