Homozygous initiation codon-altering complex variant causes rapid-onset chorioretinopathy phenotype in ABCA4 disease

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Stargardt disease is a common inherited macular dystrophy.
• ABCA4 gene mutations are a primary cause of Stargardt disease.
• Understanding genotype-phenotype correlations is crucial for prognosis.

Purpose of the Study:

• To characterize the clinical phenotype of a specific homozygous ABCA4 start codon variant.
• To evaluate the severity and prognosis of this variant in Stargardt disease.

Main Methods:

• Retrospective review of patients with homozygous ABCA4 start codon variants.
• Ophthalmic examination, multimodal imaging, and full-field electroretinography (ffERG).
• Inherited retinal disease panel testing and structural/functional retinal assessments.

Main Results:

• Three brothers presented with early-onset, profound vision loss and rapid chorioretinopathy.
• Imaging showed macular atrophy and outer retinal layer loss.
• Patients were homozygous for the complex ABCA4 variant c.[1A>G;6089G>A], consistent with null alleles.

Conclusions:

• The c.[1A>G;6089G>A] ABCA4 variant causes a severe, rapid-onset chorioretinopathy.
• This complex allele is pathogenic and expands the ABCA4 genotype-phenotype spectrum.
• Findings have implications for Stargardt disease prognosis and genetic counseling.