Francesca Girolami1, Maria Iascone2, Benedetta Tomberli2, Sara Bardi2, Matteo Benelli2, Giuseppina Marseglia2, Chiara Pescucci2, Laura Pezzoli2, Maria Elena Sana2, Cristina Basso2, Nicola Marziliano2, Piera Angelica Merlini2, Alessandra Fornaro2, Franco Cecchi2, Francesca Torricelli2, Iacopo Olivotto2. 1. From the Genetic Diagnostic Unit, Careggi University Hospital, Florence, Italy (F.G., S.B., M.B., G.M., C.P., F.T.); USSD Laboratorio Genetica Medica, Ospedali Riuniti, Bergamo, Italy (M.I., L.P., M.E.S.); Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padua, Italy (C.B.); Azienda Ospedaliera Ospedale Niguarda Cà Granda, IV Division of Cardiology, Milan, Italy (N.M.); Division of Cardiology, Azienda Ospedaliera Universitaria di Parma, Parma, Italy (N.M.); Referral Center for Myocardial Diseases, Careggi University Hospital, Florence, Italy (B.T., A.F., I.O.); and Department of Clinical and Experimental Medicine (P.A.M.), University of Florence, Florence, Italy (F.C.). girolamif@aou-careggi.toscana.it. 2. From the Genetic Diagnostic Unit, Careggi University Hospital, Florence, Italy (F.G., S.B., M.B., G.M., C.P., F.T.); USSD Laboratorio Genetica Medica, Ospedali Riuniti, Bergamo, Italy (M.I., L.P., M.E.S.); Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padua, Italy (C.B.); Azienda Ospedaliera Ospedale Niguarda Cà Granda, IV Division of Cardiology, Milan, Italy (N.M.); Division of Cardiology, Azienda Ospedaliera Universitaria di Parma, Parma, Italy (N.M.); Referral Center for Myocardial Diseases, Careggi University Hospital, Florence, Italy (B.T., A.F., I.O.); and Department of Clinical and Experimental Medicine (P.A.M.), University of Florence, Florence, Italy (F.C.).
Abstract
BACKGROUND: Next-generation sequencing might be particularly advantageous in genetically heterogeneous conditions, such as hypertrophic cardiomyopathy (HCM), in which a considerable proportion of patients remain undiagnosed after Sanger. In this study, we present an Italian family with atypical HCM in which a novel disease-causing variant in α-actinin 2 (ACTN2) was identified by next-generation sequencing. METHODS AND RESULTS: A large family spanning 4 generations was examined, exhibiting an autosomal dominant cardiomyopathic trait comprising a variable spectrum of (1) midapical HCM with restrictive evolution with marked biatrial dilatation, (2) early-onset atrial fibrillation and atrioventricular block, and (3) left ventricular noncompaction. In the proband, 48 disease genes for HCM, selected on the basis of published reports, were analyzed by targeted resequencing with a customized enrichment system. After bioinformatics analysis, 4 likely pathogenic variants were identified: TTN c.21977G>A (p.Arg7326Gln); TTN c.8749A>C (p.Thr2917Pro); ACTN2 c.683T>C (p.Met228Thr); and OBSCN c.13475T>G (p.Leu4492Arg). The novel variant ACTN2 c.683T>C (p.Met228Thr), located in the actin-binding domain, proved to be the only mutation fully cosegregating with the cardiomyopathic trait in 18 additional family members (of whom 11 clinically affected). ACTN2 c.683T>C (p.Met228Thr) was absent in 570 alleles of healthy controls and in 1000 Genomes Project and was labeled as Damaging by in silico analysis using polymorphism phenotyping v2, as Deleterious by sorts intolerant from tolerant, and as Disease-Causing by Mutation Taster. CONCLUSIONS: A targeted next-generation sequencing approach allowed the identification of a novel ACTN2 variant associated with midapical HCM and juvenile onset of atrial fibrillation, emphasizing the potential of such approach in HCM diagnostic screening.
BACKGROUND: Next-generation sequencing might be particularly advantageous in genetically heterogeneous conditions, such as hypertrophic cardiomyopathy (HCM), in which a considerable proportion of patients remain undiagnosed after Sanger. In this study, we present an Italian family with atypical HCM in which a novel disease-causing variant in α-actinin 2 (ACTN2) was identified by next-generation sequencing. METHODS AND RESULTS: A large family spanning 4 generations was examined, exhibiting an autosomal dominant cardiomyopathic trait comprising a variable spectrum of (1) midapical HCM with restrictive evolution with marked biatrial dilatation, (2) early-onset atrial fibrillation and atrioventricular block, and (3) left ventricular noncompaction. In the proband, 48 disease genes for HCM, selected on the basis of published reports, were analyzed by targeted resequencing with a customized enrichment system. After bioinformatics analysis, 4 likely pathogenic variants were identified: TTN c.21977G>A (p.Arg7326Gln); TTN c.8749A>C (p.Thr2917Pro); ACTN2 c.683T>C (p.Met228Thr); and OBSCN c.13475T>G (p.Leu4492Arg). The novel variant ACTN2 c.683T>C (p.Met228Thr), located in the actin-binding domain, proved to be the only mutation fully cosegregating with the cardiomyopathic trait in 18 additional family members (of whom 11 clinically affected). ACTN2 c.683T>C (p.Met228Thr) was absent in 570 alleles of healthy controls and in 1000 Genomes Project and was labeled as Damaging by in silico analysis using polymorphism phenotyping v2, as Deleterious by sorts intolerant from tolerant, and as Disease-Causing by Mutation Taster. CONCLUSIONS: A targeted next-generation sequencing approach allowed the identification of a novel ACTN2 variant associated with midapical HCM and juvenile onset of atrial fibrillation, emphasizing the potential of such approach in HCM diagnostic screening.
Authors: Malene E Lindholm; David Jimenez-Morales; Han Zhu; Kinya Seo; David Amar; Chunli Zhao; Archana Raja; Roshni Madhvani; Sarah Abramowitz; Cedric Espenel; Shirley Sutton; Colleen Caleshu; Gerald J Berry; Kara S Motonaga; Kyla Dunn; Julia Platt; Euan A Ashley; Matthew T Wheeler Journal: Circ Genom Precis Med Date: 2021-11-22
Authors: Xavière Lornage; Norma B Romero; Claire A Grosgogeat; Edoardo Malfatti; Sandra Donkervoort; Michael M Marchetti; Sarah B Neuhaus; A Reghan Foley; Clémence Labasse; Raphaël Schneider; Robert Y Carlier; Katherine R Chao; Livija Medne; Jean-François Deleuze; David Orlikowski; Carsten G Bönnemann; Vandana A Gupta; Michel Fardeau; Johann Böhm; Jocelyn Laporte Journal: Acta Neuropathol Date: 2019-01-30 Impact factor: 17.088