Juan Gómez1, Rebeca Lorca1, Julian R Reguero1, César Morís1, María Martín1, Salvador Tranche1, Belén Alonso1, Sara Iglesias1, Victoria Alvarez1, Beatriz Díaz-Molina1, Pablo Avanzas1, Eliecer Coto2. 1. 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.). 2. 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.
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 of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. METHODS AND RESULTS: A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate 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 of FLNC in the development of HCM. Most of the FLNC variants 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 found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.
BACKGROUND: Recent exome sequencing studies identified filamin C (FLNC) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. METHODS AND RESULTS: A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate 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 of FLNC in the development of HCM. Most of the FLNC variants 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 found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.
Authors: Allison L Cirino; Neal K Lakdawala; Barbara McDonough; Lauren Conner; Dale Adler; Mark Weinfeld; Patrick O'Gara; Heidi L Rehm; Kalotina Machini; Matthew Lebo; Carrie Blout; Robert C Green; Calum A MacRae; Christine E Seidman; Carolyn Y Ho Journal: Circ Cardiovasc Genet Date: 2017-10
Authors: Nathan R Tucker; Micheal A McLellan; Dongjian Hu; Jiangchuan Ye; Victoria A Parsons; Robert W Mills; Sebastian Clauss; Elena Dolmatova; Marisa A Shea; David J Milan; Nandita S Scott; Mark Lindsay; Steven A Lubitz; Ibrahim J Domian; James R Stone; Honghuang Lin; Patrick T Ellinor Journal: Circ Cardiovasc Genet Date: 2017-12
Authors: Julia Schuld; Peter F M van der Ven; Anne Schänzer; Elisabeth Schumann; Diana Zengeler; Lisann Gulatz; Giovanni Maroli; Uwe Ahting; Anke Sprengel; Sabine Gräf; Andreas Hahn; Christian Jux; Till Acker; Dieter O Fürst; Stefan Rupp Journal: J Muscle Res Cell Motil Date: 2021-03-12 Impact factor: 2.698