Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C.
In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied whole-exome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant. Exome analysis identified compound heterozygous variants in the FLNC gene. Histological analysis of the cardiac muscle demonstrated marked sarcomeric and myofibrillar abnormalities, and immunohistochemical staining demonstrated the presence of Filamin C aggregates in cardiac myocytes. We conclude that biallelic variants in FLNC can cause congenital dilated cardiomyopathy. As the associated clinical features of affected patients are mild, and can be easily overlooked, testing for FLNC should be considered in children presenting with dilated cardiomyopathy.
Medical Genetics Institute, Meir Medical Center, Kfar-Saba, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Eyal
E
Reinstein
Departamento de Bioquımicay Biologıa Molecular, Facultad de Medicina, Instituto Universitario de Oncologıa-IUOPA, Universidad de Oviedo, Oviedo, Spain.
Ana
A
Gutierrez-Fernandez
Genomic Research Department, emedgene Technologies, Tel Aviv, Israel.|Laboratory of Molecular Medicine, Haifa, Israel.
Shay
S
Tzur
Genomics Research Center, Gene by Gene, Houston, TX, USA.
Concetta
C
Bormans
Neurology Clinic, Bialik Street, Ramat-Gan, Israel.
Shai
S
Marcu
Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
Einav
E
Tayeb-Fligelman
Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel.
Chana
C
Vinkler
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Institute of Rare Diseases, Danek Gartener Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel.
Annick
A
Raas-Rothschild
The Raphael Recanati Genetic Institute, Rabin Medical Center, Petah Tikva, Israel.
Dana
D
Irge
Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
Meytal
M
Landau
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Bioinformatics unit, Cancer center, Sheba Medical Center, and the Medical Genetics institute of Maccabi HMO, Rechovot, Israel.
Mordechai
M
Shohat
Departamento de Bioquımicay Biologıa Molecular, Facultad de Medicina, Instituto Universitario de Oncologıa-IUOPA, Universidad de Oviedo, Oviedo, Spain.
Xose S
XS
Puente
Genomics Research Center, Gene by Gene, Houston, TX, USA.
Doron M
DM
Behar
Departamento de Bioquımicay Biologıa Molecular, Facultad de Medicina, Instituto Universitario de Oncologıa-IUOPA, Universidad de Oviedo, Oviedo, Spain.
Carlos
C
Lopez-Otın
D000328:Adult; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics*; D002460:Cell Line; D002648:Child; D005260:Female; D064448:Filamins / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D051381:Rats; D013577:Syndrome
C578661:FLNC protein, human; D064448:Filamins