Purpose: To comprehensively characterize the clinical consequences of the CRB1 variant p.(Pro836Thr). In African populations, this variant has an allele frequency of 0.329% (gnomAD v4.1.0).
Methods: This study was a retrospective case series of 14 patients from 11 families with molecularly confirmed CRB1-associated retinal dystrophy, each possessing at least one p.(Pro836Thr) variant. The age at onset of visual symptoms, best-corrected visual acuity, imaging findings, and quantitative electrophysiologic measurements of retinal function were analyzed.
Results: The p.(Pro836Thr) variant was homozygous in four families and compound heterozygous in seven families. The familial origins included Nigeria (n = 4), Ghana (n = 3), the Caribbean region (n = 2), and Uganda (n = 1). The median follow-up was 7 years (interquartile range, 3-16). Symptom onset was most common in childhood (eight patients, 57.1%). Reduced central vision was the most frequent presenting symptom (12 patients, 85%). Widefield multimodal imaging revealed peripheral retinal changes in addition to macular changes in three patients. Nine patients had international standard electrophysiology and showed generalized retinal dysfunction with a similar degree of rod and cone system involvement (n = 7) or a clear rod-cone pattern of dysfunction (n = 2). All had pattern electroretinography (ERG) evidence of macular dysfunction.
Conclusions: The study highlights the association of the p.(Pro836Thr) variant with African ancestry and characterizes their key clinical and electrophysiological features. Our study suggests that the p.(Pro836Thr) variant confers a less severe consequence on retinal function and structure than the majority of other reported CRB1 variants. Although retinal imaging may show alterations confined to the macular region, electrophysiology in this series indicates generalized cone and rod photoreceptor dysfunction.