Abstract
Noonan syndrome (NS) is a very rare heterogenous genetic disorder often characterized by short stature, facial dysmorphisms, congenital heart defects and learning disabilities in affected children. In the current study, we sought to discover the disease causal mutations, inherited or de novo, for Noonan Syndrome among Arab patients. We screened the coding regions and splice sites of 10 known RAS/MAP Kinase pathway genes in 17 NS-trios and 100 random healthy volunteers by oilgonucleotide chip testing and Sanger sequencing methods. We found pathogenic heteroallelic de novo mutations in BRAF or PTPN11 gene in 7/17 (41.17%) of NS patients. None of the 200 chromosomes of healthy volunteers had those pathogenic mutations. Genotype-phenotype analysis showed positive correlation between BRAF and PTPN11 gene mutations and classical NS clinical manifestations. Characteristic facies is the major observed clinical manifestation among PTPN11-mutation positive cases (c.236A > G, c.854T > C, c.923A > G), whereas both characteristic facies and ectodermal manifestations are seen as dominant clinical features among BRAF-mutation positive cases (c.730A > C, c.770A > G, c.1406G > A). In addition to genotyping and clinical phenotyping, we performed computational structural analysis to examine the impact of amino acid substitution mutations on the conformation and folding of BRAF and PTPN11 proteins. Our results suggested that BRAF (c.730A > C, c.770A > G, c.1406G > A) and PTPN11 (c.236A > G, c.854T > C, c.923A > G) gene mutations elicits structural and functional alterations at protein level, which would eventually lead to dysregulation of RAS-MAPK signaling cascade, which plays critical a role in cell cycle and senescence. In conclusion, our study suggest that molecular screening of BRAF and PTPN11 genetic mutations in Arab NS patients may assist in deriving competitive outcomes related to clinical phenotyping and disease diagnosis.