Distal Arthrogryposis 1B via the MYBPC1 Gene

Distal arthrogryposis (DA) syndromes are a group of multiple congenital contracture disorders with distal joint involvement, variable clinical expression, and most often autosomal dominant inheritance (Bamshad et al. 2009).

Distal Arthrogryposis type I (DA1) is the most common, affecting approximately one in 10,000 individuals (Gurnett et al. 2010). Patients with DA1 have contractures that are limited to the hands and feet with no additional anomalies. Variable expressivity, including clubfoot, vertical talus, camptodactyly, overriding fingers, ulnar deviation of the fingers, is common in families with autosomal dominant inherited DA1. DA1 caused by pathogenic variants in MYBPC1 is called DA1B (Bamshad et al. 1996).

Pathogenic variants in MYBPC1 gene cause Distal Arthrogryposis type 1B and are inherited in an autosomal dominant pattern. Myosin binding protein C (MyBP-C) consists of a family of thick filament associated proteins, and it contributes to the regular organization and stabilization of thick filaments and modulates the formation of cross-bridges between myosin and actin (Ackermann et al. 2011). Myosin Binding Protein-C (MyBP-C) includes three isoforms, the cardiac, slow skeletal, and fast skeletal isoforms. MYBPC1 contains 1141 amino acids, is located at 12q23.2 and encodes the slow skeletal isoform (Geist et al. 2016). Pathogenic variants could interfere with the interaction between myosin binding protein c and myosin (Li et al. 2015). Only missense pathogenic variants and one nonsense pathogenic variant have been reported (Human Gene Mutation Database). Small deletions/duplications, large deletions/duplications or rearrangements have not been documented (HGMD).

There is insufficient data to calculate the clinical sensitivity.

This test provides full coverage of all coding exons of the MYBPC1 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).