COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management
Diana Tambala1, Rachel Vassar2, John Snow3
1Department of Neurology, Massachusetts General Hospital, Boston, MA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
Purpose:
Collagen type 4 alpha 1 (COL4A1) and alpha 2 (COL4A2) chains, encoded by COL4A1 and COL4A2, are essential for basement membrane integrity, contributing to structural stability and cell regulation. Pathogenic variants in these genes cause a spectrum of autosomal dominant and, more rarely, autosomal recessive disorders, which are collectively known as COL4A1/A2-related disorders. These multisystem disorders can include neurologic, ophthalmologic, renal, and other organ system pathology and vary widely in symptoms, complicating diagnosis and management.
Methods:
Using a modified eDelphi method, we obtained consensus from international experts across medical subspecialties on the evaluation and management of COL4A1/A2-related disorders, with consensus set at ≥70% agreement.
Results:
Consensus was achieved on recommendations for evaluating and managing these conditions.
Conclusion:
Genetic testing and counseling are advised for individuals showing symptoms of COL4A1/A2-related disorders and for at-risk relatives. Given the complexity and rarity of these disorders, management requires a multidisciplinary approach informed by current understanding of disease mechanisms. Recommended care includes neurological and ophthalmological imaging and monitoring of cardiovascular and renal function. Ongoing research is critical to uncover genotype-phenotype links and potential modifiers, with clinical research participation encouraged to advance knowledge and treatments.
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