EMD – X-linked Emery-Dreifuss muscular dystrophy

X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is an X-linked recessive disorder characterized by early joint contractures, slowly progressive skeletal muscle wasting, and cardiac conduction defects leading to arrhythmias and risk of sudden death. Affected males present with muscle weakness and atrophy of scapulo-humeroperoneal distribution, early Achilles and elbow contractures, and variable cardiomyopathy; female carriers may exhibit isolated cardiac symptoms without overt myopathy. Emerin, encoded by EMD (HGNC:3331), is a 34-kDa inner nuclear membrane protein interacting with lamins A/C and barrier-to-autointegration factor (BAF), essential for nuclear envelope stability in mechanically stressed muscle cells ([PMID:10393813], [PMID:10323252]).

Clinical Validity (Definitive)

EMD is definitively associated with X-EDMD, supported by loss-of-function variants in over 30 unrelated probands and segregation in multiple families. A four-generation pedigree demonstrated co-segregation of a thymine insertion at nucleotide 417 in exon 2 (c.417dupT) leading to a frameshift and premature stop with absence of emerin in four affected males ([PMID:11063761]). In a cohort of 30 unrelated patients, six novel promoter and frameshift mutations, including c.619del (p.Arg207fsTer?) were identified, all abolishing emerin synthesis ([PMID:9195226]). An additional splice-site mutation, c.449+1G>A, was observed in a patient with dilated arrhythmogenic cardiomyopathy and life-threatening ventricular arrhythmias ([PMID:25502304]). Robust familial segregation and consistent phenotype across LoF variants underpin a Definitive ClinGen classification.

Genetic Evidence (Strong)

X-EDMD follows an X-linked recessive inheritance pattern with full penetrance in hemizygous males and variable expressivity in carriers. Segregation analysis identified four affected male relatives in one pedigree carrying c.417dupT (PMID:11063761). Thirty unrelated probands harboring six novel truncating mutations, promoter deletions, the initiation codon variant c.3G>A (p.Met1Ile), and frameshifts such as c.619del (p.Arg207fsTer?) establish a consistent variant spectrum of loss-of-function alleles ([PMID:9195226], [PMID:10399752]). The recurrent splice-site variant c.449+1G>A further illustrates pathogenic intronic disruption ([PMID:25502304]). Altogether, the variant burden surpasses genetic evidence thresholds, achieving a Strong genetic evidence tier.

Functional Evidence (Moderate)

Emerin deficiency disrupts nuclear envelope integrity via haploinsufficiency. In C2C12 myoblasts, missense and deletion mutants (e.g., p.Pro183Leu; p.Ser54Phe) show impaired targeting to the nuclear membrane and form cytoplasmic aggregates, weakening interactions with lamin A and BAF and altering cell cycle timing ([PMID:10393813], [PMID:10323252], [PMID:11839786]). BAF-binding mutants fail to assemble at the reforming nuclear envelope, as shown in HeLa cells ([PMID:11792822]). In vitro binding assays confirm distinct domains mediating lamin A and BAF interactions, and LEM-domain mutations such as p.Lys37del impair complex formation and mechanoresponsive stress fiber assembly ([PMID:31185657]). Concordant disruption across cellular assays supports a Moderate functional evidence tier.

Conflicting and Modifier Evidence

A common variant, p.Asp149His, occurs at appreciable frequency in East Asians without EDMD phenotype and associates with favorable metabolic traits, highlighting benign population variation ([PMID:31024910]). This underscores the need for caution in interpreting non-truncating EMD alleles.

Integration & Clinical Utility

Genetic and experimental data converge on a haploinsufficiency mechanism for EMD LoF variants causing X-EDMD. Definitive gene-disease validity and strong genetic evidence justify routine EMD sequencing in males with early contractures and conduction defects. Functional assays of novel missense variants at key LEM-domain residues enhance variant classification. Early molecular diagnosis enables proactive cardiac surveillance and timely pacemaker/ICD placement to mitigate sudden death risk.

Key Take-home: Emerin loss-of-function variants are definitively linked to X-EDMD and should prompt early genetic testing and cardiological management.

References

• Croatian medical journal • 2000 • Clinical variability and molecular diagnosis in a four-generation family with X-linked Emery-Dreifuss muscular dystrophy. PMID:11063761
• Human Mutation • 1997 • Six novel mutations in the emerin gene causing X-linked Emery-Dreifuss muscular dystrophy. PMID:9195226
• Neuromuscular disorders : NMD • 1999 • A protein truncation test for Emery-Dreifuss muscular dystrophy (EMD): detection of N-terminal truncating mutations. PMID:10399752
• Journal of Cell Science • 1999 • The Emery-Dreifuss muscular dystrophy phenotype arises from aberrant targeting and binding of emerin at the inner nuclear membrane. PMID:10393813
• Human Genetics • 1999 • Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery-Dreifuss muscular dystrophy. PMID:10323252
• Cardiology • 2015 • Dilated, arrhythmogenic cardiomyopathy in emery-dreifuss muscular dystrophy due to the emerin splice-site mutation c.449 + 1G>A. PMID:25502304
• Frontiers in Cell and Developmental Biology • 2019 • Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including 'Healthy Lipid' Emerin p.D149H in the ExAC Cohort. PMID:31024910
• Cells • 2019 • An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress. PMID:31185657

Evidence Based Scoring (AI generated)