Phenotypic conservation in RPGR mutations

Abstract

Purpose: : To describe phenotypic conservation in 13 distinct RPGR (XLRP) mutations.

Methods: : A retrospective chart review was conducted of 39 X-linked retinitis pigmentosa (XLRP) patients from 22 families with mutations in RPGR. Each mutation was found in two or more related or unrelated patients. Clinical data included visual acuity (VA), Goldmann visual fields (GVF), and electroretinography (ERG). Concordance was defined as the similarity of a clinical parameter at a given age. VA was analyzed in two different ways to look for concordance of VA at a given age as well as progression of VA. ERG phenotype (cone-rod vs. rod-cone dysfunction) was defined by the extent of photopic vs. scotopic dysfunction. GVF phenotype was determined by the GVF pattern, where central or peripheral loss suggested cone or rod dysfunction, respectively.

Results: : Patients ranged in age at first visit from 5 to 48 years. Five mutations in 15 patients displayed no concordance of VA with age. Six mutations in 17 patients displayed moderate concordance of VA with age, while two mutations in 7 patients displayed strong concordance, despite originating from different families. Six mutations displayed concordance for deterioration of VA with age. Five of 9 (56%) mutations displayed a definitive cone-rod or rod-cone ERG that was consistent between patients, while the remaining four mutations displayed both phenotypes. Four mutations could not be assessed for concordance, because of non-recordable (NR) ERG values in several patients. Twelve of 13 (92.3%) mutations displayed concordant GVF phenotypes (10 rod-cone vs. 2 cone-rod), while one mutation exhibited both GVF phenotypes. All 5 mutations displaying a constant ERG pattern revealed a GVF phenotype consistent with the ERG phenotype.

Conclusions: : Several reports have previously shown that phenotypic variability can occur in families with RPGR mutations. Our analysis reveals that despite the fact that VA and ERG phenotypes were concordant in only a portion of patients with the same mutations, assessment of GVF phenotypes, revealed strong phenotypic conservation. NR ERG values complicated assessment of concordance with respect to ERG. Importantly, this suggests that many mutations exhibit phenotypic concordance, which can be revealed with assessment of all clinical parameters, especially visual field data. Understanding phenotypic variability will be important in evaluating outcomes in future clinical trials.

Keywords: retinal degenerations: hereditary • genetics