The Phenotypic and Genotypic Features of ADAMTSL4-Related Ocular Disease

Pathogenic variants in ADAMTSL4 are an important cause of isolated ectopia lentis with an increasing number of genetically confirmed cases internationally. We sought to better describe ocular features seen with pathogenic variants in ADAMTSL4. We performed a retrospective, multicenter study examining the phenotypic and genotypic spectrum of ADAMTSL4-associated ocular disease. We identified 41 individuals from 32 families with genetically confirmed ADAMTSL4-related disease across six tertiary referral centers across Europe. Identified participants had a young age of diagnosis (median 1.3 years) and a highly myopic refractive error (mean SE -10.27 D). A diagnosis of ectopia lentis et pupillae was made in a third of cases, with a younger age at diagnosis (median 0.5 years). Subluxation tended to be in the inferior direction (~33%). Zonules were noted to be missing or absent in the majority of cases. Sixteen different pathogenic variants in ADAMTSL4 were reported. A previously reported 20-bp deletion (c.767_786del) was highly prevalent in this cohort (23/32), and all ectopia lentis et pupillae cases carried this variant. ADAMTSL4-related disease tends to present at a younger age and be associated with higher myopia than other forms of ectopia lentis (such as FBN1). Early identification of typical phenotypic features alongside genetic testing can aid early, precise diagnosis and prevent unnecessary investigations.