Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings

Abstract

In recent studies on prenatal testing for Noonan syndrome (NS) in fetuses with an increased nuchal translucency (NT) and a normal karyotype, mutations have been reported in 9-16% of cases. In this study, DNA of 75 fetuses with a normal karyotype and abnormal ultrasound findings was tested in a diagnostic setting for mutations in (a subset of) the four most commonly mutated NS genes. A de novo mutation in either PTPN11, KRAS or RAF1 was detected in 13 fetuses (17.3%). Ultrasound findings were increased NT, distended jugular lymphatic sacs (JLS), hydrothorax, renal anomalies, polyhydramnios, cystic hygroma, cardiac anomalies, hydrops fetalis and ascites. A second group, consisting of anonymized DNA of 60 other fetuses with sonographic abnormalities, was tested for mutations in 10 NS genes. In this group, five possible pathogenic mutations have been identified (in PTPN11 (n ¼ 2), RAF1, BRAF and MAP2K1 (each n ¼ 1)). We recommend prenatal testing of PTPN11, KRAS and RAF1 in pregnancies with an increased NT and at least one of the following additional features: polyhydramnios, hydrops fetalis, renal anomalies, distended JLS, hydrothorax, cardiac anomalies, cystic hygroma and ascites. If possible, mutation analysis of BRAF and MAP2K1 should be considered.

Genetic tests in lymphatic vascular malformations and lymphedema

“…For example, mutations in KRAS  (OMIM: 190070) were identified in a patient with hydrops fetalis, chylous reflux and intestinal lymphangiectasia, and in another patient with chylous reflux 45. Another paper reports a patient with chylothorax, lymphedema and cystic hygroma;46 another case with severe hydrops,47 and a patient with cystic hygroma 48. Mutations in SOS1 (OMIM: 182530)have been found in 63% of patients with Noonan syndrome and lymphedema 44.…”

Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation

“…These entities, collectively named "RASopathies", share many clinical features, including facial dysmorphisms, a wide spectrum of congenital heart defects, postnatal growth failure, variable degrees of neurocognitive impairment, skeletal and ectodermal anomalies, and increased tumor risk . Prenatal findings include increased nuchal translucency, polyhydramnios, hydrothorax, cystic hygroma, and multiple effusions [Baldassarre et al, 2011;Baldassarre et al, 2013;Croonen et al, 2013]. Despite this clinical overlap, each RASopathy usually exhibits distinctive features, helping in the intricate differential diagnosis Zenker, 2011].…”

Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome

“…2,13,14,17 Supporting this, a prior report described a pregnancy with a severe presentation including a 11-mm nuchal translucency, cystic hygroma, fetal hydrops, hydrothorax, and generalized skin edema with a de novo germline variant, c.227A4T (p.(Glu76Val)), typically seen in isolated JMML. 4 Similarly, another variant, c.1520C4A (p.(Thr507Lys)), seen exclusively in other leukemias, although not JMML, was identified in two fetuses with hydrops fetalis. 2,21 Our study lends further support to this hypothesis, given JMML variants were observed in cases 1 and 2, which both presented with severe prenatal abnormalities.…”

“…There are rare observations of Noonan-associated PTPN11 variants identified in isolated JMML, and a few reported cases of germline inheritance of JMML variants. 4,[14][15][16] These data have led to the suggestion that the strong gain-of-function variants observed in isolated JMML would be embryonic lethal if inherited as a germline variant. 2,13,14,17 Here, we present a case series supporting this model.…”

“…Pathogenic variants in RAS-MAPK pathway genes have been identified in 9-17.3% of diploid fetuses with these ultrasound findings. [2][3][4] Although germline variants in the RAS-MAPK pathway genes are associated with RASopathies, somatic variants in PTPN11, NRAS, KRAS, and CBL are initiating drivers for isolated juvenile myelomonocytic leukemia (JMML). JMML is an aggressive myeloproliferative neoplasm of early childhood that is commonly lethal without a hematopoietic stem cell transplant.…”