Stickler Syndrome Type III, Otospondylomegaepiphyseal Dysplasia, Weissenbacher-Zweymuller Syndrome, and Deafness, Autosomal Dominant 13 via the COL11A2 Gene

Stickler syndrome is a multisystem connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia or precocious arthritis (Robin et al. GeneReviews. 2010). Stickler syndrome type III (STL3; OMIM#184840) is a rare form of STL; patients with this type usually have craniofacial and joint manifestations and hearing loss but have no ocular findings.

Otospondylomegaepiphyseal dysplasia (OSMED; OMIM#215150) is characterized by sensorineural hearing loss, enlarged epiphyses, disproportionate shortness of the limbs, and abnormalities in vertebral bodies (Melkoniemi et al. Am J Hum Genet 66:368–377, 2000).

Weissenbacher-Zweymuller syndrome (WES; OMIM# 277610) is a rare condition described as “combination of a Pierre Robin sequence with a fetal chondrodysplasia”. It has features that overlap the Kniest-Stickler-dysplasia group (Pihlajamaa et al. Am J Med Genet 80:115–120, 1998).

Autosomal dominant nonsyndromic hearing loss (DFNA13; OMIM#601868) is a postlingual form of non-progressive deafness that predominantly affects middle frequencies (McGuirt et al. Nat Genet 23:413-419, 1999).

STL3, WES and DFNA13 are inherited in an autosomal dominant manner, while OSMED is inherited in an autosomal recessive manner. All four disorders can be caused by variant in the COL11A2 gene, which encodes the alpha 2 chain of type XI collagen. Type XI procollagen is a heterotrimeric protein assembled from the products of three genes: COL11A1, COL11A2, and COL2A1. Mature type XI collagen accounts for 3%–10% of the collagenous protein content of cartilage (Tompson et al. Am J Hum Genet 87:708-712, 2010). The majority of COL11A2 variants are truncating variants and missense variants mainly affecting conserved glycine residues in the triple-helical domain.

This test is predicted to detect disease variants in virtually all individuals with a clinical diagnosis of OSMED (Melkoniemi et al., 2000). Sensitivity for STL3, WES, and DFNA13 is currently unknown.

This test provides full coverage of all coding exons of the COL11A2 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).