SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.
Bottom Line: Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features.Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized.Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth.
Affiliation: IRCCS Casa Sollievo della Sofferenza, Laboratorio Mendel, San Giovanni Rotondo, Italy.Show MeSH
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Mentions: SOS1 mutation-positive subjects displayed typical facial features (Fig. 3). Macrocephaly was, however, overrepresented compared to the general NS population (61 vs. 12%) [Sharland et al., 1992]. Among these subjects, cardiac defects were frequently observed (89% of cases), with PS, ASD. and VSD being the most recurrent anomalies, while prevalence of HCM was comparable to that observed in PTPN11 mutation-associated NS, occurring in less than 10% of cases [Sarkozy et al., 2009b]. Of note, PS was found to be frequently associated with ASD (35% of cases). Finally, two subjects were documented to present with mandibular multiple giant cell lesions (MGCLs), which were associated with multiple tumors, including abdominal rhabdomyosarcoma, cerebral glioma, and skin granular cell tumors in one subject.
Affiliation: IRCCS Casa Sollievo della Sofferenza, Laboratorio Mendel, San Giovanni Rotondo, Italy.