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May 15, 2017

Mutation screening in genes known to be responsible for Retinitis Pigmentosa in 98 Small Han Chinese Families

Lulin Huang, Qi Zhang, Xin Huang, Chao Qu, Shi Ma, Yao Mao, Jiyun Yang, You Li, Yuanfeng Li, Chang Tan, Peiquan Zhao, Zhenglin Yang | Scientific Reports | Vol 7 | pg. 1948 | 16 May 2017 | doi.org/10.1038/s41598-017-00963-6


Abstract

Retinitis pigmentosa (RP) is highly heterogeneous in both clinical and genetic fields. Accurate mutation screening is very beneficial in improving clinical diagnosis and gene-specific treatment of RP patients. The reason for the difficulties in genetic diagnosis of RP is that the ethnic-specific mutation databases that contain both clinical and genetic information are largely insufficient. In this study, we recruited 98 small Han Chinese families clinically diagnosed as RP, including of 22 dominant, 19 recessive, 52 sporadic, and five X-linked. We then used whole exome sequencing (WES) analysis to detect mutations in the genes known for RP in 101 samples from these 98 families. In total, we identified 57 potential pathogenic mutations in 40 of the 98 (41%) families in 22 known RP genes, including 45 novel mutations. We detected mutations in 13 of the 22 (59%) typical autosomal dominant families, 8 of the 19 (42%) typical autosomal recessive families, 16 of the 52 (31%) sporadic small families, and four of the five (80%) X-linked families. Our results extended the mutation spectrum of known RP genes in Han Chinese, thus making a contribution to RP gene diagnosis and the pathogenetic study of RP genes.


Introduction

Retinitis pigmentosa (RP, OMIM#268,000) is caused by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina, and results in progressive vision loss1. RP is an inherited degenerative eye disease that causes severe vision damage and often results in blindness1. Affected individuals may experience difficulties in light-to-dark and dark-to-light adaptation or night blindness at the early stage of RP. RP is likely the most common type of retinal dystrophy. The worldwide prevalence of non-syndromic RP is approximately 1 in 40002. The prevalence of non-syndromic RP in China had been reported at 1 in 38003.


RP exhibits autosomal dominant (adRP), autosomal recessive (arRP), or X-linked (xlRP) models. In very rare cases, the cause is a digenic pattern of inheritance. Non-systemic RP represents about 70–80% of all cases4. Autosomal dominant, autosomal recessive, and X-linked account for approximately 30–40%, 50–60%, and 5–15% respectively of patients with RP2. Approximately 30% are sporadic cases4, most of which may belong to the autosomal recessive inheritance group.


RP genetics are complicated and heterogeneous. To date, 27 autosomal dominant, 58 autosomal recessive, and three X-linked RP genes have been identified in the RetNet database (http://www.sph.uth.tmc.edu/retnet/). Among these genes, six—BEST1, NR2E3, NRL, RHO, RP1, and RPE65—can cause both autosomal dominant and autosomal recessive RP. In addition, mutations in several genes, including ABCA4 5, PROM1 6, PRPH2 7, C8orf37 8, and PRPF31 9, can cause both RP and macular degeneration.


Because of the highly genetic heterogeneity of RP, an accurate genetic diagnosis is needed to improve clinical diagnosis10. In recent years, whole exome sequencing (WES) has been used for the molecular diagnosis of Mendelian diseases11. Although similar studies in RP have been published in the last few years, most of these reports were focused on the Caucasian population. Published RP mutations in the Chinese population are rare in the Human Gene Mutation Database (HGMD, http://www.hgmd.org/) and the Online Mendelian Inheritance in Man (OMIM, http://omim.org/). Different populations may have different mutation spectra, which is very important in studying the origin and pathogenesis of heterogeneous diseases such as RP. In this study, we investigated the mutations of known RP genes in 101 patients in 98 small Han Chinese RP families, which is beneficial for RP gene diagnosis and the pathogenic study of RP.



 

References

  1. Hamel, C. Retinitis pigmentosa. Orphanet J Rare Dis 1, 40 (2006).

  2. Hartong, D. T., Berson, E. L. & Dryja, T. P. Retinitis pigmentosa. Lancet 368, 1795–1809 (2006).

  3. Hu, D. N. Prevalence and mode of inheritance of major genetic eye diseases in China. Journal of Medical Genetics. 24, 584–588 (1987).

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  5. Sun, H., Smallwood, P. M. & Nathans, J. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet 26, 242–246 (2000).

  6. Yang, Z. et al. Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice. J Clin Invest 118, 2908–2916 (2008).

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  8. van Huet, R. A. et al. Clinical characteristics of rod and cone photoreceptor dystrophies in patients with mutations in the C8orf37 gene. Invest Ophthalmol Vis Sci 54, 4683–4690 (2013).

  9. Lu, F. et al. A novel PRPF31 mutation in a large Chinese family with autosomal dominant retinitis pigmentosa and macular degeneration. PLoS One 8, e78274 (2013).

  10. Wang, X. et al. Comprehensive molecular diagnosis of 179 Leber Congenital Amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. Journal of medical genetic (2013).

  11. Srivastava, S. et al. Clinical whole exome sequencing in child neurology practice. Annals of neurology 76, 473–483 (2014).

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