Type VI Collagenopathy via the COL6A3 Gene

Ullrich congenital muscular dystrophy (UCMD; OMIM 254090) and Bethlem myopathy (OMIM 158810) represent the spectrum of clinical disorders with abnormal type 6 collagen. Bethlem myopathy is characterized by proximal weakness and variable contractures. Most often affected by contractures are elbows, ankles, and fingers. The earliest presenting signs are decreased fetal movement, neonatal hypotonia, and congenital contractures (Jobsis et al. Brain 122:649-655, 1999). Delayed motor milestones, muscle weakness, and contractures are evident in cases of Bethlem myopathy with early childhood onset (Lampe et al. GeneReviews, 2007). The clinical course in adult-onset patients is typically slow but relentless; approximately two-thirds of patients over age 50 require ambulatory support (Jobsis et al., 1999). UCMD is characterized by congenital muscle weakness, proximal joint contractures, and striking hyperlaxity of distal joints (Lampe and Bushby. J Med Genet 42:673-685, 2005). Affected children rarely gain the ability to walk independently and spinal rigidity and scoliosis develop. Respiratory failure in the first and second decade of life is a common cause of death (Lampe and Bushby, 2005). Serum CK levels are normal or mildly elevated in both Bethlem myopathy and UCMD; however, muscle biopsies from UCMD patients are more likely to be dystrophic and show absent or reduced immunostaining of Collagen VI (Higuchi et al. Neuromuscul Disord. 13:310-316, 2003). Intelligence is normal in Bethlem Myopathy and UCMD patients.

Most cases of Bethlem myopathy reported to date have demonstrated autosomal dominant inheritance of COL6A1, COL6A2, or COL6A3 variants (Lampe and Bushby, 2005; Jobsis et al., 1999). Once thought to be strictly a recessive condition, UCMD has been shown to be inherited in a dominant manner in numerous cases (e.g., Pan et al. Am J Hum Genet 73:355-369, 2003). A dominant-negative effect underlies pathogenicity of dominantly inherited UCMD (Pan et al., 2003; Baker et al., Hum Mol Genet 14:279-293, 2005), while most cases of recessive UCMD result from truncating variants. Substitutions affecting the conserved Gly-X-Y motif of all three COL6 genes and splice site variants affecting exon 14 of COL6A1 are common pathogenic variants.

Sequence analysis using genomic DNA from peripheral blood was found to have clinical sensitivity of 66%, 56%, and 79% among patients classified as having typical Bethlem Myopathy, severe Bethlem Myopathy, and Ulrich Congenital Muscular Dystrophy, respectively (Lampe et al. J Med Genet 42:108-120, 2005).

This test provides full coverage of all coding exons of the COL6A3 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).