Distal Arthrogryposis Type 5D (DA5D) via the ECEL1 Gene

Distal arthrogryposis (DA) syndromes are a group of multiple congenital contracture disorders with distal joint involvement and variable clinical expression. Distal arthrogryposis type 5D (DA5D) is an autosomal recessive DA syndrome with unique facial features (McMillin et al. 2013. PubMed ID: 23261301). Clinical features include congenital contractures affecting mostly distal joints of upper and lower limbs, club feet, hip dislocation, short stature, and scoliosis. Campdodacytly is more severe in the fingers than the toes with the wrist and thumbs being adducted. Additional findings include ptosis, severe ophthalmoplegia, astigmatism, micrognathia, tongue groove, and cleft palate (Ullmann et al. 2018. PubMed ID: 30131190). A more severe presentation of multiple pterygia and fetal arthrogryposis has also been reported (Bayram et al. 2016. PubMed ID: 26752647).

Distal arthrogryposis type 5D is inherited in an autosomal recessive manner. Reported causative variants include missense, nonsense, splicing, and small frameshift deletions/duplications and indels that result in premature protein termination (Human Gene Mutation Database).

The ECEL1 gene encodes the endothelin-converting enzyme-like 1 (ECEL1), a type II integral transmembrane zinc metalloprotease. The ECEL1 protein localizes to the brain and peripheral nerves during fetal development and is thought to play a role in neural and neuromuscular junction development (Dieterich et al. 2013. PubMed ID: 23236030; McMillin et al. 2013. PubMed ID: 23261301).

Five of seven families with the features of distal arthrogryposis type 5D were found to have ECEL1 pathogenic variants (McMillin et al. 2013. PubMed ID: 23261301). In another study, six families were found to have ECEL1 pathogenic variants among a cohort of 20 families with non-specific distal arthrogryposis (Dieterich et al. 2013. PubMed ID: 23236030). In a larger cohort of 38 families with fetal akinesia, arthrogryposis, or severe congenital myopathy, one family was found to harbor ECEL1 pathogenic variants (Todd. 2015. PubMed ID: 26578207). To date, no gross deletions or duplications in the ECEL1 gene have been reported (Human Gene Mutation Database). All coding and non-coding regions of the ECEL1 gene that harbor causative variants reported in the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/) as of 06/28/2019 are covered by this test.

This test provides full coverage of all coding exons of the ECEL1 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).