Clinical phenotype and genotype analysis of retinitis pigmentosa sine pigmento caused by <i>BBS</i> gene mutations_Chinese Journal of Ocular Fundus Diseases

Authors：

Chen Zijie ¹ , Tao Yufei ² , Wang Yun ³ , Huang Qinyu ¹ , Yang Mingmin ³ , Liu Xuyang ¹ ,  Fan Ning ³

1. Xiamen Eye Center, Xiamen University, Xiamen 361000, China;
2. The Second Clinical Medical College, Jinan University, Shenzhen 518040, China;
3. Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University, Shenzhen 518040, China;

Corresponding author：

Fan Ning, Email: szfanning@126.com

Keywords：

BBS7 gene; BBS2 gene; Retinitis pigmentosa; Bardet Biedl syndrome

DOI：

10.3760/cma.j.cn511434-20240929-00364

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Objective To observe and analyze the pathogenic genes and clinical phenotype characteristics of retinitis pigmentosa sinepigmento(RPSP). Methods A retrospective clinical study. Two patients (proband) and five family members from two RPSP families admitted to Xiamen Eye Center of Xiamen University in December 2022 and Shenzhen Eye Hospital in July 2023 were included in the study. Two families have no blood relationship and were both Han Chinese. Detailed ocular and systemic medical history and specialized examinations were performed for all members, including color fundus photography, fundus autofluorescence (FAF), and full field electroretinogram (ff-ERG) examination. The peripheral venous blood of all members was collected, and genomic DNA was extracted. Pathogenic genes and their loci were screened using whole exome high-throughput sequencing technology. Sanger sequencing was used to verify the pathogenic genes in the two pedigrees. The pathogenicity of candidate variants was evaluated according to the American Society for American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants. Results The two probands were male, aged 9 and 7 years, respectively. The main complaint was poor binocular vision for 6 and 3 years and poor treatment effect of amblyopia. The proband (Ⅱ2) in family 1 had a pale red color on the optic disc, with leopard-like changes in the posterior pole and thinner retinal arteries. FAF showed mottled fluorescence attenuation outside the macular vascular arch. There was no significant waveform in both bright and dark visual responses of ff-ERG. He also had 6-toed deformity of both feet, renal cysts, and a slightly overweight body. The clinical diagnosis was non-pigmentary retinitis pigmentosa. The proband of family 2 (Ⅱ1) had poor binocular vision in a dark environment and had atrophy lesions on the nasal side of the optic disc and leopard print like changes in the fundus. FAF showed uneven enhancement in the fovea. ff-ERG showed severe abnormalities in dark and light response, with significant decrease and delay in b-wave amplitude and latency. He had no other systemic abnormalities. The clinical diagnosis was binocular RPSP. There were no abnormal ocular and systemic manifestations in the two family members. Gene sequencing revealed a homozygous mutation (c.534+1G>T) of BBS2 gene, which was inherited from the mother and father respectively. Based on clinical manifestations and genetic testing results, the final diagnosis was Bardet Biedl syndrome. The genetic sequencing results confirmed a novel compound heterozygous mutation (c.950T>G: p. Leu317Arg missense mutation and c.849+1G>C splicing mutation) of BBS7 gene. His father (Ⅰ1) and mother (Ⅰ2) carried M1 heterozygous variants. Combined with the clinical manifestations and genetic testing results, the final diagnosis was Bardet-Biedl syndrome (BBS). Family 2 proband (Ⅱ1) carried the BBS7 gene C.950T>G (p.Leu317Arg) (M2) missense variation and C.849 +1G>C (M3) splice site variation. His father (Ⅰ1) and mother (Ⅰ2) carried M3 shear site variation and M2 missense variation, respectively. The two families all fit the autosomal recessive inheritance pattern, and the genotype and clinical phenotype were coseparated. According to ACMG guidelines, M1, M2 and M3 were all identified as possible pathogenic variants. Conclusions BBS2 gene M1 homozygous variation and BBS7 gene M2, M3 complex heterozygous variation are the possible pathogenic genes in family 1 and family 2, respectively. Two families are affected by BBS and RPSP, respectively.

Citation： Chen Zijie, Tao Yufei, Wang Yun, Huang Qinyu, Yang Mingmin, Liu Xuyang, Fan Ning. Clinical phenotype and genotype analysis of retinitis pigmentosa sine pigmento caused by BBS gene mutations. Chinese Journal of Ocular Fundus Diseases, 2025, 41(3): 178-185. doi: 10.3760/cma.j.cn511434-20240929-00364 Copy

1.	惠延年. Retinitis pigmentosa: 术语与炎症. 中华眼底病杂志, 2023, 39(6): 494-495. DOI: 10.3760/cma.j.cn511434-20230512-00231.Hui YN. Retinitis pigmentosa: terminology and inflammation. Chin J Ocul Fundus Dis, 2023, 39(6): 494-495. DOI: 10.3760/cma.j.cn511434-20230512-00231.
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3.	冯月兰, 李宁东. 纤毛功能障碍与视觉发育相关疾病的关系研究现状[J]. 中华眼底病杂志, 2020, 36(8): 652-656. DOI: 10.3760/cma.j.cn511434-20190213-00044.Feng YL, Li ND. Research status of ciliary dysfunction and visual development related diseases[J]. Chin J Ocul Fundus Dis, 2020, 36(8): 652-656. DOI: 10.3760/cma.j.cn511434-20190213-00044.
4.	Sun C, Zhou J, Meng X. Primary cilia in retinal pigment epithelium development and diseases[J]. J Cell Mol Med, 2021, 25(19): 9084-9088. DOI: 10.1111/jcmm.16882.
5.	Takahashi VKL, Xu CL, Takiuti JT, et al. Comparison of structural progression between ciliopathy and non-ciliopathy associated with autosomal recessive retinitis pigmentosa[J]. Orphanet J Rare Dis, 2019, 14(1): 187. DOI: 10.1186/s13023-019-1163-9.
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8.	陶天畅, 王蕾, 崇伟华, 等. Bardet-Biedl综合征一例[J]. 中华实验眼科杂志, 2019, 37(1): 28-29. DOI: 10.3760/cma.j.issn.2095.0160.2019.01.006.Tao TC, Wang L, Chong WH, et al. A case of Bardet Biedl syndrome[J]. China J Exp Ophthalmol, 2019, 37(1): 28-29. DOI: 10.3760/cma.j.issn.2095.0160.2019.01.006.
9.	Nishimura DY, Fath M, Mullins RF, et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin[J]. Proc Natl Acad Sci USA, 2004, 101(47): 16588-16593. DOI: 10.1073/pnas.0405496101.
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12.	Gupta N, D'Acierno M, Zona E, et al. Bardet-Biedl syndrome: the pleiotropic role of the chaperonin-like BBS6, 10, and 12 proteins[J]. Am J Med Genet C Semin Med Genet, 2022, 190(1): 9-19. DOI: 10.1002/ajmg.c.31970.
13.	Jin H, White SR, Shida T, et al. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia[J]. Cell, 2010, 141(7): 1208-1219. DOI: 10.1016/j.cell.2010.05.015.
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15.	Hartill V, Szymanska K, Sharif SM, et al. Meckel-Gruber syndrome: an update on diagnosis, clinical management, and research advances[J/OL]. Front Pediatr, 2017, 5: 244[2017-11-20]. https://pubmed.ncbi.nlm.nih.gov/29209597/. DOI: 10.3389/fped.2017.00244.
16.	Seo S, Guo DF, Bugge K, et al. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling[J]. Hum Mol Genet, 2009, 18(7): 1323-1331. DOI: 10.1093/hmg/ddp031.
17.	Guo DF, Cui H, Zhang Q, et al. The BBSome controls energy homeostasis by mediating the transport of the Leptin receptor to the plasma membrane[J/OL]. PLoS Genet, 2016, 12(2): e1005890[2016-02-29]. https://pubmed.ncbi.nlm.nih.gov/26926121/. DOI: 10.1371/journal.pgen.1005890.
18.	Gao S, Zhang Q, Ding Y, et al. Molecular and phenotypic characteristics of Bardet-Biedl syndrome in Chinese patients[J]. Orphanet J Rare Dis, 2024, 19(1): 149. DOI: 10.1186/s13023-024-03150-9.

1. 惠延年. Retinitis pigmentosa: 术语与炎症. 中华眼底病杂志, 2023, 39(6): 494-495. DOI: 10.3760/cma.j.cn511434-20230512-00231.Hui YN. Retinitis pigmentosa: terminology and inflammation. Chin J Ocul Fundus Dis, 2023, 39(6): 494-495. DOI: 10.3760/cma.j.cn511434-20230512-00231.
2. 朱青, 李亚, 游雅, 等. PCDH15基因复合杂合新突变致无色素性视网膜色素变性表型的1F型Usher综合征一家系[J]. 中华眼底病杂志, 2021, 37(6): 444-448. DOI: 10.3760/cma.j.cn511434-20200928-00473.Zhu Q, Li Y, You Y, et al. Novel compound heterozygous mutations in the PCDH15 gene in a family affected with Usher syndrome type 1F with retinitis pigmentosa sine pigmento[J]. Chin J Ocul Fundus Dis, 2021, 37(6): 444-448. DOI: 10.3760/cma.j.cn511434-20200928-00473.
3. 冯月兰, 李宁东. 纤毛功能障碍与视觉发育相关疾病的关系研究现状[J]. 中华眼底病杂志, 2020, 36(8): 652-656. DOI: 10.3760/cma.j.cn511434-20190213-00044.Feng YL, Li ND. Research status of ciliary dysfunction and visual development related diseases[J]. Chin J Ocul Fundus Dis, 2020, 36(8): 652-656. DOI: 10.3760/cma.j.cn511434-20190213-00044.
4. Sun C, Zhou J, Meng X. Primary cilia in retinal pigment epithelium development and diseases[J]. J Cell Mol Med, 2021, 25(19): 9084-9088. DOI: 10.1111/jcmm.16882.
5. Takahashi VKL, Xu CL, Takiuti JT, et al. Comparison of structural progression between ciliopathy and non-ciliopathy associated with autosomal recessive retinitis pigmentosa[J]. Orphanet J Rare Dis, 2019, 14(1): 187. DOI: 10.1186/s13023-019-1163-9.
6. Richards CS, Bale S, Bellissimo DB, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007[J]. Genet Med, 2008, 10(4): 294-300. DOI: 10.1097/GIM.0b013e31816b5cae.
7. Melluso A, Secondulfo F, Capolongo G, et al. Bardet-Biedl syndrome: current perspectives and clinical outlook[J]. Ther Clin Risk Manag, 2023, 19: 115-132. DOI: 10.2147/TCRM.S338653.
8. 陶天畅, 王蕾, 崇伟华, 等. Bardet-Biedl综合征一例[J]. 中华实验眼科杂志, 2019, 37(1): 28-29. DOI: 10.3760/cma.j.issn.2095.0160.2019.01.006.Tao TC, Wang L, Chong WH, et al. A case of Bardet Biedl syndrome[J]. China J Exp Ophthalmol, 2019, 37(1): 28-29. DOI: 10.3760/cma.j.issn.2095.0160.2019.01.006.
9. Nishimura DY, Fath M, Mullins RF, et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin[J]. Proc Natl Acad Sci USA, 2004, 101(47): 16588-16593. DOI: 10.1073/pnas.0405496101.
10. Barnes CL, Malhotra H, Calvert PD. Compartmentalization of photoreceptor sensory cilia[J/OL]. Front Cell Dev Biol, 2021, 9: 636737[2021-02-04]. https://pubmed.ncbi.nlm.nih.gov/33614665/. DOI: 10.3389/fcell.2021.636737.
11. Wensel TG, Potter VL, Moye A, et al. Structure and dynamics of photoreceptor sensory cilia[J]. Pflugers Arch, 2021, 473(9): 1517-1537. DOI: 10.1007/s00424-021-02564-9.
12. Gupta N, D'Acierno M, Zona E, et al. Bardet-Biedl syndrome: the pleiotropic role of the chaperonin-like BBS6, 10, and 12 proteins[J]. Am J Med Genet C Semin Med Genet, 2022, 190(1): 9-19. DOI: 10.1002/ajmg.c.31970.
13. Jin H, White SR, Shida T, et al. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia[J]. Cell, 2010, 141(7): 1208-1219. DOI: 10.1016/j.cell.2010.05.015.
14. 尉慧, 樊玉, 孙岳, 等. 16号染色体父源单亲二倍体致Bardet-Biedl综合征1例[J]. 中华眼底病杂志, 2022, 38(5): 403-404. DOI: 10.3760/cma.j.cn511434-20210813-00437.Yu H, Fan Y, Sun Y, et al. A case of Bardet Biedl syndrome caused by parental diploid of chromosome 16[J]. Chin J Ocul Fundus Dis, 2022, 38(5): 403-404. DOI: 10.3760/cma.j.cn511434-20210813-00437.
15. Hartill V, Szymanska K, Sharif SM, et al. Meckel-Gruber syndrome: an update on diagnosis, clinical management, and research advances[J/OL]. Front Pediatr, 2017, 5: 244[2017-11-20]. https://pubmed.ncbi.nlm.nih.gov/29209597/. DOI: 10.3389/fped.2017.00244.
16. Seo S, Guo DF, Bugge K, et al. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling[J]. Hum Mol Genet, 2009, 18(7): 1323-1331. DOI: 10.1093/hmg/ddp031.
17. Guo DF, Cui H, Zhang Q, et al. The BBSome controls energy homeostasis by mediating the transport of the Leptin receptor to the plasma membrane[J/OL]. PLoS Genet, 2016, 12(2): e1005890[2016-02-29]. https://pubmed.ncbi.nlm.nih.gov/26926121/. DOI: 10.1371/journal.pgen.1005890.
18. Gao S, Zhang Q, Ding Y, et al. Molecular and phenotypic characteristics of Bardet-Biedl syndrome in Chinese patients[J]. Orphanet J Rare Dis, 2024, 19(1): 149. DOI: 10.1186/s13023-024-03150-9.

Chinese Journal of Ocular Fundus Diseases

Clinical phenotype and genotype analysis of retinitis pigmentosa sine pigmento caused by BBS gene mutations

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