Autosomal Dominant Limb-Girdle Muscular Dystrophy, Type 1E (LGMD1E) via the DNAJB6 Gene

Limb-girdle muscular dystrophy (LGMD) is a descriptive term for a group of disorders with atrophy and weakness of proximal limb-girdle muscles. At least ten genes are recognized as causative for autosomal recessive LGMD (AR-LGMD), which is overall more common than autosomal dominant LGMD (AD-LGMD, Moore et al. J Neuropath Exp Neurol 65:995-1003, 2006). To date, four genes have been reported to be causative for AD-LGMD (see Genetics Section below and Gordon et al. GeneReviews, 2009). LGMD1E (OMIM 603511) is an adult-onset disorder of proximal weakness first presenting in the hip girdle. The age of onset has been reported to range from 20 to 60 years (Sandell et al. J Neurol Neurosurg Psychiat 81:834-839, 2010) and 18 to 35 years (Harms et al. Ann Neurol 71:407-416, 2012) in two affected families. Difficulty climbing stairs is a common presenting symptom. Disease progression is slow and shoulder girdles are eventually also affected. By the 8th decade of life, independent ambulation may be limited (Sandell et al. 2010; Hackman et al. Neuromusc Disord 21:338-344, 2011). Facial weakness and pulmonary and cardiac involvement are not features of LGMD1E. Dysphagia appears to be a variable finding. Serum CpK values are elevated, and EMG studies reveal myopathic changes. Muscle biopsies are remarkable for a dystrophic process including fiber size variation, atrophic fibers, mild to moderate fibrosis, adipose tissue, rimmed vacuoles, and internally placed nuclei (Sandell et al. 2010). Cytoplasmic inclusions that contain DNAJB6 protein are present. Electron microscopy of affected muscle reveals Z-disc myofibrillar disintegration and autophagic rimmed vacuoles (Sarparanta et al. Nature Genet 44: 450-455, 2012).

LGMD1A, 1B, 1C, and 1E are inherited as autosomal dominant disorders secondary to variants in the MYOT, LMNA, CAV3, and DNAJB6 genes, respectively. Thus far four different DNAJB6 variants (p.Phe89Ile, p.Phe93Gly, p.Phe93Leu, p.Pro96Arg) have been reported (Harms et al. 2012 and Sarparanta et al. 2012). These variants extend the half-life of the DNAJB6 protein and lead to a toxic gain-of-function effect (Sarparanta et al. 2012).

The DNAJB6 protein is coded by exons 2-10 of the DNAJB6 gene (OMIM 611332) located on chromosome 7q36.3.

LGMD1E is a rare disorder and most affected families reported have been from Finland. Clinical sensitivity cannot be accurately predicted because of the low rate of occurrence of this disorder. Analytical sensitivity may be high because all variants thus far reported are expected to be detected by this method.

This test provides full coverage of all coding exons of the DNAJB6 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).