Submission Details

The relationship between FKTN and myopathy caused by variation in FKTN (muscular dystrophy-dystroglycanopathy types 4A, 4B and 4C and dilated Cardiomyopathy 1X included) inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of June, 2020. This association was made using case-level and experimental data. The FKTN gene is located on chromosome 9q31.2 and encodes multiple transcript variants. The commonly referred transcript (NM_001079802.2) is 7.4 kb long with 10 exons encoding a 461-amino acid protein. More than 70 pathogenic variants reported in humans with autosomal recessive myopathy caused by variation in FKTN are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. Myopathy caused by variation in FKTN encompasses a spectrum of phenotypes including severe forms with muscle-eye-brain disease, Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome and milder forms of muscular dystrophy dystroglycanopathy without intellectual disability, limb-girdle muscular dystrophy and cardiomyopathy. Patients often show an elevated serum creatine kinase and progressive muscle weakness. FKTN has been reported in association with autosomal recessive myopathy caused by variation in FKTN as early as 1998 by Kobayahsi et al (PMID: 9690476).

OMIM entities: Cardiomyopathy, dilated, 1X, (MIM# 611615); Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (MIM# 253800); Muscular dystrophy-dystroglycanopathy (congenital without mental retardation), type B, 4 (MIM# 613152); Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 (MIM# 611588).

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities were originally lumped into one disease entity, “myopathy caused by variation in FKTN”. In order to improve the consistency of the nomenclature relating to qualitative or quantitative defects of proteins involved in O-glycosylation of alpha-dystroglycan and better represent the spectrum of phenotypes associated with variation in these genes, the LGMD GCEP proposed the nomenclature revision: myopathy caused by variation in gene.

Summary of Case Level Data (12 points): The association is seen in at least 9 probands in 6 publications (PMID: 12601708, 19396839, 17036286, 9690476, 17044012, 14627679). The Japanese founder variant, a 3-kb retrotransposon insertion in the 3'UTR of FKTN is frequently reported and patients homozygous for this variant show a milder phenotype compared to patients compound heterozygous with a null variant (PMID: 9690476, 17036286). FKTN variants have also been identified in patients with dilated cardiomyopathy and only mild or subclinical skeletal muscle involvement (PMID: 17036286). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.

The mechanism for disease is expected to be biallelic loss of function.

Summary of Experimental Data (6 points): This gene-disease relationship is supported by animal models, expression studies, functional assays and rescue evidence. Fukutin is localized to the Golgi and has a role the glycosylation of alpha-dystroglycan in skeletal muscle and may be involved in brain development (PMID: 9690476, 21979053, 17034757). It is expressed in skeletal muscles, brain and retina (PMID: 9690476, 10852541). Fukutin interacts with other members involved in the process of dystroglycan glycosylation (PMID: 29477842, 17005282). Many model organisms have been developed including mouse and zebrafish models (PMID: 22922256, 19017726, 21317159) and rescue in mouse models and patient cells (PMID: 21979053) are also reported.

In summary, FKTN - myopathy caused by variation in FKTN gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on July 1st, 2020 (SOP Version 7), but has since been updated to reflect SOP V9 (June 19, 2023).

The relationship between FKTN and myopathy caused by variation in FKTN (muscular dystrophy-dystroglycanopathy types 4A, 4B and 4C and dilated Cardiomyopathy 1X included) inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of June, 2020. This association was made using case-level and experimental data. The FKTN gene is located on chromosome 9q31.2 and encodes multiple transcript variants. The commonly referred transcript (NM_001079802.2) is 7.4 kb long with 10 exons encoding a 461-amino acid protein. More than 70 pathogenic variants reported in humans with autosomal recessive myopathy caused by variation in FKTN are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. Myopathy caused by variation in FKTN encompasses a spectrum of phenotypes including severe forms with muscle-eye-brain disease, Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome and milder forms of muscular dystrophy dystroglycanopathy without intellectual disability, limb-girdle muscular dystrophy and cardiomyopathy. Patients often show an elevated serum creatine kinase and progressive muscle weakness. FKTN has been reported in association with autosomal recessive myopathy caused by variation in FKTN as early as 1998 by Kobayahsi et al (PMID: 9690476).

OMIM entities: Cardiomyopathy, dilated, 1X, (MIM# 611615); Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (MIM# 253800); Muscular dystrophy-dystroglycanopathy (congenital without mental retardation), type B, 4 (MIM# 613152); Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 (MIM# 611588).

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities were originally lumped into one disease entity, “myopathy caused by variation in FKTN”. In order to improve the consistency of the nomenclature relating to qualitative or quantitative defects of proteins involved in O-glycosylation of alpha-dystroglycan and better represent the spectrum of phenotypes associated with variation in these genes, the LGMD GCEP proposed the nomenclature revision: myopathy caused by variation in gene.

Summary of Case Level Data (12 points): The association is seen in at least 9 probands in 6 publications (PMID: 12601708, 19396839, 17036286, 9690476, 17044012, 14627679). The Japanese founder variant, a 3-kb retrotransposon insertion in the 3'UTR of FKTN is frequently reported and patients homozygous for this variant show a milder phenotype compared to patients compound heterozygous with a null variant (PMID: 9690476, 17036286). FKTN variants have also been identified in patients with dilated cardiomyopathy and only mild or subclinical skeletal muscle involvement (PMID: 17036286). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.

The mechanism for disease is expected to be biallelic loss of function.

Summary of Experimental Data (6 points): This gene-disease relationship is supported by animal models, expression studies, functional assays and rescue evidence. Fukutin is localized to the Golgi and has a role the glycosylation of alpha-dystroglycan in skeletal muscle and may be involved in brain development (PMID: 9690476, 21979053, 17034757). It is expressed in skeletal muscles, brain and retina (PMID: 9690476, 10852541). Fukutin interacts with other members involved in the process of dystroglycan glycosylation (PMID: 29477842, 17005282). Many model organisms have been developed including mouse and zebrafish models (PMID: 22922256, 19017726, 21317159) and rescue in mouse models and patient cells (PMID: 21979053) are also reported.

In summary, FKTN - myopathy caused by variation in FKTN gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on July 1st, 2020 (SOP Version 7), but has since been updated to reflect SOP V9 (June 19, 2023).

Data provided by the ClinGen Prenatal GCEP from October 21, 2025 secondary analysis: Prenatal detection of congenital anomalies in fetuses with myopathy caused by variation in FKTN has been reported in a small number of cases, primarily affecting the central nervous system. Specific anomalies that have been reported prenatally include cerebral ventriculomegaly (often severe), cerebellar anomalies, lissencephaly, abnormalities of the corpus callosum, abnormalities of the brainstem, renal anomalies, eye anomalies, and growth restriction (PMID: 19266496, 20961758, 25814170, 28749478, 31641664, 31756055, 33200426, 35843586).