Distal Myopathy 2 via the MATR3 Gene

A variant in the matrin 3 protein, encoded by MATR3 (OMIM 164015), has been found to be causative for a form of distal myopathy often associated with vocal cord and pharyngeal weakness (VCPDM; OMIM 606070). Two large families, one of North American origin (Feit et al. Am J Mum Genet 63:1732-1742, 1998) and one of Bulgarian origin (Senderek et al. Am J Hum Genet 84:511-518, 2009) demonstrate autosomal dominant inheritance of a distal myopathy with onset typically between 35-57 years of age. The earliest sign among patients from these families is usually ankle and feet muscle weakness, although some cases present with hand weakness and in still others the first symptom is voice change. The pattern of weakness of the hands is unique, because the extensors are each affected to varying degrees (Feit et al. 1998). An asymmetric pattern of muscle involvement is typical in the early stage of the disease, but slow progression leads to symmetric weakness of the distal muscles. Shoulder and pelvic girdle muscles are eventually affected but ambulation is preserved. Most affected individuals have some vocal cord or swallowing complications. Muscle biopsies from affected individuals reveal variations in fiber size, fiber splitting, and rimmed vacuoles (Senderek et al. 2009). Serum CK levels are at the most only moderately elevated.

Distal myopathy with vocal cord and pharyngeal weakness associated with a MATR3 variant is inherited as an autosomal dominant condition. The same exon 2 p.Ser85Cys variant has been found on two distinct haplotype backgrounds in two VCPDM families, indicating at least two unique mutational origins (Senderek et al. 2009). No other MATR3 variants have been reported. Matrin 3 is expressed in skeletal muscle and is a nuclear matrix protein.

Analytical sensitivity for the known missense variant is expected to be close to 100%. Clinical sensitivity cannot be estimated at this time.

This test provides full coverage of all coding exons of the MATR3 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).