title: The rare Costello variant HRAS c.173C>T (p.T58I) with severe neonatal hypertrophic cardiomyopathy.
abstract: We report a 10-year-old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide-selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.5 (Dassault Systèmes Biovia, San Diego, CA). The patient with hypertrophic cardiomyopathy and normal cognitive development was diagnosed with an HRAS mutation c.173C>T (p.T58I), a milder variant of Costello syndrome affecting a highly conserved amino acid, threonine 58. Our analysis suggests that the p.G12 mutations slow GTP hydrolysis rendering HRAS unresponsive to GTPase activating proteins, and resulting in permanently active state. The p.T58I mutation likely affects binding of guanidine-nucleotide-exchange factors, thereby promoting the active state but also allowing for slow inactivation. Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome. We expand the clinical and molecular picture of the rare HRAS mutation by reporting the first case in Europe and the fourth case in the literature. Our protein structure analysis offers insights into the mechanism of the mildly activating p.T58I mutation. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatric Cardiology, Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Anita
authors.initials: A
authors.lastname: Hiippala
authors.affiliation: Research Program Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Catalina
authors.initials: C
authors.lastname: Vasilescu
authors.affiliation: Blueprint Genetics, Helsinki, Finland.
authors.forename: Jonna
authors.initials: J
authors.lastname: Tallila
authors.affiliation: Blueprint Genetics, Helsinki, Finland.|Pediatric Research Laboratory, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
authors.affiliation: Department of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.affiliation: Research Program Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Tyni
authors.affiliation: Research Program Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.affiliation: Research Program Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Liliya
authors.initials: L
authors.lastname: Euro
authors.affiliation: Department of Pediatric Cardiology, Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Ojala
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D000483:Alleles; D015415:Biomarkers; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000235:genetics*; D056685:Costello Syndrome / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004452:Echocardiography; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013902:Radiography, Thoracic; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Costello; HRAS; cardiomyopathy; p.T58I