Emery-Dreifuss Muscular Dystrophy Panel, Sequencing

Use to assess for EDMD in individuals with clinical findings or family history of EDMD.

  • Recommended test for a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s test result documenting the familial variant is required.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by a clinical triad of early onset joint contractures (commonly involving elbows, ankles, and neck), slowly progressive limb muscle weakness and wasting, and cardiac disease. Age of onset, severity, and disease progression are variable, although penetrance is high. Typical presentation includes joint contractures in the first two decades of life, followed by muscle weakness and wasting, with cardiac involvement occurring in the second to third decades. Muscle histopathology may show myopathic or dystrophic changes, and serum creatine kinase may be normal or moderately elevated. Inheritance may be X-linked (XL) (EMD or FHL1), autosomal dominant (AD) (LMNA), and rarely autosomal recessive (AR) (LMNA). Carrier females of XL-EDMD are usually asymptomatic but are at risk for developing cardiac disease and, less commonly, mild muscle disease.  

Disease Overview

Symptoms

EDMD has inter- and intrafamilial variability in age of onset and disease severity, but typical disease presentation includes:

  • Early joint contractures (typically the first sign in XL-EDMD and present in the first decade, but may appear after muscle weakness in AD-EDMD):
    • Elbow flexors
    • Achilles tendon
    • Neck extensors resulting in limited neck flexion and later limitation of extension of the entire spine
  • Slowly progressive muscle wasting and weakness:
    • Initially of the humeroperoneal muscles, with progression to scapular and pelvic girdle muscles
    • Loss of ability to walk due to progressive muscle weakness (more common in AD-EDMD but rare in XL-EDMD)
    • Severe muscular disease may result from biallelic LMNA variants
  • Cardiac disease:
    • Cardiac symptoms (eg,  palpitations, presyncope/syncope, poor exercise tolerance, or sudden death)
    • Atrial or ventricular arrhythmias
    • Dilated or hypertrophic cardiomyopathy
    • Cardiac conduction defects
      • Includes sinus bradycardia and atrioventricular and bundle-branch blocks
      • 20% of female carriers of EDMD1 develop conduction defects 

Prevalence

1-2/100,000 

Genetics

Etiology

EDMD is caused by pathogenic germline variants in EMD, FHL1, or LMNA, with each gene accounting for the following amount of cases :

  • LMNA: 26.5% of cases
  • EMD: 8.5% of cases
  • FHL1: 1.2% of cases

Inheritance

Gene Inheritance Pattern

EMD

XL

FHL1

XL

LMNA

Typically AD

De novo variants common (up to 65% of cases)

AR (biallelic variation) is rare

Genotype-Phenotype Correlations

The majority of causative variants in EMD are null variants, resulting in absence of emerin expression, which often result in more severe disease compared with missense variants associated with decreased expression.

LMNA missense variants are typically associated with EDMD2, whereas truncating variants have been associated with a later onset limb-girdle muscular dystrophy phenotype.

Test Interpretation

Clinical Sensitivity

Estimated at 36% for EDMD 

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a diagnosis of Emery-Dreifuss muscular dystrophy.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted genes
    • Regulatory region and deep intronic variants
    • Large deletions/duplications in any of the tested genes (putative large deletions in EMD or FHL1 identified in males using massively parallel sequencing should be confirmed by a validated method)
    • Noncoding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

Genes Tested

Gene MIM # Disorder Inheritance

EMD

300384

EDMD1

XL

FHL1

300163

EDMD6

Myopathy with postural muscle atrophy

Reducing body myopathy 1a, severe infantile or early childhood onset

Reducing body myopathy 1b, with late childhood or adult onset

Scapuloperoneal myopathy

Uruguay faciocardiomuscular syndrome

XL

LMNA

613205

EDMD2

Dilated cardiomyopathy 1A

Congenital muscular dystrophy

AD

EDMD3

AR

References