Submission Details

The relationship between DYSF and limb girdle muscular dystrophy (LGMD; also known as LGMD 2B, LGMD R2 and generally as dysferlinopathy) inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of April, 2020. This association was made using case-level and experimental data. The DYSF gene is located on chromosome 2p13.2 and encodes multiple transcript variants. The most commonly used transcript is 6.7 kb long with 55 exons encoding a 2080-amino acid protein. More than 200 pathogenic variants reported in humans with autosomal recessive LGMD are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. In addition to ClinVar and LOVD, the UMD-DYSF database hosts an extensive list of DYSF variants (http://www.umd.be/DYSF/W_DYSF/mutation.html). Limb girdle muscular dystrophy is characterized by progressive weakness in muscles including but not limited to the proximal muscles, and affecting the pelvic and shoulder girdle which can lead to difficulty walking or complete loss of ambulation requiring wheelchair use. It is also accompanied by an elevated serum creatine kinase. DYSF has been reported in association with autosomal recessive LGMD as early as 1998 by Liu et al and Bashir et al (PMIDs: 9731526, 9731527). Summary of Case Level Data (12 points): The association is seen in at least 16 probands in 7 publications (PMID: 9731526, 16010686, 21522182, 14678801, 17825554, 16087766, 10196377). Variants in this gene segregated with disease in 8 additional family members. 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 has been reported 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. Dysferlin has a role in sarcolemmal repair and T-tubule organization (PMID: 12736685, 24302765, 28104817). It is strongly expressed in skeletal muscles and localizes to the membrane (PMID: 10196375). Dysferlin has multiple protein interaction partners (PMID: 11532985, 21079765). A number of mouse models (PMID: 23473732, 15254015, 12736685) and rescue in mouse models and patient cells (PMID: 27858744, 20861509, 19834057, 28707952, 31890729, 31019989) are also reported. In summary, the DYSF-autosomal recessive limb-girdle muscular dystrophy gene-disease relationship is definitive. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on 4/14/20 (SOP Version 7).

This gene curation was re-approved and published on 11/14/24 by the Muscular Dystrophies and Myopathies GCEP to reflect the change in the panel's name from LGMD GCEP to MDM GCEP. As part of this process, the genetic evidence was re-scored in accordance with SOP version 11.

Lumping & Splitting Consideration: OMIM disease entities: Miyoshi muscular dystrophy 1 (254130); Muscular dystrophy, limb-girdle, autosomal recessive 2 (253601); Myopathy, distal, with anterior tibial onset (606768). Variants in DYSF have been described in individuals with additional phenotypes including scapulo-peroneal myopathy, pseudo-metabolic myopathy, asymptomatic hyperCKemia,, and even congenital onset 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 have been lumped into one disease entity, autosomal recessive limb girdle muscular dystrophy (MONDO:0015152).