Irene Bottillo1, Daniela D'Angelantonio2, Viviana Caputo3, Alessandro Paiardini4, Martina Lipari2, Carmelilia De Bernardo2, Diana Giannarelli5, Antonio Pizzuti3, Silvia Majore2, Marco Castori2, Elisabetta Zachara6, Federica Re6, Paola Grammatico2. 1. Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy. Electronic address: i.bottillo@gmail.com. 2. Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy. 3. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. 4. Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy. 5. Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy. 6. Cardiomyopathies Unit, Division of Cardiology and Cardiac Arrhythmias, San Camillo-Forlanini Hospital, Rome, Italy.
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. METHODS AND 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.
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. METHODS AND 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: M Alejandra Restrepo-Cordoba; Oscar Campuzano; Tomás Ripoll-Vera; Marta Cobo-Marcos; Irene Mademont-Soler; José M Gámez; Fernando Dominguez; Esther Gonzalez-Lopez; Laura Padron-Barthe; Enrique Lara-Pezzi; Luis Alonso-Pulpon; Ramon Brugada; Pablo Garcia-Pavia Journal: J Cardiovasc Transl Res Date: 2017-01-30 Impact factor: 4.132
Authors: Matthew A Caporizzo; Christina Yingxian Chen; Ken Bedi; Kenneth B Margulies; Benjamin L Prosser Journal: Circulation Date: 2020-01-16 Impact factor: 29.690
Authors: Megan H Hawley; Naif Almontashiri; Leslie G Biesecker; Natalie Berger; Wendy K Chung; John Garcia; Theresa A Grebe; Melissa A Kelly; Matthew S Lebo; Daniela Macaya; Hui Mei; Julia Platt; Gabi Richard; Ashley Ryan; Kate L Thomson; Matteo Vatta; Roddy Walsh; James S Ware; Matthew Wheeler; Hana Zouk; Heather Mason-Suares; Birgit Funke Journal: Hum Mutat Date: 2020-06-24 Impact factor: 4.700