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Identification of a novel de novo deletion in RAF1 associated with biventricular hypertrophy in Noonan syndrome
Author(s) -
Sana Maria Elena,
Spitaleri Andrea,
Spiliotopoulos Dimitrios,
Pezzoli Laura,
Preda Laura,
Musco Giovanna,
Ferrazzi Paolo,
Iascone Maria
Publication year - 2014
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36588
Subject(s) - noonan syndrome , exome sequencing , pathogenesis , ventricle , differential diagnosis , exome , gene , muscle hypertrophy , biology , mutation , genetics , computational biology , medicine , pathology
Biventricular hypertrophy (BVH) is a disease state characterized by the thickening of the ventricle walls. The differential diagnosis of BVH with other congenital and familial diseases in which increased ventricle wall thickness is a prominent clinical feature is fundamental due to its therapeutic and prognostic value, mainly during infancy. We describe a 2‐month‐old infant presenting BVH. Using exome sequencing, we identified a novel de novo 3‐bp deletion in the RAF1 gene that is located in the binding active site for the 14‐3‐3 peptide. Based on docking calculations, we demonstrate that this novel mutation impairs protein/target binding, thus constitutively activating Ras signaling, which is a dysregulation associated with Noonan syndrome. Finally, our study underlines the importance of molecular modeling to understand the roles of novel mutations in pathogenesis. © 2014 Wiley Periodicals, Inc.