title: Novel α-actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study.
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.
  
  
  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.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Girolami
authors.affiliation: 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.).
authors.forename: Maria
authors.initials: M
authors.lastname: Iascone
authors.affiliation: 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.).
authors.forename: Benedetta
authors.initials: B
authors.lastname: Tomberli
authors.affiliation: 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.).
authors.forename: Sara
authors.initials: S
authors.lastname: Bardi
authors.affiliation: 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.).
authors.forename: Matteo
authors.initials: M
authors.lastname: Benelli
authors.affiliation: 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.).
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Marseglia
authors.affiliation: 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.).
authors.forename: Chiara
authors.initials: C
authors.lastname: Pescucci
authors.affiliation: 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.).
authors.forename: Laura
authors.initials: L
authors.lastname: Pezzoli
authors.affiliation: 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.).
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Sana
authors.affiliation: 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.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Basso
authors.affiliation: 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.).
authors.forename: Nicola
authors.initials: N
authors.lastname: Marziliano
authors.affiliation: 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.).
authors.forename: Piera Angelica
authors.initials: PA
authors.lastname: Merlini
authors.affiliation: 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.).
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fornaro
authors.affiliation: 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.).
authors.forename: Franco
authors.initials: F
authors.lastname: Cecchi
authors.affiliation: 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.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Torricelli
authors.affiliation: 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.).
authors.forename: Iacopo
authors.initials: I
authors.lastname: Olivotto
mesh_terms: D000185:Actinin / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D006346:Heart Septum / Q000473:pathology; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014463:Ultrasonography; D055815:Young Adult
chemical_list: C401401:ACTN2 protein, human; D000185:Actinin
keywords: atrial fibrillation; cardiomyopathy, hypertrophic; genetic testing