Clinical findings and RS1 genotype in 90 Chinese families with X-linked retinoschisis

Abstract

Purpose: X-linked retinoschisis (XLRS) is an early-onset retinal degenerative disorder caused by mutations in the RS1 gene. The objective of this study was to describe the clinical and genetic findings in 90 unrelated Chinese patients with XLRS.

Methods: All patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, and spectral domain-optical coherence tomography (SD-OCT). A combination of molecular screening methods, including Sanger-DNA sequencing of RS1 and targeted next-generation sequencing (TES), were used to detect mutations. In silico programs were used to analyze the pathogenicity of all the variants. Long-range PCR with subsequent DNA sequencing was employed to find the breakpoints of large deletions.

Results: The 90 probands (mean age 17.29±12.94 years; 3-52 years) showed a variety of clinical phenotypes, and their average best correct visual acuity was 0.81±0.48 (logarithm of the minimal angle of resolution, 0-3). Of the 175 eyes analyzed, 140 (80%) had macular retinoschisis, 84 (48%) had peripheral retinoschisis, 28 (16%) had macular atrophy, and five (3%) had a normal macular structure. We identified 68 mutations in this cohort of patients, including 15 novel mutations. Most mutations (65%) were missense; the remaining null mutations included nonsense, splicing effect, frameshift indel, and large genomic DNA deletions. The 62 patients with missense mutations seemed to have relatively milder visual defects than the 28 patients with null mutations.

Conclusions: Patients with RS1 mutations present profound phenotypic variability and show no clear genotype-phenotype correlations. Patients with null mutations tend to have more severe XLRS-related visual defects.

Figure 1

The distribution of 68 distinct mutations of RS1 detected in our study and the breakpoints in two large deletions. A: The distribution of 68 mutations on exons of RS1. B: Lengths and positions of the two gross deletions of RS1 (in box with blue border). E indicates exon. Red squares indicate exons in coding regions. Black squares indicate exons in non-coding regions, and thick black lines indicate introns and upstream or downstream non-coding regions. The blue numbers indicate lengths of deletions in each corresponding region.

Figure 2

Colored fundus (CF) photographs, optical coherence tomography (OCT) scans, and fundus autofluorescence (FAF) of five patients with RS displaying typical macular and peripheral retinoschisis or macular atrophy. A: CF photographs, OCT scans, and FAF of patient 113690 showing macular retinoschisis and a spoke-wheel pattern of hyperfluorescence. B: CF photograph and OCT scan of patient 113190 displaying macular retinoschisis. C: CF photograph, OCT scan, and FAF of patient 113370 displaying macular atrophy and hypofluorescence in the macular region. D: CF photograph and OCT scan of patient 113660 presenting both macular and peripheral retinoschisis. E–H: CF photograph and OCT scan of patient 113310 showing normal macular structure (E and F) and peripheral retinoschisis (E and G). H: FAF of patient 113310 presenting almost-normal fluorescent pattern in the macular region and a hypofluorescent region corresponding to the peripheral retinoschisis.

Figure 3

Colored fundus (CF) photographs and optical coherence tomography (OCT) scans of four patients with X-linked retinoschisis displaying atypical fundus appearances. A: CF photographs of patient 113270 showing bilateral peripheral retinoschisis involving the macula and severe retinal pigment degeneration with pigmentation, sheathed retinal vessels, and white dots at the temporal retina. B: CF photographs of patient 019143 presenting bilateral macular atrophy and retinal pigment degeneration with bone spicules and arteriole narrowing in the peripheral retina. C: CF photographs of patient 113580 showing macular atrophy with pigmentation, white spiculations in the peripheral retina of the right eye, and pigmentation in the peripheral retina of the both eyes and OCT scans presenting bilateral macular atrophy and peripheral retinoschisis in the right eye. D: CF photographs and OCT scans of patient 1131090 displaying symmetric macular atrophy with pigmentation.

Figure 4

Comparison of the age, visual acuity, and clinical characteristics of groups A and B. A: Scatter plot and regression line of visual acuity with age in group A (red filled circles) and group B (solid green pentagrams). B: Bar chart of the clinical characteristics of the patients in groups A and B. Asterisks mark statistically significant differences (p<0.05). The numbers on the top of each bar indicate numbers of eyes with different clinical features.