Submission Details

The relationship between DMD and progressive muscular dystrophy (including Duchenne muscular dystrophy, DMD and Becker muscular dystrophy, BMD) inherited in the X-linked inheritance pattern, has been evaluated using the ClinGen Clinical Validity Framework as of September, 2020. This association was made using case-level and experimental data. The DMD gene is located on chromosome Xp21.2 and is the largest human gene (~2.3MB), encoding multiple transcript variants. The muscle-specific transcript is the longest (NM_004006.3); it is 14 kb long with 79 exons encoding a 3685-amino acid protein isoform, referred to as Dp427m. Variants affecting specific transcript expression have been known to cause specific/isolated phenotypes. More than 1500 pathogenic variants reported in humans with DMD or BMD are recorded in ClinVar, a majority of them being large deletions (>70%), some large duplications (~7%), and many small alterations, including small deletions/duplications, nonsense, splice and missense variants (duchenne.com). A "reading-frame rule" is proposed by which in-frame deletions and duplications are associated with milder phenotype (BMD), while out-of-frame deletions and duplications are associated with severe phenotype (DMD). Although the reading frame rule applies to a majority of deletions/duplications, exceptions to the rule do exist. Two hot-spot regions in the gene are described: deletion cluster region I spanning exons 44-53, which removes part of the rod domain, and deletion cluster region II spanning exons 2-20, which removes some or all of the actin-binding sites, together with part of the rod domain (PMID: 11917091). Progressive muscular dystrophy encompasses a spectrum of phenotypes including the severe DMD with onset at ages 2-5 years and wheelchair dependence by age 12 years and milder BMD with later age of onset, milder progression and individuals remaining mobile until old age. Both DMD and BMD have a similar clinical course including waddling gait, difficulty in climbing stairs and running, delay in walking, unsteadiness, pseudohypertrophy of the calf muscles, proximal limb muscle weakness, and Gowers' sign (PMID: 11917091). Additional phenotypes associated with variants in DMD include dilated cardiomyopathy type 3B, familial isolated cardiomyopathy, non-syndromic X-linked intellectual disability, symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers. Individuals with these phenotypes have not been scored for this curation.

The DMD locus had been studied since the 1980s and the gene in association with X-linked progressive muscular dystrophy was identified as early as 1986 by independent groups (PMID: 3607877, 4039107, 3001530, 3024018). Summary of Case Level Data (12 points): The association is seen in at least 13 probands in 6 publications (PMID: 31081998, 8401582, 15952989, 1601417, 32504006, 31754439). The gene variants segregated with disease in several additional family members across families (PMID: 6086495). 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 hemizygous loss of function.

Summary of Experimental Data (6 points): This gene-disease relationship is supported by animal models, functional assays and rescue evidence. The dystrophin protein connects the dystrophin-glycoprotein complex to the intracellular contractile apparatus and the extracellular matrix and stabilizes the sarcolemma (PMID: 9146999, 27230049). The dystrophin and β-dystroglycan proteins physically interact to form the dystrophin-glycoprotein complex (PMID: 7592992). DMD alterations result in a number of abnormalities of the muscle cell and tissue, including calcium-leak and neuronal-type nitric oxide synthase deficiency (PMID: 10926682, 11087833). Many different animal models have been described with naturally occurring DMD variants. Though many features of the human disease are recapitulated, especially in dogs, the muscle weakness attributes, severity and progression are different (PMID: 2662404, 1577476, 7881288). Several therapeutic strategies, including AAV-mediated delivery of mini- and micro-dystrophins, antisense oligonucleotides to induce exon-skipping, CRISPR-mediated gene editing, have been shown to mitigate the severity of progressive muscular dystrophy in animal models and are in various phases of human clinical trials (PMID: 30093306, 29404407, 11120883, 8355788).

In summary, the DMD-X-linked progressive muscular dystrophy 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 approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on April 9, 2021 (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 entities: Duchenne muscular dystrophy, Becker muscular dystrophy, dilated cardiomyopathy type 3B.

Orphanet entities: Duchenne muscular dystrophy, Becker muscular dystrophy, dilated cardiomyopathy type 3B, familial isolated cardiomyopathy, non-syndromic X-linked intellectual disability, symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers.

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 between the DMD and BMD disease entities, which represent a continuous spectrum of severity. Therefore, the two disease entities have been lumped into one entity, X-linked progressive muscular dystrophy. The entities, dilated cardiomyopathy type 3B, familial isolated cardiomyopathy, non-syndromic X-linked intellectual disability, and symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers, are split from this curation as they present isolated phenotypes due to variants affecting specific transcripts.