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FKTN – Dilated Cardiomyopathy 1X

Dilated cardiomyopathy 1X is an autosomal recessive disorder characterized by dilated cardiomyopathy with mildest limb-girdle muscle involvement and normal cognition. Genetic evidence includes three unrelated families: a 25-year-old woman with compound heterozygous FKTN variants presented during pregnancy (PMID:26566449), a DCM patient with a 3-kb insertion and a p.Cys101Phe missense allele (PMID:19015585), and two Mexican siblings homozygous for c.1270G>A (p.Gly424Ser) with early-onset DCM and healthy carrier parents (PMID:33048919). In total, four probands from three families with biallelic FKTN variants have been reported, including segregation of the homozygous variant in one sibship (2 affected relatives). Based on this limited cohort and lack of large‐scale case–control data, we assign a Limited clinical validity for the FKTN–dilated cardiomyopathy 1X association.

Mechanistically, loss of fukutin impairs α-dystroglycan glycosylation in cardiomyocytes. Regulatory and coding FKTN variants reduce α-dystroglycan glycosylation in patient myocardium, in human cardiomyocyte reporter assays, and in zebrafish CRISPR knockouts, demonstrating a key role in cardiac muscle integrity (PMID:35288587). These functional studies provide Moderate experimental support but cardiac rescue experiments are pending. Recognition of FKTN as a cause of autosomal recessive DCM 1X aids diagnostic genetic testing and family counseling. Key Take-home: Biallelic FKTN mutations should be considered in unexplained early-onset dilated cardiomyopathy with mild muscle findings.

References

  • Oxford medical case reports • 2015 • A case of pregnancy complicated with dilated cardiomyopathy 1X. PMID:26566449
  • Circulation journal : official journal of the Japanese Circulation Society • 2009 • Mutational analysis of fukutin gene in dilated cardiomyopathy and hypertrophic cardiomyopathy. PMID:19015585
  • Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion • 2020 • Homozygous Fukutin Missense Mutation in Two Mexican Siblings with Dilated Cardiomyopathy. PMID:33048919
  • NPJ genomic medicine • 2022 • Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy. PMID:35288587

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Four probands across three families with biallelic FKTN variants, one family with segregation, no large cohort or definitive cardiac rescue studies

Genetic Evidence

Limited

Four probands (three families) with compound heterozygous or homozygous FKTN variants causing DCM 1X

Functional Evidence

Moderate

Patient myocardium, human cardiomyocyte assays, and zebrafish CRISPR knockouts show impaired α-dystroglycan glycosylation due to FKTN variants