Distal Arthrogryposis/Gordon Syndrome via the PIEZO2 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).

Pathogenic variants in PIEZO2 cause Gordon syndrome and distal arthrogryposis type 5. Gordon syndrome (distal arthrogryposis type 3) is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet (Bamshad et al. 2009). Distal arthrogryposis type 5 is distinguished from other forms of DA by the presence of ocular abnormalities, typically ptosis, ophthalmoplegia, and/or strabismus, in addition to contractures of the skeletal muscles (Okubo et al. 2015).

Pathogenic variants in PIEZO2 gene cause Distal Arthrogryposis type 5 or 3 and are inherited in autosomal dominant pattern. PIEZO2 (Piezo-type mechanosensitive ion channel component 2) contains 52 exons, encodes 2752 amino acids and spans over 48 kb on Chromosome 18p11.21 (Coste et al. 2010). The protein encoded by PIEZO2 is an essential component of mechanosensory ion channels, which transduce mechanical forces to biological signals and is responsible for a variety of mechanosensory responses, such as, light touch, proprioception, pain, etc. (Coste et al 2010). A functional study indicated that pathogenic variants in PIEZO2 could increase channels activity by slowing inactivation or recovering faster from inactivation (Coste et al. 2013). Only missense pathogenic variants and small deletions have been reported (Human Gene Mutation Database). Nonsense variants, large deletions/duplications or rearrangements have not been documented (HGMD).      

It has been reported that pathogenic variants in PIEZO2 were identified in 24/29 (82%) distal arthrogryposis type 5-affected families and in 10 out of 12 (83%) Gordon syndrome-affected families (McMillin et al. 2014).

This test provides full coverage of all coding exons of the PIEZO2 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).