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

Abstract

RASopathies are a group of syndromes with partially overlapping clinical features caused by germline mutations of the RAS/MAPK signaling pathway genes. The most common disorder is Noonan syndrome (NS; MIM 163950). We report the first prenatal case of NS with SOS2 (NM_006939.4) mutation in a euploid fetus with a severe increase in nuchal translucency (NT > 12 mm). Trio‐based custom next‐generation sequencing detected a de novo heterozygous missense mutation in the SOS2 gene: c.800 T > A (p.Met267Lys). Owing to the marked variable expressivity of NS and the scarcity of SOS2 mutation‐related NS cases reported in the literature, it is difficult to provide appropriate genetic counseling. Several issues such as the best management technique and optimal NT cutoff have been discussed. In addition, in general, the fine balance between the advantages of an early prenatal diagnosis and the challenge of determining if the detected gene variant is pathogenic and, primarily, the stress of the counselees when providing a genetic counseling with limited information on the prenatal phenotype have been discussed. A prenatal path comprising examinations and multidisciplinary counseling is essential to support couples in a shared decision‐making process.

SOS2 Comes to the Fore: Differential Functionalities in Physiology and Pathology

“…SOS1 is the second most frequently mutated gene in this syndrome (~16.5% of cases; up to 70 different mutations described [ 5 , 63 ]). Whereas early screenings reported only SOS1 mutations [ 62 , 63 ], more recent studies have identified a number of SOS2 mutations, including missense activating mutations in seven specific residues located in the SOS2 DH domain (T264K, T264R, E266_M267delins, M267K, M267R, M267T and T376S; Figure 1 C) that have thus defined the SOS2-specific NS9 subtype of this syndrome (OMIM #616559) [ 5 , 40 ]. In general, the clinical findings of NS patients harboring SOS2 mutations are similar to those with SOS1-mutated genes, although some SOS2-realted variants appear as rare cases of NS with particular predisposition for lymphatic complications [ 39 ].…”

“…A recent phenotype–genotype correlation study has revealed the association between mutant variations of SOS2 in NS patients with lower diastolic and systolic blood pressures, and lower percent of body fat [ 64 ]. The first prenatal case of NS with SOS2 mutations was reported in a euploid fetus with a severe increase in nuchal translucency and other relevant anomalies noticeable at ultrasound study, as well as markers of aneuploidies, caused by a de novo heterozygous missense mutation in SOS2 gene (c.800 T > A; p.M267K) [ 40 ].…”

“…In this regard, a significant number of gain-of-function SOS1 mutations (and, more rarely, SOS2 mutations), resulting in subsequent hyperactivation of RAS signaling, have been identified in inherited RASopathies, such as Noonan syndrome (NS) or hereditary gingival fibromatosis, as well as in various sporadic human cancers, including endometrial tumors and lung adenocarcinoma, among others [ 5 ]. However, during the last few years, a previously undetected but relevant involvement of SOS2 in some of these pathologies is also coming to light in a series of studies describing specific SOS2 gene alterations that have been identified in several forms of cancers and RASopathies, as well as the potential therapeutic effect of explicit SOS2 removal in certain tumor cell lines [ 36 , 37 , 38 , 39 , 40 ]. All in all, these observations and the above-described timeline of experimental evidence support the notion that, besides SOS1, SOS2 may also constitute a worthy therapy target for prevention and/or treatment of some specific tumor and nontumor pathologies with epidermal origin or dysregulated PI3K/AKT signal transmission [ 25 ].…”