title: Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype-phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges.
  
  
  RESULTS
  We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype-phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants.
  
  
  CONCLUSIONS
  Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context.
authors.affiliation: Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy. Electronic address: i.bottillo@gmail.com.
authors.forename: Irene
authors.initials: I
authors.lastname: Bottillo
authors.affiliation: Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Angelantonio
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Paiardini
authors.affiliation: Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Lipari
authors.affiliation: Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
authors.forename: Carmelilia
authors.initials: C
authors.lastname: De Bernardo
authors.affiliation: Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pizzuti
authors.affiliation: Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Majore
authors.affiliation: Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
authors.affiliation: Cardiomyopathies Unit, Division of Cardiology and Cardiac Arrhythmias, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zachara
authors.affiliation: Cardiomyopathies Unit, Division of Cardiology and Cardiac Arrhythmias, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Re
authors.affiliation: Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
mesh_terms: D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology; D003896:Desmosomes / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D059645:Mutation Rate; D010641:Phenotype; D011110:Polymorphism, Genetic; D012518:Sarcomeres / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins
keywords: Genetic testing; HCM; Hypertrophic cardiomyopathy; NGS; Next generations sequencing; Sarcomere