Stickler Syndrome Type II, Marshall Syndrome, and Fibrochondrogenesis via the COL11A1 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). About 10-20% of individuals with Stickler syndrome have type II “beaded” congenital vitreous anomaly and significant hearing loss (STL2, OMIM#604841). Marshall syndrome (OMIM#154780) shares many manifestations in common with STL, but patients more often have short stature, deafness, and abnormalities in cranial ossification as well as more-pronounced dysmorphic features (Annunen et al. Am J Hum Genet 65:974-983, 1999). Fibrochondrogenesis (OMIM#228520) is a severe short-limbed skeletal dysplasia, characterized by a flat mid-face, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen (Tompson et al. Am J Hum Genet 87:708-712, 2010).

STL2 and Marshall syndrome are inherited in an autosomal dominant manner. Fibrochondrogenesis is inherited in an autosomal recessive manner. All three disorders are caused by variant in the COL11A1 gene, which encodes the alpha 1 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. 2010). The majority of COL11A1 variants are missense variants (mainly affecting conserved glycine residues) in the triple-helical domain, splice site alternations, and truncating variants. Gross gene deletions have also been reported (Martin et al. Eur J Hum Genet 7:807-814, 1999) but are very rare. Genotype-phenotype correlation remains to be established.

This test is predicted to detect disease variants in ~10-20% of individuals with a clinical diagnosis of STL2 (Robin et al. GeneReview, 2010) and 23-68% of individuals with Marshall syndrome or overlapping Marshall-Stickler phenotype (Annunen et al., 1999; Majava et al. Am J Med Genet 143A:258–264, 2007). Sensitivity for fibrochondrogenesis is currently unknown.

This test provides full coverage of all coding exons of the COL11A1 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).