Diagnostic genetic testing indications and findings in type II, IX and XI collagenopathies

Type II, IX and XI collagenopathies encompass Stickler syndrome and a spectrum of related connective tissue disorders with diverse and overlapping phenotypes. This study evaluated outcomes of commercial gene panels to understand how genetic testing was used in these collagenopathies.

A retrospective review was undertaken of genetic tests including genes COL2A1, COL11A1, COL11A2, COL9A1, COL9A2 and COL9A3 from a clinical diagnostic laboratory. Cases harbouring pathogenic/likely pathogenic (P/LP) variants were categorised by the ordering panel. Indications for testing were classified into ocular, orofacial, auditory, musculoskeletal, cardiovascular or other symptoms/signs.

Between February 2020 and May 2024, 7798 diagnostic panels were ordered containing the six collagen genes of interest, with 214 unique cases reporting at least one P/LP variant. Overall, Stickler syndrome was the main indication for testing in 48% of cases. Family history and ocular signs were the most common indications in Stickler syndrome genetic testing, while musculoskeletal and neurological/developmental signs more frequently prompted testing with other panel types. The diagnostic yield of Stickler syndrome panels was 50%, with a higher rate among cases reporting a family history (OR: 2.6 (95% CI 1.3 to 5.4); p=0.005) or presenting with ocular signs (OR: 2.2 (95% CI 1.1 to 4.5), p=0.03).

Stickler syndrome is the primary indication for half of the genetic tests ordered for type II, IX and XI collagenopathies, yet accurate diagnosis remains challenging due to overlapping collagenopathy phenotypes. Diagnosis and management could be enhanced through comprehensive documentation of multisystem signs, identification of syndrome-specific features and multidisciplinary care approaches.