Whole exome sequencing in 78 Noonan syndrome individuals identifies two new candidate genes. G. L. Yamamoto1,2, R. Atique2, M. Aguena2, L. Testai1, M. Buscarilli1, A. Jorge3, A. C. Pereira4, A. Malaquias3, C. A. Kim1, M. R. Passos-Bueno2, D. R. Bertola1,2 1) Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil; 2) Instituto de Biociências, Universidade de São Paulo, São Paulo/SP, Brazil; 3) Endocrinologia, LIM/25, Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil; 4) Instituto do Coração, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil.

   Noonan syndrome is an autosomal dominant disorder characterized by facial dysmorphisms, short stature and cardiac abnormalities along with deregulation of the RAS/MAPK pathway. It exhibits great genetic heterogeneity, caused by heterozygous mutations in PTPN11, KRAS, SOS1, RAF1, SHOC2, NRAS, CBL and RIT1, observed in approximately 75% of the patients. We have studied 70 Noonan syndrome probands by WES that were tested negative for the most common mutations in PTPN11, SOS1, RAF1, KRAS and SHOC2, as well as nine relatives from five families. Segregation of the mutations in candidate genes with the phenotype was further investigated by Sanger sequencing in 10 more relatives. We have identified probable pathogenic mutations in two genes never before associated with Noonan syndrome in 6 probands. Mutations in gene A are segregating with the disease in two families and occurred de novo in one sporadic case. Mutations in gene B are segregating with the disease in one family, occurred de novo in one sporadic patient, and in another sporadic individual segregation status is under analysis. Gene A is not directly associated to the RAS pathway in the literature but it has been previously associated with a tumoral disease, while gene B is known to be directly associated to the RAS pathway involved with Noonan syndrome. We believe that these two new genes could be responsible for the disease in a small fraction of the molecularly undiagnosed individuals with Noonan syndrome and functional studies are underway to further confirm the pathogenicity of the mutations. FAPESP 2011/17299-3; CNPq.

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