CLASSIFYING ABCA4 MUTATION SEVERITY USING AGE-DEPENDENT ULTRA-WIDEFIELD FUNDUS AUTOFLUORESCENCE-DERIVED TOTAL LESION SIZE

Abstract

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 mm2 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 mm2. 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 mm2. 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.