PUBLICATION
De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy
- Authors
- Kiselev, A., Vaz, R., Knyazeva, A., Khudiakov, A., Tarnovskaya, S., Liu, J., Sergushichev, A., Kazakov, S., Frishman, D., Smolina, N., Pervunina, T., Jorholt, J., Sjoberg, G., Vershinina, T., Rudenko, D., Arner, A., Sejersen, T., Lindstrand, A., Kostareva, A.
- ID
- ZDB-PUB-180603-4
- Date
- 2018
- Source
- Human Mutation 39(9): 1161-1172 (Journal)
- Registered Authors
- Vaz, Raquel
- Keywords
- cardiomyopathy, filamin C, mutation, myopathy, zebrafish model
- MeSH Terms
-
- Adolescent
- Cardiomyopathy, Restrictive/genetics*
- Cardiomyopathy, Restrictive/physiopathology
- Child, Preschool
- Congenital Abnormalities/genetics*
- Congenital Abnormalities/physiopathology
- DNA Mutational Analysis
- Female
- Filamins/genetics*
- Humans
- Infant
- Infant, Newborn
- Male
- Muscular Diseases/genetics*
- Muscular Diseases/physiopathology
- Mutation
- Pedigree
- Phenotype
- PubMed
- 29858533 Full text @ Hum. Mutat.
Citation
Kiselev, A., Vaz, R., Knyazeva, A., Khudiakov, A., Tarnovskaya, S., Liu, J., Sergushichev, A., Kazakov, S., Frishman, D., Smolina, N., Pervunina, T., Jorholt, J., Sjoberg, G., Vershinina, T., Rudenko, D., Arner, A., Sejersen, T., Lindstrand, A., Kostareva, A. (2018) De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy. Human Mutation. 39(9):1161-1172.
Abstract
Mutations in FLNC for a long time are known in connection to neuromuscular disorders and only recently were described in association with various cardiomyopathies. Here we report a new clinical phenotype of filaminopathy in four unrelated patients with early-onset restrictive cardiomyopathy (RCM) in combination with congenital myopathy due to FLNC mutations (NM_001458.4:c.3557C > T, p.A1186V, rs1114167361 in three probands and c.[3547G > C; 3548C > T], p.A1183L, rs1131692185 in one proband). In all cases, concurrent myopathy was confirmed by neurological examination, electromyography, and morphological studies. Three of the patients also presented with arthrogryposis. The pathogenicity of the described missense variants was verified by cellular and morphological studies and by in vivo modelling in zebrafish. Combination of in silico and experimental approaches revealed that FLNC missense variants localized in Ig-loop segments often lead to development of RCM. The described FLNC mutations associated with early-onset RCMP extend cardiac spectrum of filaminopathies and facilitate the differential diagnosis of restrictive cardiac phenotype associated with neuromuscular involvement in children. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping