Early onset flecked retinal dystrophy associated with new compound heterozygous RPE65 variants

To report genetic and clinical features of two unrelated Japanese patients with early onset flecked retinal dystrophy.

Patients underwent comprehensive ophthalmic examinations that included electroretinography (ERG) after 30 min and 24 h of dark adaptation (DA). Disease-causing gene variants were identified with whole exome sequencing (WES), with identified candidates confirmed with direct sequencing.

WES identified compound heterozygous RPE65 variants in both patients. Variants in patient 1 included c.1543C>T (p.R515W) and c.683A>C (p.Q228P), while patient 2 exhibited c.1028T>A (p.L343*) and c.683A>C (p.Q228P). Although variants p.R515W and p.L343* have been previously reported as pathogenic, variant p.Q228P was reported as uncertain significance. Each unaffected parent carried the variant heterozygously. Both patients had similar ophthalmic findings, including decreased visual acuity with early onset night blindness, numerous dense white dots/flecks occurring mainly outside the vascular arcades, a diffuse and/or disrupted ellipsoid line as shown with optical coherence tomography, and non-recordable rod and combined responses along with decreased cone responses after 30 min of DA. After 24 h of DA, both patients exhibited marked or partial recovery of the combined responses.

The results indicate that the recovery of combined or residual cone responses might be associated with a mild form of RPE65-related early onset flecked retinal dystrophy with new compound heterozygous variants.