Purpose:

To establish a mutation-specific age-dependent ultra-widefield fundus autofluorescence (UWF-FAF) trajectory in a large Stargardt disease (STGD1) cohort using total lesion size (TLS) and to develop a clinical method for variant classification.

Methods:

A retrospective study of patients with biallelic ABCA4 mutations that were evaluated with UWF-FAF. Boundaries of TLS, defined by stippled hyper/hypoautofluorescence, were outlined manually. Pathogenicity was assessed according to ACMG/AMP criteria, and mutation severities were classified based on the current literature. Age-dependent trajectories in TLS were examined in patients with nullizygous, mild, and intermediate mutations. Mutations of uncertain severities were classified using a clinical criterion based on age of symptom onset and TLS.

Results:

Eighty-one patients with STGD1 (mean age= 42±20 years and mean visual acuity= 20/200) were recruited from 65 unrelated families. Patients with biallelic null/severe variants (n= 6) demonstrated an increase in TLS during their second decade reaching a mean±SD of 796±29 mm 2 by age 40. Those harboring mild mutations c. 5882G> A or c. 5603A> T had lesions confined to the posterior pole with a mean±SD TLS of 30±39 mm 2. Intermediate mutations c. 6079C> T or c.[2588G> C; 5603A> T] in trans with a null/severe mutation had a mean±SD TLS of 397±29 mm 2. Thirty-two mutations were predicted to cause severe (n= 22), intermediate (n= 6), and mild (n= 5) impairment of ABCA4 function based on age of symptom onset and TLS.

Conclusion:

Age-dependent TLS showed unique ABCA4 mutation-specific trajectories. Our novel clinical criterion using age of symptom onset and TLS to segregate ABCA4 mutations into three severity groups requires further molecular studies to confirm its validity.