Aims To reveal the Usher syndrome type IIA (USH2A) gene variant profile in a large cohort of Chinese patients with non-syndromic retinitis pigmentosa (RP) or Usher syndrome type II (USH2) and to explore the genotype–phenotype correlation.
Methods Targeted exome capture plus next-generation sequencing confirmed that 284 patients from 260 unrelated Chinese families carried USH2A disease-associated variants. Both personal medical history and family histories were reviewed. Ocular examinations were performed and audiograms were recorded if hearing loss was suspected. The genotype–phenotype correlation was evaluated by statistical analyses.
Results A total of 230 variants in the USH2A gene were identified, of which 90 (39.13%) were novel. The most common variants in the RP and USH2 probands were p.Cys934Trp and p.Tyr2854_2894del, respectively, and 26.42% and 63.64% of the alleles in the RP and USH2 groups were truncating, respectively. Patients harbouring biallelic truncating variants had a younger age at the initial clinical visit and symptom onset than patients with missense variants; furthermore, the patients with USH2 had a younger age at the initial clinical visit and nyctalopia onset compared with the patients with RP (p<0.001). For the patients with USH2, the age of nyctalopia onset was positively correlated with that of hearing loss (p<0.05, r=0.219). In addition, three pseudo-dominant pedigrees were identified carrying biallelic USH2A variants.
Conclusions This study enrolled the largest cohort of Chinese patients with USH2A and identified the most prevalent USH2A variants in USH2 and RP. We found that the patients with USH2 had more truncating variants and experienced an earlier decline in visual function. The findings enhance the current knowledge of USH2A heterogeneity and provide valuable information for future therapies.
- Eye (Globe)
- Stem Cells
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TZ and D-FC served jointly as first authors.
Some of this article was presented as a poster at the 57th Annual Symposium of International Society for Clinical Electrophysiology of Vision (ISCEV) on 10 October 2019 in Seoul, Korea.
Correction notice This paper has been updated since it was published online. Two statements in the gutter of the first page were omitted and these have now been reinstated.
Contributors RS and Z-BJ have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design were done by TZ, D-FC, Z-BJ and RS. Acquisition of data were done by all authors. Analysis or interpretation of data was done by HL, Z-BJ and RS. Drafting of the manuscript was done by TZ, D-FC, Z-BJ and RS. Statistical analysis was done by TZ and D-FC. Critical revision of the manuscript for important intellectual content was done by TZ, D-FC, HL, Z-BJ and RS.
Funding This work was supported by National Nature Science Foundation of China, China (81873687, 81970838); Beijing Natural Science Foundation, China (7152116); CAMS Innovation Fund for Medical Sciences (CIFMS 2016-I2M-1-002) and Foundation Fighting Blindness (CD-CL-0214-0631-PUMCH).
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval This study was approved by the Institutional Review Board of PUMCH and The Eye Hospital of Wenzhou Medical University.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data relevant to the study are included in the article or uploaded as supplementary information.
Data availability statement Unpublished data are available on contacting the corresponding author.