Journal Article

Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications

Chune Valérie, Kuechler Alma, Tartaglia, Marco, Radio Francesca Clementina, Legendre Marine, Marion, Gérard, Capri Yline, Kutsche Kerstin, Andreucci, Elena, Brinkmann, Julia, Leenders, Erika, Lepri Francesca, Daniele, Paola, Cave Hélène, Scarano Emanuela, Mastromoro Gioia, De, Luca Alessandro, Lissewski Christina, Mazzanti, Laura, Rinne Tuula, Digilio, Maria Cristina, Ranguin Kara, Pantaleoni Francesca, Vial Yoann, van der Burgt Ineke, Zenker, Martin

2021

Overview

RASopathies are caused by variants in genes encoding components or modulators of the RAS/MAPK signaling pathway. Noonan syndrome is the most common entity among this group of disorders and is characterized by heart defects, short stature, variable developmental delay, and typical facial features. Heterozygous variants in SOS2, encoding a guanine nucleotide exchange factor for RAS, have recently been identified in patients with Noonan syndrome. The number of published cases with SOS2-related Noonan syndrome is still limited and little is known about genotype–phenotype correlations. We collected previously unpublished clinical and genotype data from 17 individuals carrying a disease-causing SOS2 variant. Most individuals had one of the previously reported dominant pathogenic variants; only four had novel changes at the established hotspots for variants that affect protein function. The overall phenotype of the 17 patients fits well into the spectrum of Noonan syndrome and is most similar to the phenotype observed in patients with SOS1-related Noonan syndrome, with ectodermal anomalies as common features and short stature and learning disabilities as relatively infrequent findings compared to the average Noonan syndrome phenotype. The spectrum of heart defects in SOS2-related Noonan syndrome was consistent with the known spectrum of cardiac anomalies in RASopathies, but no specific heart defect was particularly predominating. Notably, lymphatic anomalies were extraordinarily frequent, affecting more than half of the patients. We therefore conclude that SOS2-related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.

• Publisher: Nature Publishing Group
• Subject: Genotype & phenotype / Genotypes / Guanine / Guanine nucleotide exchange factor / Heart / MAP kinase / Morbidity / Noonan's syndrome / Phenotypes / Quality of life / Ras protein / Signal transduction