Stickler Syndrome Panel, Sequencing

Stickler syndrome and related disorders are a group of inherited conditions characterized by ocular abnormalities, hearing loss, and skeletal or joint problems. Most individuals with Stickler syndrome have a distinct facial appearance with a flattened midface, sometimes with Pierre Robin sequence. The majority of cases of Stickler syndrome are caused by variants in the COL2A1 gene, which codes for type II collagen. Variants in COL2A1 are also associated with a number of related disorders with variable severity, including achondrogenesis type II, spondyloepiphyseal dysplasia congenita, and spondyloperipheral dysplasia. Pathogenic variants in COL11A1 and other collagen genes cause a smaller percentage of Stickler syndrome cases, as well as other disorders with overlapping features such as fibrochondrogenesis and multiple epiphyseal dysplasia. Diagnosis of Stickler syndrome or a related disorder may be suspected based on clinical features, but confirmation of the condition requires genetic testing.

Disease Overview

Symptoms

• Ocular abnormalities (eg, high myopia, vitreous abnormalities, retinal detachment)
• Hearing impairment (both conductive and sensorineural)
• Skeletal abnormalities (eg, early-onset arthritis, short stature, spondyloepiphyseal dysplasia upon radiographic evaluation, scoliosis, or kyphosis)
• Craniofacial features (eg, flat facial profile/midface hypoplasia or cleft palate, sometimes with Pierre Robin sequence)

Genetics

Genes

COL11A1, COL11A2, COL2A1, COL9A1, COL9A2, COL9A3, VCAN

Etiology

Stickler syndrome may be caused by pathogenic variants in the COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, and COL9A3 genes. In some rare families, other unknown genes may be involved. Pathogenic variants in VCAN cause Wagner syndrome, a condition with overlapping ocular symptoms.

Penetrance

100%

Prevalence

1/7,500 to 1/9,000 among newborns

Inheritance

See Genes Tested table below

Variable, dependent on phenotype/condition

Analytic Sensitivity

For massively parallel sequencing:

Limitations

• A negative result does not exclude a diagnosis of Stickler syndrome or a related disorder.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
  • Regulatory region and deep intronic variants
  • Noncoding transcripts
  • Large deletions/duplications in any of the tested genes (large deletions/duplications account for <1% of causative variants for Stickler syndrome)
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Some variants, due to technical limitations in the presence of pseudogenes or repetitive or homologous regions
  • Low-level somatic variants

Genes Tested