Diagnosis and genetic analysis of a case with Bardet-Biedl syndrome caused by compound heterozygous mutations in the BBS12 gene
Received date: 2022-05-30
Revised date: 2022-08-26
Online published: 2022-09-08
Supported by
the National Natural Science Foundation of China(81770865)
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy, which is caused by mutations mainly in genes encoding BBSome complex and IFT complex. Here, we reported a 21-year-old female with BBS characterized by three primary features including obesity, retinitis pigmentosa sine pigmento and bilateral renal cysts. She also had some secondary features such as diabetes mellitus, nonalcoholic fatty liver disease, subclinical hypothyroidism and mild conductive hearing damage. Whole exome sequencing revealed two compound heterozygous mutations in exon 2 of the BBS12 gene (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) in this patient. Sanger sequencing showed that her father and mother carried c.188delC (p.T63fs) and c.1993_1995del (p.665_665del) variants, respectively, while her parents were free of BBS-related symptoms. In conclusion, this case reported two novel mutations (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) of the BBS12 gene in a girl presented with BBS, which provides novel genetic resources for studies of the disease. Meanwhile, the BBS case shows the entire development progress from her birth to adulthood, which helps facilitate clinicians’ understanding of BBS.
Key words： Bardet-Biedl syndrome; BBS12 gene; whole exome sequencing
Yanting Shen, Yan Ling, Zhiqiang Lu, Xiaomu Li, Hua Bian, Hongmei Yan, Mingfeng Xia, Xinxia Chang, Jingjing Jiang, Jing Zhang, Xin Gao . Diagnosis and genetic analysis of a case with Bardet-Biedl syndrome caused by compound heterozygous mutations in the BBS12 gene[J]. Hereditas(Beijing), 2022 , 44(10) : 975 -982 . DOI: 10.16288/j.yczz.22-182
| [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(6): 437-446. |
| [2] | Suspitsin EN, Imyanitov EN. Bardet-Biedl syndrome. Mol Syndromol, 2016, 7(2): 62-71. |
| [3] | Janssen S, Ramaswami G, Davis EE, Hurd T, Airik R, Kasanuki JM, Van Der Kraak L, Allen SJ, Beales PL, Katsanis N, Otto EA, Hildebrandt F. Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals. Human Genet, 2011, 129(1): 79-90. |
| [4] | Farag TI, Teebi AS. High incidence of Bardet Biedl syndrome among the bedouin. Clin Genet, 1989, 36(6): 463-464. |
| [5] | Mitchison HM, Valente EM. Motile and non-motile cilia in human pathology: from function to phenotypes. J Pathol, 2017, 241(2): 294-309. |
| [6] | National Clinical Research Center for Child Health, Rare Disease Group of Chinese Pediatric Society of Chinese Medical Association. Expert consensus on the diagnosis and treatment of Bardet-Biedl syndrome in children in China. Chin J Pract Pediatr, 2022, 37(4): 241-247. |
| [6] | 国家儿童健康与疾病临床医学研究中心, 中华医学会儿科学分会罕见病学组. 中国儿童Bardet-Biedl综合征诊治专家共识. 中国实用儿科杂志, 2022, 37(4): 241-247. |
| [7] | Álvarez-Satta M, Castro-Sánchez S, Valverde D. Bardet-Biedl syndrome as a chaperonopathy: dissecting the major role of chaperonin-like bbs proteins (BBS6-BBS10-BBS12). Front Mol Biosci, 2017, 4: 55. |
| [8] | Mujahid S, Hunt KF, Cheah YS, Forsythe E, Hazlehurst JM, Sparks K, Mohammed S, Tomlinson JW, Amiel SA, Carroll PV, Beales PL, Huda MSB, Mcgowan BM. The endocrine and metabolic characteristics of a large Bardet-Biedl syndrome clinic population. J Clin Endocrinol Metab, 2018, 103(5): 1834-1841. |
| [9] | Zhai YH, Xu H, Shen Q, Wu BB. Novel mutations in the BBS12 gene of two Chinese Bardet-Biedl syndrome pedigrees. Chin J Nephrol, 2018, 34(8): 592-600. |
| [9] | 翟亦晖, 徐虹, 沈茜, 吴冰冰. 儿童巴尔得-别德尔综合征2个家系研究——BBS12基因新突变. 中华肾脏病杂志, 2018, 34(8): 592-600. |
| [10] | Schwartz R, Hildebrandt F, Benzing T, Katsanis N. Mechanisms of disease ciliopathies. N Engl J Med, 2011, 16364(21): 1533-1543. |
| [11] | Loktev AV, Zhang QH, Beck JS, Searby CC, Scheetz TE, Bazan JF, Slusarski DC, Sheffield VC, Jackson PK, Nachury MV. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell, 2008, 15(6): 854-865. |
| [12] | Wei Q, Zhang YX, Li YJ, Zhang Q, Ling K, Hu JH. The BBSome controls IFT assembly and turnaround in cilia. Nat Cell Bio, 2012, 14(9): 950-957. |
| [13] | Nachury MV, Loktev AV, Zhang QH, Westlake CJ, Peränen J, Merdes A, Slusarski DC, Scheller RH, Bazan JF, Sheffield VC, Jackson PK. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell, 2007, 129(6): 1201-1213. |
| [14] | Billingsley G, Bin J, Fieggen KJ, Duncan JL, Gerth C, Ogata K, Wodak SS, Traboulsi EI, Fishman GA, Paterson A, Chitayat D, Knueppel T, Millán JM, Mitchell GA, Deveault C, Héon E. 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(7): 453-463. |
| [15] | Cardenas-Rodriguez M, Badano JL. Ciliary biology: understanding the cellular and genetic basis of human ciliopathies. Am J Med Genet C Semin Med Genet, 2009, 151C(4): 263-280. |
| [16] | Pawlik B, Mir A, Iqbal H, Li Y, Nürnberg G, Becker C, Qamar R, Nürnberg P, Wollnik B. A novel familialBBS12 mutation associated with a mild phenotype: implications for clinical and molecular diagnostic strategies. Mol Syndromol, 2010, 1(1): 27-34. |
| [17] | Khan SA, Muhammad N, Khan MA, Kamal A, Rehman ZU, Khan S. Genetics of human Bardet-Biedl syndrome, an updates. Clin Genet, 2016, 90(1): 3-15. |
| [18] | Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul NA, Vicaire S, Jacquelin C, Plewniak F, Leitch CC, Sarda P, Hamel C, De Ravel TJL, Lewis RA, Friederich E, Thibault C, Danse JM, Verloes A, Bonneau D, Katsanis N, Poch O, Mandel JL, Dollfus H. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet, 2007, 80(1): 1-11. |
| [19] | Nikkhah E, Safaralizadeh R, Mohammadiasl J, Tahmasebi Birgani M, Hosseinpour Feizi MA, Golchin N. Identification of a novel compound heterozygous mutation in BBS12 in an iranian family with Bardet-Biedl syndrome using targeted next generation sequencing. Cell J, 2018, 20(2): 284-289. |
| [20] | Castro-Sánchez S, Álvarez-Satta M, Cortón M, Guillén E, Ayuso C, Valverde D. Exploring genotype-phenotype relationships in Bardet-Biedl syndrome families. J Med Genet, 2015, 52(8): 503-513. |
| [21] | Deveault C, Billingsley G, Duncan JL, Bin J, Theal R, Vincent A, Fieggen KJ, Gerth C, Noordeh N, Traboulsi EI, Fishman GA, Chitayat D, Knueppel T, Millán JM, Munier FL, Kennedy D, Jacobson SG, Innes AM, Mitchell GA, Boycott K, Héon E. BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition. Hum Mutat, 2011, 32(6): 610-619. |
| [22] | Baker K, Beales PL. Making sense of cilia in disease: the human cilioplathies. Am J Med Genet P C Semin Med Genet, 2009, 151C(4): 281-295. |
| [23] | Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis, 2007, 2: 7. |
| [24] | Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet, 2007, 28(3): 113-125. |
| [25] | Pomeroy J, Krentz AD, Richardson JG, Berg RL, Vanwormer JJ, Haws RM. Bardet-Biedl syndrome: weight patterns and genetics in a rare obesity syndrome. Pediatr Obes, 2021, 16(2): e12703. |
| [26] | Forsythe E, Sparks K, Best S, Borrows S, Hoskins B, Sabir A, Barrett T, Williams D, Mohammed S, Goldsmith D, Milford DV, Bockenhauer D, Foggensteiner L, Bealest PL. Risk factors for severe renal disease in Bardet-Biedl syndrome. J Am Soc Nephrol, 2017, 28(3): 963-970. |
| [27] | Harnett JD, Green JS, Cramer BC, Johnson G, Chafe L, Mcmanamon P, Farid NR, Pryse-Phillips W, Parfrey PS. The spectrum of renal disease in Laurence-Moon-Biedl syndrome. N Engl J Med, 1988, 319(10): 615-618. |
| [28] | Imhoff O, Marion V, Stoetzel C, Durand M, Holder M, Sigaudy S, Sarda P, Hamel CP, Brandt C, Dollfus H, Moulin B. Bardet-Biedl syndrome: a study of the renal and cardiovascular phenotypes in a French cohort. Clin J Am Soc Nephrol, 2011, 6(1): 22-29. |
| [29] | Starks RD, Beyer AM, Guo DF, Boland L, Zhang QH, Sheffield VC, Rahmouni K. Regulation of insulin receptor trafficking by Bardet Biedl syndrome proteins. PLoS Genet, 2015, 11(6): e1005311. |
| [30] | Gerdes JM, Christou-Savina S, Xiong Y, Moede T, Moruzzi N, Karlsson-Edlund P, Leibiger B, Leibiger IB, Östenson CG, Beales PL, Berggren PO. Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents. Nat Commun, 2014, 5: 5308. |
| [31] | Marion V, Mockel A, De Melo C, Obringer C, Claussmann A, Simon A, Messaddeq N, Durand M, Dupuis L, Loeffler J-P, King P, Mutter-Schmidt C, Petrovsky N, Stoetzel C, Dollfus H. BBS-induced ciliary defect enhances adipogenesis, causing paradoxical higher-insulin sensitivity, glucose usage, and decreased inflammatory response. Cell Metab, 2012, 16(3): 363-377. |
| [32] | Maratou E, Hadjidakis DJ, Kollias A, Tsegka K, Peppa M, Alevizaki M, Mitrou P, Lambadiari V, Boutati E, Nikzas D, Tountas N, Economopoulos T, Raptis SA, Dimitriadis G. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol, 2009, 160(5): 785-790. |
| [33] | Walczak K, Sieminska L. Obesity and thyroid axis. Int J Environ Res Public Health, 2021, 18(18): 9434. |
| [34] | Bruinstroop E, Dalan R, Cao Y, Bee YM, Chandran K, Cho LW, Soh SB, Teo EK, Toh SA, Leow MKS, Sinha RA, Sadananthan SA, Michael N, Stapleton HM, Leung C, Angus PW, Patel SK, Burrell LM, Lim SC, Sum CF, Velan SS, Yen PM. Low-dose levothyroxine reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and NAFLD. J Clin Endocrinol Metab, 2018, 103(7): 2698-2706. |
| [35] | Seo S, Mullins RF, Dumitrescu AV, Bhattarai S, Gratie D, Wang K, Stone EM, Sheffield V, Drack AV.Subretinal gene therapy of mice with Bardet-Biedl syndrome type 1. Inves Ophthalmol Vis Sci, 2013, 54(9): 6118-6132. |
| [36] | Rahmouni K, Fath MA, Seo S, Thedens DR, Berry CJ, Weiss R, Nishimura DY, Sheffield VC. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest, 2008, 118(4): 1458-1467. |
| [37] | Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet, 2009, 18(7): 1323-1331. |
| [38] | Oh EC, Vasanth S, Katsanis N. Metabolic regulation and energy homeostasis through the primary cilium. Cell Metab, 2015, 21(1): 21-31. |
| [39] | Wang LH, Liu Y, Stratigopoulos G, Panigrahi S, Sui LN, Zhang YY, Leduc CA, Glover HJ, De Rosa MC, Burnett LC, Williams DJ, Shang LS, Goland R, Tsang SH, Wardlaw S, Egli D, Zheng D, Doege CA, Leibel RL. Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC- derived neurons. J Clin Invest, 2021, 131(8): e146287. |
| [40] | Daskalakis M, Till H, Kiess W, Weiner RA. Roux-en-Y gastric bypass in an adolescent patient with Bardet-Biedl syndrome, a monogenic obesity disorder. Obes Surg, 2010, 20(1): 121-125. |
| [41] | Boscolo M, Féry F, Cnop M. Beneficial outcomes of sleeve gastrectomy in a morbidly obese patient with Bardet-Biedl syndrome. J Endocr Soc, 2017, 1(4): 317-322. |
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