Japanese Journal of Ophthalmology

, Volume 62, Issue 4, pp 458–466 | Cite as

Clinical characteristics of a Japanese patient with Bardet-Biedl syndrome caused by BBS10 mutations

  • Kentaro Kurata
  • Katsuhiro Hosono
  • Akiko Hikoya
  • Akihiko Kato
  • Hirotomo Saitsu
  • Shinsei Minoshima
  • Tsutomu Ogata
  • Yoshihiro Hotta
Clinical Investigation



Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by retinal dystrophy, renal dysfunction, central obesity, mental impairment, polydactyly, and hypogonadism. Only limited information on BBS is available from Japanese patients. In addition, there are currently no reports of Japanese patients with BBS caused by BBS10 mutations. The purpose of this study was to present the characteristics of a Japanese patient with BBS caused by BBS10 mutations.

Patient and methods

The patient was a 22-year-old Japanese woman. Comprehensive ophthalmic examinations, including visual acuity measurements, perimetry, electroretinography (ERG), fundus autofluorescence imaging, and optical coherence tomography, were performed. Trio-based whole-exome sequencing was performed to identify potential pathogenic mutations, confirmed by Sanger sequencing.


The patient showed neither renal malformation nor dysfunction, and visual impairment seemed to be relatively mild for BBS. The fundus examination revealed diffuse retinal degeneration without pigmentary deposits, and ERG scans showed undetectable responses. She had a history of surgically corrected polydactyly, and displayed symptoms of obesity. There was also a menstrual irregularity that could require progestin administration. Genetic analysis revealed compound heterozygous BBS10 mutations in the patient: a novel missense mutation c.98G>A [p.(G33E)], and a novel nonsense mutation c.2125A>T [p.(R709*)].


To our knowledge, this is the first description of a Japanese patient with BBS caused by BBS10 mutations. The clinical characteristics of our patient were mild, as neither renal impairment nor legal blindness was observed. Early diagnosis would play a role in providing counseling, and in some cases, therapeutic interventions for BBS patients.


Bardet-Biedl syndrome BBS10 gene retinal dystrophy systemic findings 



The authors would like to thank Editage ( for English language editing. This work was supported by a Grant from the Initiative on Rare and Undiagnosed Diseases for Adults (no. 16ek0109151h0002) from the Japan Agency for Medical Research and Development (AMED), and the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (no. 26462659 awarded to Y. H. and no. 16K11284 awarded to K. H.).

Conflicts of interest

K. Kurata, None; K. Hosono, None; A. Hikoya, None; A. Kato, None; H. Saitsu, None; S. Minoshima, None; T. Ogata, None; Y. Hotta, None.

Supplementary material

10384_2018_591_MOESM1_ESM.pdf (74 kb)
Supplementary material 1 (PDF 73 kb)
10384_2018_591_MOESM2_ESM.pdf (62 kb)
Supplementary material 2 (PDF 62 kb)
10384_2018_591_MOESM3_ESM.pdf (102 kb)
Supplementary material 3 (PDF 101 kb)
10384_2018_591_MOESM4_ESM.pdf (50 kb)
Supplementary material 4 (PDF 50 kb)


  1. 1.
    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.PubMedPubMedCentralGoogle Scholar
  2. 2.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Klein D, Ammann F. The syndrome of Laurence–Moon–Bardet–Biedl and allied diseases in Switzerland. Clinical, genetic and epidemiological studies. J Neurol Sci. 1969;9:479–513.CrossRefPubMedGoogle Scholar
  4. 4.
    Daiger SD, Sullivan LS, Bowne SJ. The Retinal Information Network. The University of Texas Health Science Center, USA. Accessed 27 Apr 2017.
  5. 5.
    Zaghloul NA, Katsanis N. Mechanistic insights into Bardet–Biedl syndrome, a model ciliopathy. J Clin Investig. 2009;119:428–37.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Muller J, Stoetzel C, Vincent MC, Leitch CC, Laurier V, Danse JM, et al. Identification of 28 novel mutations in the Bardet–Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease. Hum Genet. 2010;127:583–93.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, et al. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nature. 2006;38:521–4.Google Scholar
  8. 8.
    Billingsley G, Bin J, Fieggen KJ, Duncan JL, Gerth C, Ogata K, et al. Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet–Biedl syndrome patient population. J Med Genet. 2010;47:453–63.CrossRefPubMedGoogle Scholar
  9. 9.
    M’hamdi O, Ouertani I, Maazoul F, Chaabouni-Bouhamed H. Prevalence of Bardet–Biedl syndrome in Tunisia. J Community Genet. 2011;2:97–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Farag TI, Teebi AS. Bardet–Biedl and Laurence–Moon syndromes in a mixed Arab population. Clin Genet. 1988;33:78–82.CrossRefPubMedGoogle Scholar
  11. 11.
    Hjortshøj TD, Grønskov K, Philp AR, Nishimura DY, Riise R, Sheffield VC, et al. Bardet–Biedl syndrome in Denmark—report of 13 novel sequence variations in six genes. Hum Mutat. 2010;31:429–36.CrossRefPubMedGoogle Scholar
  12. 12.
    Woods MO, Young TL, Parfrey PS, Hefferton D, Green JS, Davidson WS. Genetic heterogeneity of Bardet–Biedl syndrome in a distinct Canadian population: evidence for a fifth locus. Genomics. 1999;55:2–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Nakamura F, Sasaki H, Kajihara H, Yamanoue M. Laurence–Moon–Biedl syndrome accompanied by congenital hepatic fibrosis. J Gastroenterol Hepatol. 1990;5:206–10.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamada K, Miura M, Miyayama H, Sakashita N, Kochi M, Ushio Y. Diffuse brainstem glioma in a patient with Laurence–Moon–(Bardet–)Biedl syndrome. Pediatr Neurosurg. 2000;33:323–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Tonomura Y, Hirano M, Shimada K, Asai H, Ikeda M, Kataoka H, et al. Treatable fluctuating mental impairment in a patient with Bardet–Biedl syndrome. Clin Neurol Neurosurg. 2009;111:102–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Hirano M, Ohishi M, Yamashita T, Ikuno Y, Iwahashi H, Mano T, et al. Abnormal cystatin C levels in two patients with Bardet–Biedl syndrome. Clin Med Insights Case Rep. 2011;4:17–20.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Saida K, Inaba Y, Hirano M, Satake W, Toda T, Suzuki Y, et al. A case of Bardet–Biedl syndrome complicated with intracranial hypertension in a Japanese child. Brain Dev. 2014;36:721–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Hirano M, Satake W, Ihara K, Tsuge I, Kondo S, Saida K, et al. The first nationwide survey and genetic analyses of Bardet–Biedl syndrome in Japan. PLoS One. 2015;10:e0136317.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M. ISCEV Standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol. 2009;118:69–77.CrossRefPubMedGoogle Scholar
  20. 20.
    Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. 2013. arXiv:1303.3997v2. Preprint at
  21. 21.
    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    The 1000 Genomes Project data. In: The 1000 Genomes Project Consortium. Accessed 27 Apr 2017.
  24. 24.
    ExAC database. In: The Exome Aggregation Consortium. Accessed 27 Apr 2017.
  25. 25.
    Higasa K, Miyake N, Yoshimura J. Human genetic variation database. Kyoto University, Japan. Accessed 27 Apr 2017.
  26. 26.
    Integrative Japanese Genome Variation Database. Tohoku University, Japan. Accessed 27 Apr 2017.
  27. 27.
    The Human Gene Mutation Database. Institute of Medical Genetics in Cardiff. Accessed 27 Apr 2017.
  28. 28.
    Katagiri S, Akahori M, Sergeev Y, Yoshitake K, Ikeo K, Furuno M, et al. Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa. PLoS One. 2014;9:e108721.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hosono K, Harada Y, Kurata K, Hikoya A, Sato M, Minoshima S, et al. Novel GUCY2D gene mutations in Japanese male twins with Leber congenital amaurosis. J Ophthalmol. 2015;693468. Scholar
  30. 30.
    Miyamichi D, Asahina M, Nakajima J, Sato M, Hosono K, Nomura T, et al. Novel HPS6 mutations identified by whole-exome sequencing in two Japanese sisters with suspected ocular albinism. J Hum Genet. 2016;61:839–42.CrossRefPubMedGoogle Scholar
  31. 31.
    Sorting Tolerant From Intolerant. In: J. Craig Venter Institute. Accessed 27 Apr 2017.
  32. 32.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.CrossRefPubMedGoogle Scholar
  34. 34.
    Hosono K, Ishigami C, Takahashi M, Park DH, Hirami Y, Nakanishi H, et al. Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population. PLoS One. 2012;7:e31036.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hosono K, Sasaki T, Minoshima S, Shimizu N. Identification and characterization of a novel gene family YPEL in a wide spectrum of eukaryotic species. Gene. 2004;340:31–43.CrossRefPubMedGoogle Scholar
  36. 36.
    NCBI Reference Sequence Database. In: National Center for Biotechnology Information, USA. Accessed 27 Apr 2017.
  37. 37.
    Scheidecker S, Hull S, Perdomo Y, Studer F, Pelletier V, Muller J, et al. Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet–Biedl syndrome. Am J Ophthalmol. 2015;160:364–72.CrossRefPubMedGoogle Scholar
  38. 38.
    Hentze MW, Kulozik AE. A perfect message: RNA surveillance and nonsense-mediated decay. Cell. 1999;96:307–10.CrossRefPubMedGoogle Scholar
  39. 39.
    Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem. 2007;76:51–74.CrossRefPubMedGoogle Scholar
  40. 40.
    Agha Z, Iqbal Z, Azam M, Hoefsloot LH, van Bokhoven H, Qamar R. A novel homozygous 10 nucleotide deletion in BBS10 causes Bardet–Biedl syndrome in a Pakistani family. Gene. 2013;519:177–81.CrossRefPubMedGoogle Scholar
  41. 41.
    Gerth C, Zawadzki RJ, Werner JS, Héon E. Retinal morphology in patients with BBS1 and BBS10 related Bardet–Biedl syndrome evaluated by Fourier-domain optical coherence tomography. Vis Res. 2008;48:392–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Tica I, Tica OS, Nicoară AD, Tica VI, Tica AA. Ovarian teratomas in a patient with Bardet–Biedl syndrome, a rare association. Romanian J Morphol Embryol. 2016;57:1403–8.Google Scholar
  43. 43.
    Simons DL, Boye SL, Hauswirth WW, Wu SM. Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet–Biedl syndrome mouse model. Proc Natl Acad Sci USA. 2011;108:6276–81.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Seo S, Mullins RF, Dumitrescu AV, Bhattarai S, Gratie D, Wang K, et al. Subretinal gene therapy of mice with Bardet–Biedl syndrome type 1. Invest Ophthalmol Vis Sci. 2013;54:6118–32.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Japanese Ophthalmological Society 2018

Authors and Affiliations

  • Kentaro Kurata
    • 1
  • Katsuhiro Hosono
    • 1
  • Akiko Hikoya
    • 1
  • Akihiko Kato
    • 2
  • Hirotomo Saitsu
    • 3
  • Shinsei Minoshima
    • 4
  • Tsutomu Ogata
    • 5
  • Yoshihiro Hotta
    • 1
  1. 1.Department of OphthalmologyHamamatsu University School of MedicineShizuokaJapan
  2. 2.Blood Purification UnitHamamatsu University HospitalShizuokaJapan
  3. 3.Department of BiochemistryHamamatsu University School of MedicineShizuokaJapan
  4. 4.Department of Photomedical Genomics, Preeminent Medical Photonics Education and Research Center, Institute for Medical Photonics ResearchHamamatsu University School of MedicineShizuokaJapan
  5. 5.Department of PediatricsHamamatsu University School of MedicineShizuokaJapan

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