Abstract 18770: Elucidation of MRAS-Mediated Noonan Syndrome With Cardiac Hypertrophy
Introduction: Noonan syndrome (NS) is an autosomal dominant disorder with a characteristic clinical phenotype of facial dysmorphisms, short stature, and congenital heart defects. NS is a member of a family of developmental disorders termed “Rasopathies”, caused mainly by gain-of-function mutations in genes encoding RAS-mitogen-activated protein kinase (MAPK) signaling pathway proteins.
Methods: Whole exome sequencing (WES) and trio-based genomic triangulation was performed on a 15-year old, female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents. Sequencing data was analyzed using Golden Helix VarSeq software with appropriate filters to identify rare, de novo variants or those inherited in a compound heterozygous or homozygous recessive manner. Homology-based modeling and molecular dynamic simulations (MDS) were performed for wildtype (WT) MRAS and the G23V-MRAS variant. Comparative analyses measured changes in bonding patterns, root-mean-square deviation (RMSD), and root-mean-square fluctuation (RMSF). A subsequent cohort analysis was performed and 110 phenotype-positive, genotype-negative NS patients were sequenced for additional NS-associated mutations in MRAS.
Results: Following analysis and filtering, WES identified 176 candidate variants in 67 genes, and subsequent gene ranking identified MRAS (G23V) as the most likely novel NS-susceptibility gene. MRAS-encoded RAS-related protein 3 (MRAS) interacts directly with the MAPK pathway via SHOC2 and PP1. Molecular modeling, in silico mutagenesis, and MDS indicate that G23V-MRAS impacts effector interaction regions and the GTP binding site, supporting the notion that G23V-MRAS is an activated form of MRAS, akin to the established activating mutations at G13 in MRAS’ paralogue HRAS. Subsequent cohort analysis identified an additional rare, de novo T68I-MRAS missense mutation in a female NS patient.
Conclusions: Herein, with the discovery of a two de novo variants (G23V and T68I) identified by WES or direct DNA sequencing, we have established MRAS as the newest NS-susceptibility gene. MRAS plays a crucial role in the NS-associated Ras/MAPK pathway and interacts directly with several previously identified NS-associated proteins.
Author Disclosures: E.M. Higgins: None. J.M. Bos: None. J.P. Ackerman: None. H. Mason-Suares: None. C.A. MacRae: None. K. Sol-Church: None. K.W. Gripp: None. R.A. Urrutia: None. M.J. Ackerman: Consultant/Advisory Board; Modest; Boston Scientific, Gilead Sciences, Medtronic, St. Jude Medical.
- © 2016 by American Heart Association, Inc.