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Telethon-Italy ERA-Net for research programs on rare diseases 2009 (European network on Noonan Syndrome and related disorders) Associazione Italiana Sindromi di Costello e Cardiofaciocutanea NIH Italian Ministry of Health Italian Ministry of Education, University and Research 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. Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy IRCCS Casa Sollievo Sofferenza, Lab Mendel, San Giovanni Rotondo, Italy Univ Roma Tor Vergata, Dipartimento Sci & Tecnol Chim, Rome, Italy St Orsola Marcello Malpighi Hosp, UO Genet Med, Bologna, Italy Univ Turin, Dipartimento Pediat, Turin, Italy GeneDx, Gaithersburg, MD USA Universidade Federal de São Paulo, São Paulo, Brazil Univ Bari, Dept Biomed Dev Age, Bari, Italy Osped Pediat, Brescia, Italy Osped Bolzano, Serv Aziendale Consulenza Genet, Bolzano, Italy Ospedali Galliera, SC Genet Umana, Genoa, Italy Univ Politecn Marche, Ist Sci Materno Infantili, Ancona, Italy Univ Roma La Sapienza, Dept Pediat, Div Pediat Cardiol, Rome, Italy Univ Cattolica Sacro Cuore, Ist Genet Med, Rome, Italy Univ Milano Bicocca, AOS Gerardo Fdn MBBM, Pediat Clin, Monza, Italy Univ Bologna, Dipartimento Pediat, Bologna, Italy IRCCS, Osped Pediat Bambino Gesu, Rome, Italy Univ Cattolica Sacro Cuore, Ist Clin Pediat, Rome, Italy Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA Universidade Federal de São Paulo, EPM, São Paulo, Brazil Telethon-Italy: GGP07115 Telethon-Italy: GGP10020 NIH: HL71207 Italian Ministry of Health: RC2009 Italian Ministry of Health: RC2010 Italian Ministry of Education, University and Research: FIRB RBIP06PMF2_005 Web of Science