title: Screening of theFilamin CGene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.
abstract: BACKGROUND
  Recent exome sequencing studies identified filamin C (FLNC) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate ofFLNCcandidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes.
  
  
  RESULTS
  A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for theMYH7, MYBPC3,TNNT2,TNNI3,ACTC1,TNNC1,MYL2,MYL3,TPM1, andFLNCgenes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20FLNCcandidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (P=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign.
  
  
  CONCLUSIONS
  We provide a compelling evidence of the involvement ofFLNCin the development of HCM. Most of theFLNCvariants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who foundFLNCvariants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Juan
authors.initials: J
authors.lastname: Gómez
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Rebeca
authors.initials: R
authors.lastname: Lorca
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Julian R
authors.initials: JR
authors.lastname: Reguero
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: César
authors.initials: C
authors.lastname: Morís
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: María
authors.initials: M
authors.lastname: Martín
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Salvador
authors.initials: S
authors.lastname: Tranche
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Belén
authors.initials: B
authors.lastname: Alonso
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Sara
authors.initials: S
authors.lastname: Iglesias
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Beatriz
authors.initials: B
authors.lastname: Díaz-Molina
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.).
authors.forename: Pablo
authors.initials: P
authors.lastname: Avanzas
authors.affiliation: From the Unidad de Referencia de Cardiopatías Familiares-HUCA, Genética Molecular y Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain (J.G., R.L., J.R.R., C.M., M.M., B.A., S.I., V.A., B.D.-M., P.A., E.C.); Fundación Asturcor, Spain (J.R.R., C.M.); Departamento de Medicina, Universidad de Oviedo, Spain (C.M., E.C.); Centro Salud El Cristo, Oviedo, Spain (S.T.); and Red de Investigación Renal (REDINREN), Madrid, Spain (E.C.). eliecer.coto@sespa.es.
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
mesh_terms: D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D064448:Filamins / Q000235:genetics*; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D019683:Penetrance
chemical_list: C578661:FLNC protein, human; D064448:Filamins
keywords: cardiomyopathy, hypertrophic; filamin C; genetics, diagnostics; genetics, human; next-generation sequencing