SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations

Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. 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. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies. Hum Mutat 32:760-772, 2011. (C) 2011 Wiley-Liss, Inc.Telethon-ItalyERA-Net for research programs on rare diseases 2009 (European network on Noonan Syndrome and related disorders)Associazione Italiana Sindromi di Costello e CardiofaciocutaneaNIHItalian Ministry of HealthItalian Ministry of Education, University and ResearchIst Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, ItalyIRCCS Casa Sollievo Sofferenza, Lab Mendel, San Giovanni Rotondo, ItalyUniv Roma Tor Vergata, Dipartimento Sci & Tecnol Chim, Rome, ItalySt Orsola Marcello Malpighi Hosp, UO Genet Med, Bologna, ItalyUniv Turin, Dipartimento Pediat, Turin, ItalyGeneDx, Gaithersburg, MD USAUniversidade Federal de São Paulo, São Paulo, BrazilUniv Bari, Dept Biomed Dev Age, Bari, ItalyOsped Pediat, Brescia, ItalyOsped Bolzano, Serv Aziendale Consulenza Genet, Bolzano, ItalyOspedali Galliera, SC Genet Umana, Genoa, ItalyUniv Politecn Marche, Ist Sci Materno Infantili, Ancona, ItalyUniv Roma La Sapienza, Dept Pediat, Div Pediat Cardiol, Rome, ItalyUniv Cattolica Sacro Cuore, Ist Genet Med, Rome, ItalyUniv Milano Bicocca, AOS Gerardo Fdn MBBM, Pediat Clin, Monza, ItalyUniv Bologna, Dipartimento Pediat, Bologna, ItalyIRCCS, Osped Pediat Bambino Gesu, Rome, ItalyUniv Cattolica Sacro Cuore, Ist Clin Pediat, Rome, ItalyMt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USAUniversidade Federal de São Paulo, São Paulo, BrazilTelethon-Italy: GGP07115Telethon-Italy: GGP10020NIH: HL71207Italian Ministry of Health: RC2009Italian Ministry of Health: RC2010Italian Ministry of Education, University and Research: FIRB RBIP06PMF2_005Web of Scienc