COL2A1-Related Disorders via the COL2A1 Gene

Stickler syndrome (STL) is a multisystem disorder characterized by ocular, skeletal, orofacial and auditory defects. Ocular defects include myopia, cataract, and retinal detachment. Hearing loss can be both conductive and sensorineural. Other features include midfacial underdevelopment and cleft palate and mild spondyloepiphyseal dysplasia and/or precocious arthritis (Robin et al. 2017). Pathogenic variants in COL2A1, COL11A1, COL11A2, COL9A1, COL9A2 and COL9A3 are responsible for type I, Type II, Type III, Type IV, Type V and type VI Stickler syndrome, respectively (Robin et al. 2017; Van Camp et al. 2006; Baker et al. 2011; Nikopoulos et al. 2011; Vijzelaar et al. 2013). Stickler syndrome Type I (STL1) is characterized by “membranous” congenital vitreous anomaly; Stickler syndrome Type II (STL2) is characterized by “beaded” congenital vitreous anomaly, Stickler syndrome (STL3) has craniofacial and joint abnormalities and hearing loss, but no ocular findings. Stickler syndrome Type IV and Type V have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy (Baker et al. 2011). Stickler syndrome Type VI features moderate-to-severe sensorineural hearing loss, moderate-to-high myopia, and midface retrusion (Faletra et al. 2014). One study suggested that hearing loss (mostly mild to moderate) was found in ~60% of Stickler patients. Hearing loss was seen in patients with COL11A1 (~80%), COL11A2 (~94%) and COL2A1 (~52%) pathogenic variants (Acke et al. 2012). Stickler syndrome was also found in 39 out of 141 newborns who were diagnosed with Pierre-Robin sequence (Thouvenin et al. 2013).

Pathogenic variants in COL2A1 mainly cause autosomal dominant Stickler syndrome, as well as autosomal dominant Achondrogenesis type II/Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital, Spondyloepimetaphyseal dysplasia, Strudwick type, Spondyloperipheral dysplasia, Kniest dysplasia, Osteoarthritis with mild chondrodysplasia, Platyspondylic lethal skeletal dysplasia, Torrance type and Multiple Epiphyseal Dysplasia (Jackson 2012). Pathogenic variants in the COL2A1 gene were also reported to be associated with autosomal recessive Otospondylomegaepiphyseal dysplasia (Tham et al. 2015). COL2A1 encodes the alpha 1 chain of type II collagen, a major structural component of cartilaginous tissues. More than 500 pathogenic variants have been reported: missense (~47%), nonsense (~8%), splicing (~18%), small deletions/insertions (~26%), and a few large deletions/complex rearrangements (~1%) (Human Gene Mutation Database). Glycine substitution in the collagen triple helix repeat domain of the COL2A1 protein accounts for almost 34% of all deleterious variants identified in the COL2A1 gene (Barat-Houari et al. 2016).

In one study, pathogenic variants in the COL2A1 gene were found in 100 of 188 probands with clinically diagnosed Stickler syndrome (Hoornaert et al. 2010).

This test provides full coverage of all coding exons of the COL2A1 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).