[en] Bardet-Biedl syndrome (BBS) is a rare genetically heterogeneous ciliopathy which accompanies retinitis pigmentosa (RP). However, the BBS5 mutation remains unclear in Iranians with BBS. The purpose of study is to evaluate genetic analyses of a BBS Iranian family using targetted exome sequencing (TES). A male 11-year-old proband and three related family members were recruited. Biochemical tests, electrocardiography and visual acuity testing, such as funduscopic, fundus photography (FP), optical coherence tomography (OCT), and standard electroretinography, were conducted. Molecular analysis and high-throughput DNA sequence analysis were performed. The proband was diagnosed with possible BBS based on the presence of three primary features and two secondary features. The TES analysis of the proband with BBS resulted in the identification of a novel, homozygous splicing variant c. 208+2T>C of the BBS5 gene (NM_152384.2) in this Iranian BBS family. This variant was confirmed and was completely co-segregated with the disease in this family by Sanger sequencing. Thus, we report a novel, homozygous splicing site variant c.208+2T>C in the BBS5 gene for the first time in the Iranian family.
Disciplines :
Ophthalmology
Author, co-author :
Imani, Saber; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
Cheng, Jingliang; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
Fu, Jiewen; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China ; Institute of Medical Technology, Xiangtan Medicine and Health Vocational College, Xiangtan, Hunan, China
Mobasher-Jannat, Abdolkarim; Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
Wei, Chunli; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China ; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
Mohazzab-Torabi, Saman; Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran
Jadidi, Khosrow; Department of Ophthalmology, Bina Eye Hospital Research Center, Tehran, Iran
Khosravi, Mohammad Hossein ; Université de Liège - ULiège ; Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
Shasaltaneh, Marzieh Dehghan; Department of Biology, Faculty of Science, University of Zanjan, Zanjan, Iran
Yang, Lisha; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
Khan, Md Asaduzzaman; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
Fu, Junjiang ; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China fujunjiang@hotmail.com ; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
Language :
English
Title :
Novel splicing variant c. 208+2T>C in BBS5 segregates with Bardet-Biedl syndrome in an Iranian family by targeted exome sequencing.
Publication date :
2019
Journal title :
Bioscience Reports
ISSN :
0144-8463
eISSN :
1573-4935
Publisher :
Portland Press Ltd, England
Volume :
39
Issue :
3
Peer reviewed :
Peer Reviewed verified by ORBi
Funding text :
We thank the patients and the families for their collaboration during the project. We also thank Dr. Rui Chen in Baylor College of Medicine, Shangyi Fu from the University of Houston/Baylor College of Medicine for reading and revising the manuscript. This work was supported by the National Natural Science Foundation of China [grant numbers 81672887, 31701087, 30371493]; the Research Foundation of the Education Department of Sichuan Province [grant numbers 17ZA0427, 17ZB0467]; and the Joint Research Foundation of Luzhou City and Southwest Medical University [grant number 2018LZXNYD-YL01].This work was supported by the National Natural Science Foundation of China [grant numbers 81672887, 31701087, 30371493]; the Research Foundation of the Education Department of Sichuan Province [grant numbers 17ZA0427, 17ZB0467]; and the Joint Research Foundation of Luzhou City and Southwest Medical University [grant number 2018LZXNYD-YL01].
Hafler, B.P. (2017) Clinical progress in inherited retinal degenerations: gene therapy clinical trials and advances in genetic sequencing. Retina 37, 417-423, https://doi.org/10.1097/IAE.0000000000001341
Beales, P.L., Elcioglu, N., Woolf, A.S., Parker, D. and Flinter, F.A. (1999) New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J. Med. Genet. 36, 437-446
Abecasis, G.R., Altshuler, D., Auton, A., Brooks, L.D., Durbin, R.M., 1000 Genomes Project Consortium et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467, 1061-1073, https://doi.org/10.1038/nature09534
Forsythe, E. and Beales, P.L. (2013) Bardet-Biedl syndrome. Eur. J. Hum. Genet. 21, 8-13, https://doi.org/10.1038/ejhg.2012.115
Zaghloul, N.A. and Katsanis, N. (2009) Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J. Clin. Invest. 119, 428-437, https://doi.org/10.1172/JCI37041
Putoux, A., Attie-Bitach, T., Martinovic, J. and Gubler, M.C. (2012) Phenotypic variability of Bardet-Biedl syndrome: focusing on the kidney. Pediatr. Nephrol. 27, 7-15, https://doi.org/10.1007/s00467-010-1751-3
Rooryck, C. and Lacombe, D. (2008) Bardet-Biedl syndrome. Ann. Endocrinol. 69, 463-471, https://doi.org/10.1016/j.ando.2008.10.001
Li, J.B., Gerdes, J.M., Haycraft, C.J., Fan, Y., Teslovich, T.M., May-Simera, H. et al. (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117, 541-552, https://doi.org/10.1016/S0092-8674(04)00450-7
Hjortshoj, T.D., Gronskov, K., Philp, A.R., Nishimura, D.Y., Adeyemo, A., Rotimi, C.N. et al. (2008) Novel mutations in BBS5 highlight the importance of this gene in non-Caucasian Bardet-Biedl syndrome patients. Am. J. Med. Genet. Part A 146A, 517-520, https://doi.org/10.1002/ajmg.a.32136
Nachury, M.V., Loktev, A.V., Zhang, Q., Westlake, C.J., Peranen, J., Merdes, A. et al. (2007) A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201-1213, https://doi.org/10.1016/j.cell.2007.03.053
Schaefer, E., Zaloszyc, A., Lauer, J., Durand, M., Stutzmann, F., Perdomo-Trujillo, Y. et al. (2011) Mutations in SDCCAG8/NPHP10 cause Bardet-Biedl syndrome and are associated with penetrant renal disease and absent polydactyly. Mol. Syndromol. 1, 273-281, https://doi.org/10.1159/000331268
Yuan, Z., Li, B., Xu, M., Chang, E.Y., Li, H., Yang, L. et al. (2017) The phenotypic variability of HK1-associated retinal dystrophy. Sci. Rep. 7, 7051, https://doi.org/10.1038/s41598-017-07629-3
Meehan, T.F., Conte, N., West, D.B., Jacobsen, J.O., Mason, J., Warren, J. et al. (2017) Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. Nat. Genet. 49, 1231-1238, https://doi.org/10.1038/ng.3901
Mockel, A., Perdomo, Y., Stutzmann, F., Letsch, J., Marion, V. and Dollfus, H. (2011) Retinal dystrophy in Bardet-Biedl syndrome and related syndromic ciliopathies. Prog. Retin. Eye Res. 30, 258-274, https://doi.org/10.1016/j.preteyeres.2011.03.001
Wang, F., Wang, H., Tuan, H.F., Nguyen, D.H., Sun, V., Keser, V. et al. (2014) Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum. Genet. 133, 331-345, https://doi.org/10.1007/s00439-013-1381-5
Ece Solmaz, A., Onay, H., Atik, T., Aykut, A., Cerrah Gunes, M., Ozalp Yuregir, O. et al. (2015) Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes. Eur. J. Med. Genet. 58, 689-694, https://doi.org/10.1016/j.ejmg.2015.10.011
Arno, G., Agrawal, S.A., Eblimit, A., Bellingham, J., Xu, M., Wang, F. et al. (2016) Mutations in REEP6 cause autosomal-recessive retinitis pigmentosa. Am. J. Hum. Genet. 99, 1305-1315, https://doi.org/10.1016/j.ajhg.2016.10.008
Zhang, Q., Xu, M., Verriotto, J.D., Li, Y., Wang, H., Gan, L. et al. (2016) Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands. Sci. Rep. 6, 32792, https://doi.org/10.1038/srep32792
Imani, S., Cheng, J., Mobasher-Jannat, A., Wei, C., Fu, S., Yang, L. et al. (2018) Identification of a novel RPGRIP1 mutation in an Iranian family with leber congenital amaurosis by exome sequencing. J. Cell. Mol. Med. 22, 1733-1742, https://doi.org/10.1111/jcmm.13454
Huang, J., Fu, J., Fu, S., Yang, L., Nie, K., Duan, C. et al. (2018) Diagnostic value of a combination of next-generation sequencing, chorioretinal imaging and metabolic analysis: lessons from a consanguineous Chinese family with gyrate atrophy of the choroid and retina stemming from a novel OAT variant. Br. J. Ophthalmol. 103, 428-435
Yang, L., Fu, J., Cheng, J., Wei, C., Zhou, Q., Ijaz, I. et al. (2018) A novel variant of the FZD4 gene in a chinese family causes autosomal dominant familial exudative vitreoretinopathy. Cell. Phys. Biochem. 51, 2445-2455, https://doi.org/10.1159/000495901
Wang, K., Li, M. and Hakonarson, H. (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164, https://doi.org/10.1093/nar/gkq603
Yang, L., Ijaz, I., Cheng, J., Wei, C., Tan, X., Khan, M.A. et al. (2018) Evaluation of amplification refractory mutation system (ARMS) technique for quick and accurate prenatal gene diagnosis of CHM variant in choroideremia. Appl. Clin. Genet. 11, 1-8
Fu, S., Cheng, J., Wei, C., Yang, L., Xiao, X., Zhang, D. et al. (2017) Development of diagnostic SCAR markers for genomic DNA amplifications in breast carcinoma by DNA cloning of high-GC RAMP-PCR fragments. Oncotarget 8, 43866-43877
Fu, J., Cheng, J., Liu, X., Li, J., Wei, C., Zheng, X. et al. (2018) Evaluation genotypes of cancer cell lines HCC1954 and SiHa by short tandem repeat (STR) analysis and DNA sequencing. Mol. Biol. Rep., https://doi.org/10.1007/s11033-018-4438-7
den Dunnen, J.T., Dalgleish, R., Maglott, D.R., Hart, R.K., Greenblatt, M.S., McGowan-Jordan, J. et al. (2016) HGVS recommendations for the description of sequence variants: 2016 update. Hum. Mutat. 37, 564-569, https://doi.org/10.1002/humu.22981
Mykytyn, K., Nishimura, D.Y., Searby, C.C., Shastri, M., Yen, H.J., Beck, J.S. et al. (2002) Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat. Genet. 31, 435-438, https://doi.org/10.1038/ng935
Imani, S., Ijaz, I., Shasaltaneh, M.D., Fu, S., Cheng, J. and Fu, J. (2018) Molecular genetics characterization and homology modeling of the CHM gene mutation: a study on its association with choroideremia. Mutat. Res. 775, 39-50, https://doi.org/10.1016/j.mrrev.2018.02.001
Fu, J., Ma, L., Cheng, J., Yang, L., Wei, C., Fu, S. et al. (2018) A novel, homozygous nonsense variant of the CDHR1 gene in a Chinese family causes autosomal recessive retinal dystrophy by NGS-based genetic diagnosis. J. Cell. Mol. Med. 22, 5662-5669, https://doi.org/10.1111/jcmm.13841
Chandrasekar, S.P., Namboothiri, S., Sen, P. and Sarangapani, S. (2018) Screening for mutation hotspots in Bardet-Biedl syndrome patients from India. Indian J. Med. Res. 147, 177-182, https://doi.org/10.4103/ijmr.IJMR.1822.15
Fattahi, Z., Rostami, P., Najmabadi, A., Mohseni, M., Kahrizi, K., Akbari, M.R. et al. (2014) Mutation profile of BBS genes in Iranian patients with Bardet-Biedl syndrome: genetic characterization and report of nine novel mutations in five BBS genes. J. Hum. Genet. 59, 368-375, https://doi.org/10.1038/jhg.2014.28
Scheidecker, S., Etard, C., Pierce, N.W., Geoffroy, V., Schaefer, E., Muller, J. et al. (2014) Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J. Med. Genet. 51, 132-136, https://doi.org/10.1136/jmedgenet-2013-101785
Scheidecker, S., Hull, S., Perdomo, Y., Studer, F., Pelletier, V., Muller, J. et al. (2015) Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl syndrome. Am. J. Ophthalmol. 160, 364-372.e1, https://doi.org/10.1016/j.ajo.2015.05.007
Moore, S.J., Green, J.S., Fan, Y., Bhogal, A.K., Dicks, E., Fernandez, B.A. et al. (2005) Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study. Am. J. Med. Genet. Part A 132A, 352-360, https://doi.org/10.1002/ajmg.a.30406
Khan, M.A., Mohan, S., Zubair, M. and Windpassinger, C. (2016) Homozygosity mapping identified a novel protein truncating mutation (p.Ser100Leufs*24) of the BBS9 gene in a consanguineous Pakistani family with Bardet Biedl syndrome. BMC Med. Genet. 17, 10, https://doi.org/10.1186/s12881-016-0271-9