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Phenotypic diversity observed in a Chinese patient cohort with biallelic variants in Bardet-Biedl syndrome genes

Eye volume 37, pages 3398–3405 (2023)Cite this article

Subjects

Abstract

Purpose

Bardet-Biedl syndrome (BBS) is a rare multisystem ciliopathy. The aim of this study was to describe the clinical and genetic features of a cohort of Chinese patients carrying biallelic BBS gene variants.

Methods

We recruited 34 patients from 31 unrelated pedigrees who carried biallelic pathogenic variants in BBS genes. All patients underwent ophthalmic and systematic evaluations, as well as comprehensive molecular genetic analyses. Ultimately, 14 patients were followed up over time.

Results

We identified 47 diseasing-causing variants in 10 BBS genes; 33 were novel. Diagnosis of BBS and non-syndromic retinitis pigmentosa (RP) were established in 28 patients from 27 pedigrees and 6 patients, respectively. The two most prevalent genes in patients with BBS were BBS2 and BBS4, accounting for 51.8% of the probands. The patients exhibited clinical heterogeneity, from patients with all six primary clinical components to patients suffering from non-syndromic RP. The common components were retinal dystrophy, polydactyly, and obesity, with frequencies of 78.6% to 100%, while renal anomaly frequencies were only 7.1%. Patients exhibited early and severe visual defects and retinal degeneration. Patients with biallelic missense variants in BBS2 suffered fewer clinical symptoms and mild visual impairment. Patients with BBS10 variants tended to have cone dystrophy.

Conclusions

Our study defined the mutated gene profiles and established the configuration of the variation frequencies for each BBS gene in Chinese patients. Overall, our patients showed early and severe visual defects and retinal degeneration. Genetic analysis is therefore crucial for diagnosis, genetic counseling, and future gene therapy in these patients.

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Fig. 1: Summary of the proportions of patients in this study with variants of the involved genes and the frequencies of each primary clinical feature of BBS observed in patients with variants in genes encoding BBSome and Chaperonin‐like proteins (CP).
Fig. 2: Systemic manifestations of patient (0191418) with BBS.
Fig. 3: The best corrected visual acuity (BCVA) for the better-seeing eye as function of age.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

References

  1. Chandra B, Tung ML, Hsu Y, Scheetz T, Sheffield VC. Retinal ciliopathies through the lens of Bardet-Biedl Syndrome: Past, present and future. Prog Retin Eye Res. 2022;89:101035.

    Article  CAS  PubMed  Google Scholar 

  2. Florea L, Caba L, Gorduza EV. Bardet-Biedl Syndrome-Multiple Kaleidoscope Images: Insight into mechanisms of genotype-phenotype correlations. Genes. 2021;12:1–13.

  3. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999;36:437–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Riazuddin SA, Iqbal M, Wang Y, Masuda T, Chen Y, Bowne S, et al. A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa. Am J Hum Genet. 2010;86:805–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pretorius PR, Aldahmesh MA, Alkuraya FS, Sheffield VC, Slusarski DC. Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration. Hum Mol Genet. 2011;20:1625–32.

    Article  CAS  PubMed  Google Scholar 

  6. Shevach E, Ali M, Mizrahi-Meissonnier L, McKibbin M, El-Asrag M, Watson CM, et al. Association between missense mutations in the BBS2 gene and nonsyndromic retinitis pigmentosa. JAMA Ophthalmol. 2015;133:312–8.

    Article  PubMed  Google Scholar 

  7. Niederlova V, Modrak M, Tsyklauri O, Huranova M, Stepanek O. Meta-analysis of genotype-phenotype associations in Bardet-Biedl syndrome uncovers differences among causative genes. Hum Mutat. 2019;40:2068–87.

    Article  CAS  PubMed  Google Scholar 

  8. Guardiola GA, Ramos F, Izquierdo NJ, Oliver AL. A genotype-phenotype analysis of the Bardet-Biedl Syndrome in Puerto Rico. Clin Ophthalmol. 2021;15:3757–64.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Manara E, Paolacci S, D’Esposito F, Abeshi A, Ziccardi L, Falsini B, et al. Mutation profile of BBS genes in patients with Bardet-Biedl syndrome: an Italian study. Ital J Pediatr. 2019;45:72.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Esposito G, Testa F, Zacchia M, Crispo AA, Di Iorio V, Capolongo G, et al. Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants. BMC Med Genet. 2017;18:10.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Maria M, Lamers IJ, Schmidts M, Ajmal M, Jaffar S, Ullah E, et al. Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum. Sci Rep. 2016;6:34764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Castro-Sanchez S, Alvarez-Satta M, Corton M, Guillen E, Ayuso C, Valverde D. Exploring genotype-phenotype relationships in Bardet-Biedl syndrome families. J Med Genet. 2015;52:503–13.

    Article  CAS  PubMed  Google Scholar 

  13. Daniels AB, Sandberg MA, Chen J, Weigel-DiFranco C, Fielding Hejtmancic J, Berson EL. Genotype-phenotype correlations in Bardet-Biedl syndrome. Arch Ophthalmol. 2012;130:901–7.

    Article  PubMed  Google Scholar 

  14. Imhoff O, Marion V, Stoetzel C, Durand M, Holder M, Sigaudy S, et al. Bardet-Biedl syndrome: a study of the renal and cardiovascular phenotypes in a French cohort. Clin J Am Soc Nephrol. 2011;6:22–9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li H, Ji CY, Zong XN, Zhang YQ. Body mass index growth curves for Chinese children and adolescents aged 0 to 18 years. Chin J Pediatr. 2009;47:493–8.

    Google Scholar 

  16. Zhou B. Predictive values of body mass index and waist circumference to risk factors of related diseases in Chinese adult population. Zhonghua Liuxingbingxue Zazhi 2002;23:5–10.

    PubMed  Google Scholar 

  17. Sun T, Xu K, Ren Y, Xie Y, Zhang X, Tian L, et al. Comprehensive molecular screening in Chinese usher syndrome patients. Invest Ophthalmol Vis Sci. 2018;59:1229–37.

    Article  CAS  PubMed  Google Scholar 

  18. Meng X, Long Y, Ren J, Wang G, Yin X, Li S. Ocular characteristics of patients with bardet-biedl syndrome caused by pathogenic BBS gene variation in a Chinese cohort. Front Cell Dev Biol. 2021;9:635216.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Huang L, Sun L, Wang Z, Li S, Chen C, Luo X, et al. Novel compound heterozygous BBS2 and homozygous MKKS variants detected in Chinese families with Bardet-Biedl Syndrome. J Ophthalmol. 2021;2021:6751857.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tang HY, Xie F, Dai RC, Shi XL. Novel homozygous protein-truncating mutation of BBS9 identified in a Chinese consanguineous family with Bardet-Biedl syndrome. Mol Genet Genom Med. 2021;9:e1731.

    Article  CAS  Google Scholar 

  21. Tao T, Wang L, Chong W, Yang L, Li G. Characteristics of genotype and phenotype in Chinese patients with Bardet-Biedl syndrome. Int Ophthalmol. 2020;40:2325–43.

    Article  PubMed  Google Scholar 

  22. Xing DJ, Zhang HX, Huang N, Wu KC, Huang XF, Huang F, et al. Comprehensive molecular diagnosis of Bardet-Biedl syndrome by high-throughput targeted exome sequencing. PLoS One. 2014;9:e90599.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Guo DF, Beyer AM, Yang B, Nishimura DY, Sheffield VC, Rahmouni K. Inactivation of Bardet-Biedl syndrome genes causes kidney defects. Am J Physiol Ren Physiol. 2011;300:F574–80.

    Article  CAS  Google Scholar 

  24. Murphy D, Singh R, Kolandaivelu S, Ramamurthy V, Stoilov P. Alternative splicing shapes the phenotype of a mutation in BBS8 to cause nonsyndromic Retinitis Pigmentosa. Mol Cell Biol. 2015;35:1860–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pretorius PR, Baye LM, Nishimura DY, Searby CC, Bugge K, Yang B, et al. Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform. PLoS Genet. 2010;6:e1000884.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Denniston AK, Beales PL, Tomlins PJ, Good P, Langford M, Foggensteiner L, et al. Evaluation of visual function and needs in adult patients with bardet-biedl syndrome. Retina 2014;34:2282–9.

    Article  PubMed  Google Scholar 

  27. Berezovsky A, Rocha DM, Sacai PY, Watanabe SS, Cavascan NN, Salomão SR. Visual acuity and retinal function in patients with Bardet-Biedl syndrome. Clinics 2012;67:145–9.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Grudzinska Pechhacker MK, Jacobson SG, Drack AV, Scipio MD, Strubbe I, Pfeifer W, et al. Comparative natural history of visual function from patients with Biallelic variants in BBS1 and BBS10. Invest Ophthalmol Vis Sci. 2021;62:26.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the National Key R&D Program of China (2016YFC0905200). The funding organizations had no role in designing or conducting this research.

Funding

This work was supported by the National Key R&D Program of China, 2016YFC0905200. The funding organization had no role in the design or conduct of this research.

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Author notes

  1. These authors contributed equally: Junwei Zhong, Yue Xie.

Authors and Affiliations

  1. Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing, China

    Junwei Zhong, Yue Xie, Chunjie Chen, Tengyang Sun, Ke Xu, Xiaohui Zhang & Yang Li

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  1. Junwei Zhong
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Contributions

JZ and YX participated in the study design, acquired the data, and drafted the manuscript. HY, CC, TS, KX, and XZ analyzed the data and aided in interpreting the results. YL designed the current study and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yang Li.

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Zhong, J., Xie, Y., Ye, H. et al. Phenotypic diversity observed in a Chinese patient cohort with biallelic variants in Bardet-Biedl syndrome genes. Eye 37, 3398–3405 (2023). https://doi.org/10.1038/s41433-023-02516-w

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