title: A Novel HRAS Mutation Independently Contributes to Left Ventricular Hypertrophy in a Family with a Known MYH7 Mutation.
abstract: Several genetic conditions can lead to left ventricular hypertrophy (LVH). Among them, hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomere genes, is the most common inherited cardiac disease. Instead, RASopathies, a rare class of disorders characterized by neuro-cardio-facial-cutaneous abnormalities and sometimes presenting with LVH, are caused by mutations in the RAS-MAPK pathway. We report on a 62-years-old male who presented isolated severe obstructive LVH but did not carry the sarcomere mutation previously identified in his affected relatives. By exome sequencing, we detected a novel mutation in HRAS gene (NM_005343.2:p.Arg68Trp), present also in the proband's daughter, who showed mild LVH and severe intellectual disability. The cardiac phenotype was indistinguishable between family members carrying either mutation. In silico studies suggested that the mutated HRAS protein is constitutionally activated. Consistently, functional characterization in vitro confirmed elevated HRAS-GTP accumulation and downstream RAS-MAPK pathway activation that are known to drive cell proliferation in LVH. Our study emphasizes the role of RAS signaling in cardiac hypertrophy and highlights the complexity in differential diagnosis of RASopathies. In fact, the mild features of RASopathy and the recurrence of sarcomeric HCM in this family delayed the correct diagnosis until comprehensive genetic testing was performed.
authors.affiliation: USSD Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.|FROM Research Foundation, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Sana
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, Indiana, United States of America.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Quilliam
authors.affiliation: CONCEPT Lab, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Spitaleri
authors.affiliation: USSD Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pezzoli
authors.affiliation: USSD Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Marchetti
authors.affiliation: USSD Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Lodrini
authors.affiliation: USC di Anatomia Patologica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Candiago
authors.affiliation: USSD Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Lincesso
authors.affiliation: Centro per la Cardiomiopatia Ipertrofica e le Cardiopatie Valvolari, Policlinico di Monza, Monza, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferrazzi
authors.affiliation: USSD Laboratorio di Genetica Medica, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Iascone
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D024722:Cardiac Myosins / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C501641:MYH7 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains; D018631:ras Proteins