Expansion of the ABCA4-Associated Retinopathy Spectrum: Severe Variants Can be Associated With Early-Onset Severe Retinal Dystrophy.

Purpose: Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are inherited retinal diseases that are characterized by severe visual loss very early in life. Whereas LCA is characterized by loss of vision in the first year of life, nystagmus, and absent or abnormal electrical signals on electroretinogram, persons with EOSRD show onset of disease between 1 and 5 years of age, with better preserved visual acuity and some signals on an electroretinogram. We investigated the genetic cause of disease and clinical characteristics in three probands with EOSRD.

Methods: All patients were examined by at least two ophthalmologists to reach a clinical diagnosis. APEX microarray screening, smMIP-based sequencing, and whole exome and whole genome sequencing were used to obtain a genetic diagnosis and investigate potential modifiers.

Results: The EOSRD phenotype of these three probands was established through ophthalmological investigation. Biallelic severe ABCA4 variants were identified after the phenotypic diagnosis of EOSRD in these probands. We then asked whether additional gene defects may be involved and worsen the phenotype. Through whole genome sequencing we identified two NBAS variants in patient 1 and a well-known homozygous, hypomorphic missense variant in CNGB3 in patient 3.

Conclusions: We propose that biallelic severe ABCA4 variants can be implicated in EOSRD. We hypothesize that the ABCA4 and CNGB3 variants could have an additive effect given the colocalization of the encoded proteins in cone photoreceptors cell membranes. Whether the CNGB3 and NBAS variants play a modifying role remains to be investigated.