FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations.
Alleles
Cardiomyopathies
/ diagnosis
Echocardiography
Electrocardiography
Female
Filamins
/ genetics
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Testing
Genetic Variation
Genotype
High-Throughput Nucleotide Sequencing
Humans
Magnetic Resonance Imaging
Male
Mutation
Pedigree
Phenotype
Prevalence
Sequence Analysis, DNA
FLNC
Genotype-phenotype correlation
cardiomyopathies
myopathy
next generation sequencing
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
11
03
2019
revised:
14
05
2019
accepted:
15
05
2019
pubmed:
28
6
2019
medline:
4
9
2020
entrez:
28
6
2019
Statut:
ppublish
Résumé
Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.
Substances chimiques
FLNC protein, human
0
Filamins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
317-329Informations de copyright
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Fürst DO, Goldfarb LG, Kley RA, Vorgerd M, Olivé M, van der Ven PF. Filamin C-related myopathies: pathology and mechanisms. Acta Neuropathol. 2013;125(1):33-46.
Valdés-Mas R, Gutiérrez-Fernández A, Gómez J, et al. Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy. Nat Commun. 2014;5:5326.
Brodehl A, Ferrier RA, Hamilton SJ, et al. Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy. Hum Mutat. 2016;37(3):269-279.
Begay RL, Tharp CA, Martin A, et al. FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy. JACC Basic Transl Sci. 2016;1(5):344-359.
Miszalski-Jamka K, Jefferies JL, Mazur W, et al. Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2017;10(4).
Thompson TG, Chan YM, Hack AA, et al. Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein. J Cell Biol. 2000;148(1):115-126.
van der Flier A, Sonnenberg A. Structural and functional aspects of filamins. Biochim Biophys Acta. 2001;1538(2-3):99-117.
Fujita M, Mitsuhashi H, Isogai S, et al. Filamin C plays an essential role in the maintenance of the structural integrity of cardiac and skeletal muscles, revealed by the medaka mutant zacro. Dev Biol. 2012;361(1):79-89.
Takada F, Vander Woude DL, Tong HQ, et al. Myozenin: an alpha-actinin- and gamma-filamin-binding protein of skeletal muscle Z lines. Proc Natl Acad Sci U S A. 2001;98(4):1595-1600.
Leber Y, Ruparelia AA, Kirfel G, et al. Filamin C is a highly dynamic protein associated with fast repair of myofibrillar microdamage. Hum Mol Genet. 2016;25(13):2776-2788.
Ortiz-Genga MF, Cuenca S, Dal Ferro M, et al. Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies. J Am Coll Cardiol. 2016;68(22):2440-2451.
Elliott PM, Anastasakis A, Borger MA, et al. ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014;35(39):2733-2779.
Rammos A, Meladinis V, Vovas G, Patsouras D. Restrictive Cardiomyopathies: The Importance of Noninvasive Cardiac Imaging Modalities in Diagnosis and Treatment-A Systematic Review. Radiol Res Pract. 2017;2017:2874902.
Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86(6):666-671.
Pinto YM, Elliott PM, Arbustini E, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2016;37(23):1850-1858.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
Walsh R, Thomson KL, Ware JS, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017;19(2):192-203.
Pérez-Serra A, Toro R, Sarquella-Brugada G, et al. Genetic basis of dilated cardiomyopathy. Int J Cardiol. 2016;224:461-472.
Gómez J, Lorca R, Reguero JR, et al. Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients. Circ Cardiovasc Genet. 2017;10(2).
Cui H, Wang J, Zhang C, et al. Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy. Mol Genet Genomic Med. 2018;6(6):1104-1113.
Walsh R, Mazzarotto F, Whiffin N, et al. Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy. Genome Med. 2019;11(1):5.
Reinstein E, Gutierrez-Fernandez A, Tzur S, et al. Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C. Eur J Hum Genet. 2016;24(12):1792-1796.