Related Experiment Video

Updated: Feb 4, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

11.4K

Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

Jeffrey Schubert1,2, Muhammad Tariq3, Gabrielle Geddes4

  • 1Department of Molecular Genetics, Microbiology, and Biochemistry, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Human Mutation
|September 28, 2018
PubMed

Insights

Genetic variants in the filamin C (FLNC) gene are linked to restrictive cardiomyopathy (RCM) in children. This finding expands the known genetic causes of RCM and highlights FLNC for early-onset cardiomyopathy genetic testing.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Diseases

Background:

  • Restrictive cardiomyopathy (RCM) is a rare cardiac condition defined by impaired diastolic function with normal ventricular size and systolic function.
  • Genetic underpinnings of RCM, particularly in early-onset cases, remain largely unidentified.
  • Previous studies implicated sarcomeric and cytoskeletal genes, but a significant portion of RCM cases lack a clear genetic diagnosis.

Purpose of the Study:

  • To investigate the genetic basis of restrictive cardiomyopathy (RCM) in two families with childhood-onset disease.
  • To identify novel gene variants associated with autosomal dominant RCM and RCM in twins.
  • To elucidate the role of filamin C (FLNC) in the pathogenesis of pediatric RCM.

Main Methods:

  • Whole exome sequencing was performed on affected individuals from two distinct RCM families.
  • Segregation analysis was conducted to confirm the inheritance pattern of identified variants.
  • In vitro functional studies using C2C12 myoblast cells were employed to assess the impact of mutant FLNC proteins.

Main Results:

  • Pathogenic variants in the filamin C (FLNC) gene were identified in both families: p.Pro2298Leu in the autosomal dominant family and p.Tyr2563Cys in the affected twins.
  • Both identified FLNC variants segregated with the disease phenotype within their respective families.
  • In vitro expression studies revealed that mutant FLNC proteins formed aggregates with actin in muscle cells, suggesting a mechanism for cellular dysfunction.

Conclusions:

  • The study provides strong evidence implicating filamin C (FLNC) gene variants in the etiology of pediatric restrictive cardiomyopathy (RCM).
  • These findings expand the spectrum of cardiomyopathies associated with FLNC mutations.
  • Genetic testing for FLNC variants should be considered in the diagnostic workup of children presenting with RCM, especially those with early onset.

Keywords:
exome sequencingheart failureheart transplantprotein aggregationvariant interpretation

More Related Videos

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model03:45

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

Published on: August 8, 2022

4.3K
Culture of Small Colony Variant of Pseudomonas aeruginosa and Quantitation of its Alginate09:06

Culture of Small Colony Variant of Pseudomonas aeruginosa and Quantitation of its Alginate

Published on: February 22, 2020

9.2K

Related Concept Videos

Cardiomyopathy IV: Restrictive Cardiomyopathy01:29

Cardiomyopathy IV: Restrictive Cardiomyopathy

Restrictive cardiomyopathy (RCM) is a rare heart muscle disease characterized by impaired ventricular filling due to stiffened ventricular walls, leading to significant diastolic dysfunction.EtiologyRestrictive cardiomyopathy can arise from both inherited and acquired diseases, many of which are systemic. It is categorized into four main types: infiltrative, storage, non-infiltrative, and endomyocardial diseases.Infiltrative diseases, such as amyloidosis, lead to RCM by depositing amyloid...
545
Cardiomyopathy II: Dilated Cardiomyopathy01:30

Cardiomyopathy II: Dilated Cardiomyopathy

Dilated cardiomyopathy, or DCM, is a progressive myocardial disorder characterized by ventricular chamber dilation and contractile dysfunction.EtiologyVarious factors can cause DCM, including hypertension and heavy alcohol intake, which contribute to the weakening and enlargement of the heart muscle. Viral infections, such as Coxsackievirus B, adenoviruses, and influenza, can lead to DCM by causing inflammation and damage to heart tissue. Certain chemotherapeutic agents, including daunorubicin,...
573
Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

Cardiomyopathy III: Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
494
Histone Variants at the Centromere02:30

Histone Variants at the Centromere

Histone variants are the histone proteins with structural and sequence variations. These variants may be regarded as “mutant” forms that replace their canonical histone counterparts in the nucleosomes. Specific post-translational modifications on the histone variants enable further chromatin complexity and regulate tissue-specific gene expression. The most common histone variants are from histone H2A, H2B, and linker histone H1 families. However, several variants of histone H3...
5.1K
Restriction Enzymes01:11

Restriction Enzymes

Restriction enzymes are bacterial enzymes used to cut DNA in a sequence-specific manner. To cleave DNA, they bind to specific palindromic sequences called restriction sites. Such palindromic DNA sequences or inverted repeats are commonly found in regions of functional significance, such as the origin of replication, gene operator sites, and regions containing transcription termination signals.
The host bacteria protect their own genomic DNA from these enzymes by methylating these sites. Some...
36.1K
Cardiomyopathy V: Interprofessional Care01:29

Cardiomyopathy V: Interprofessional Care

Managing cardiomyopathy involves addressing underlying or precipitating causes, treating heart failure with medications, and implementing dietary changes and a balanced exercise and rest regimen.Lifestyle ModificationsCardiomyopathy patients should adopt a low-sodium diet to reduce fluid retention and manage heart failure. A personalized exercise and rest plan helps maintain physical fitness without overstraining the heart. Avoiding alcohol and tobacco is essential to prevent further damage to...
455