一例BBS12基因复合杂合突变导致Bardet-Biedl综合征的诊断和基因检测分析

doi:10.16288/j.yczz.22-182

遗传 ›› 2022, Vol. 44 ›› Issue (10): 975-982.doi: 10.16288/j.yczz.22-182

一例BBS12基因复合杂合突变导致Bardet-Biedl综合征的诊断和基因检测分析

沈艳婷^1,²(), 凌雁^1,², 陆志强^1,², 李晓牧^1,², 卞华^1,², 颜红梅^1,², 夏明锋^1,², 常新霞^1,², 蒋晶晶^1,², 张晶^1,²(), 高鑫^1,²

1. 复旦大学附属中山医院内分泌科,上海 200032
2. 复旦大学慢性代谢性疾病研究所,上海 200032

收稿日期:2022-05-30 修回日期:2022-08-26 出版日期:2022-10-20 发布日期:2022-09-08
通讯作者: 张晶 E-mail:19211210076@fudan.edu.cn;zhang_jing2016@126.com
作者简介:沈艳婷,在读硕士研究生,专业方向：内分泌与代谢病。E-mail: 19211210076@fudan.edu.cn
基金资助:
国家自然科学基金项目(81770865)

Diagnosis and genetic analysis of a case with Bardet-Biedl syndrome caused by compound heterozygous mutations in the BBS12 gene

Yanting Shen^1,²(), Yan Ling^1,², Zhiqiang Lu^1,², Xiaomu Li^1,², Hua Bian^1,², Hongmei Yan^1,², Mingfeng Xia^1,², Xinxia Chang^1,², Jingjing Jiang^1,², Jing Zhang^1,²(), Xin Gao^1,²

1. Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
2. Institute of Chronic Metabolic Diseases of Fudan University, Shanghai 200032, China

Received:2022-05-30 Revised:2022-08-26 Online:2022-10-20 Published:2022-09-08
Contact: Zhang Jing E-mail:19211210076@fudan.edu.cn;zhang_jing2016@126.com
Supported by:
the National Natural Science Foundation of China(81770865)

摘要/Abstract

摘要：

Bardet-Biedl综合征(Bardet-Biedl syndrome, BBS)是一种罕见的常染色体隐性遗传的纤毛相关疾病,其病因主要与编码BBS蛋白复合体BBSome、鞭毛内运输复合体等基因突变有关。本文报道了1例21岁的女性BBS患者,该患者具有肥胖、视网膜色素变性、双肾囊肿的典型特征,还存在2型糖尿病、非酒精性脂肪肝、亚临床甲状腺功能减退症、轻度传导性听力下降等不典型表现。全外显子组测序发现该患者的BBS12基因2号外显子存在复合杂合突变(c.188delC, p.T63fs和c.1993_1995del, p.665_665del)。进一步通过Sanger测序发现患者的父亲和母亲分别携带c.188delC(p.T63fs)和c.1993_1995del(p.665_665del)突变,但均无相关症状。综上所述,本病例报告发现了BBS12基因的两个新的突变位点(c.188delC, p.T63fs和c.1993_1995del, p.665_665del),为该疾病的研究提供了新的遗传资源,同时该病例还展示了患者从出生到成人期间的整个疾病发展过程,能够帮助临床医生更好地理解BBS。

关键词: Bardet-Biedl综合征, BBS12基因, 全外显子组测序

Abstract:

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

沈艳婷, 凌雁, 陆志强, 李晓牧, 卞华, 颜红梅, 夏明锋, 常新霞, 蒋晶晶, 张晶, 高鑫. 一例BBS12基因复合杂合突变导致Bardet-Biedl综合征的诊断和基因检测分析[J]. 遗传, 2022, 44(10): 975-982.

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.

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参考文献 41

[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. pmid: 10874630
[2]	Suspitsin EN, Imyanitov EN. Bardet-Biedl syndrome. Mol Syndromol, 2016, 7(2): 62-71. doi: 10.1159/000445491 pmid: 27385962
[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. doi: 10.1007/s00439-010-0902-8
[4]	Farag TI, Teebi AS. High incidence of Bardet Biedl syndrome among the bedouin. Clin Genet, 1989, 36(6): 463-464. doi: 10.1111/j.1399-0004.1989.tb03378.x pmid: 2591073
[5]	Mitchison HM, Valente EM. Motile and non-motile cilia in human pathology: from function to phenotypes. J Pathol, 2017, 241(2): 294-309. doi: 10.1002/path.4843
[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.
	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. doi: 10.3389/fmolb.2017.00055 pmid: 28824921
[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. doi: 10.1210/jc.2017-01459 pmid: 29409041
[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. doi: 10.3760/cma.j.issn.1001-7097.2018.08.006
	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. doi: 10.3760/cma.j.issn.1001-7097.2018.08.006
[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. doi: 10.1016/j.devcel.2008.11.001 pmid: 19081074
[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. doi: 10.1038/ncb2560
[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. pmid: 17574030
[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. doi: 10.1136/jmg.2009.073205 pmid: 20472660
[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. doi: 10.1002/ajmg.c.30227
[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. doi: 10.1159/000276763 pmid: 20648243
[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. doi: 10.1111/cge.12737 pmid: 26762677
[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. pmid: 17160889
[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. doi: 10.22074/cellj.2018.5012 pmid: 29633607
[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. doi: 10.1136/jmedgenet-2015-103099 pmid: 26082521
[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. doi: 10.1002/humu.21480 pmid: 21344540
[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. pmid: 17270046
[24]	Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet, 2007, 28(3): 113-125. pmid: 17896309
[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. doi: 10.1681/ASN.2015091029 pmid: 27659767
[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. doi: 10.1056/NEJM198809083191005
[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. doi: 10.2215/CJN.03320410
[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. doi: 10.1371/journal.pgen.1005311
[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. doi: 10.1038/ncomms6308 pmid: 25374274
[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. doi: 10.1016/j.cmet.2012.08.005 pmid: 22958920
[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. doi: 10.1530/EJE-08-0797 pmid: 19141606
[33]	Walczak K, Sieminska L. Obesity and thyroid axis. Int J Environ Res Public Health, 2021, 18(18): 9434. doi: 10.3390/ijerph18189434
[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. doi: 10.1210/jc.2018-00475 pmid: 29718334
[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. doi: 10.1167/iovs.13-11673
[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. doi: 10.1172/JCI32357 pmid: 18317593
[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. doi: 10.1093/hmg/ddp031 pmid: 19150989
[38]	Oh EC, Vasanth S, Katsanis N. Metabolic regulation and energy homeostasis through the primary cilium. Cell Metab, 2015, 21(1): 21-31. doi: 10.1016/j.cmet.2014.11.019 pmid: 25543293
[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. doi: 10.1172/JCI146287
[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. doi: 10.1007/s11695-009-9915-6 pmid: 19847573
[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. doi: 10.1210/js.2017-00071 pmid: 29264490

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症状	既往报道患者	本例患者
主要症状
视网膜色素变性	+	+
多指/趾	+	-
肥胖	+	+
智力障碍	+	-
性腺发育异常	+	-
肾脏异常	+	+
次要症状
肝功能异常	+	+
糖尿病	+	+
神经运动异常	NA	-
语言障碍	+	-
行为异常	+	-
先天面部畸形	NA	-
牙齿异常	+	-
发育迟缓	+	-
高血压	NA	-
心血管系统异常	+	-
听力受损	+	+
嗅觉缺失/减退	+	-
呼吸系统异常	+	-
甲状腺功能减退	+	+
并指/趾	+	-

一例BBS12基因复合杂合突变导致Bardet-Biedl综合征的诊断和基因检测分析

Diagnosis and genetic analysis of a case with Bardet-Biedl syndrome caused by compound heterozygous mutations in the BBS12 gene

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