WNT10A双等位基因突变导致非综合征型先天缺牙1例的遗传学分析及文献复习

doi:10.6040/j.issn.1671-7554.0.2024.1342

摘要/Abstract

摘要： 目的探讨1例非综合征型先天缺牙患者的致病基因突变情况,并对其牙齿缺失特点进行研究分析。方法收集患者家系及正常对照的血液样本并提取DNA。通过外显子测序及Sanger测序来发现并验证致病基因突变。使用预测软件Polyphen-2、Mutation Taster、CADD及fathmm来分析突变对功能的影响。使用保守性分析及蛋白质三维结构分析来预测突变对蛋白质功能的影响。检索以往发表文献,分析突变基因相关的缺牙表型。结果在1例非综合征先天缺牙患者中发现了罕见的WNT10A双等位基因突变(c.637G>A/p.Gly213Ser和c.1009G>T/p.Val337Phe),其中c.1009G>T突变是新突变。Polyphen-2、CADD及fathmm预测这两个突变是有害的;Mutation Taster预测c.637G>A突变是良性的,预测c.1009G>T突变是有害的。保守性分析显示这两个突变位点(213Gly和337Val)位于进化过程中高度保守区域,蛋白质三维结构分析显示氨基酸改变(p.Gly213Ser和p.Val337Phe)对蛋白质功能造成了影响。总结142例WNT10A突变导致的非综合征型先天缺牙患者资料,发现患者缺牙情况左右对称。最容易缺失的牙齿位置依次为下颌第二前磨牙(60.2%)、上颌第二前磨牙(58.5%)和上颌侧切牙(53.9%);最不容易缺失的牙齿依次为上颌中切牙(2.1%)、下颌第一磨牙(12.0%)和上颌第一磨牙(12.3%)。结论本研究在中国人群中的1例非综合征型先天缺牙患者中鉴定出WNT10A双等位基因突变(c.637G>A/p.Gly213Ser和 c.1009G>T/p.Val337Phe),其中c.1009G>T(p.Val337Phe)为首次报道的变异,扩大了WTN10A基因突变谱。另外,我们进行了WNT10A相关的非综合征型先天缺牙表型分析,为临床诊断、治疗和遗传咨询提供借鉴参考。

关键词: 非综合征型先天缺牙, 基因突变, WNT10A, 基因型表型分析, 遗传咨询

Abstract: Objective To investigate the pathogenic gene mutations in a patient with non-syndromic tooth agenesis(NSTA)and analyze the characteristics of tooth absence. Methods Blood samples were collected from the patients family and normal controls, and DNA was extracted. Whole exon sequencing(WES)and Sanger sequencing were used to identify and verify the pathogenic gene mutations. Functional impacts of the mutations were analyzed using the prediction software Polyphen-2, Mutation Taster, CADD, and fathmm. Conservation analysis and protein three-dimensional structure analysis were used to predict the effects of the mutations on protein function. Previously published literature was reviewed to analyze the tooth agenesis phenotypes associated with the mutated gene. Results Rare compound heterozygous mutations in WNT10A(c.637G>A/p.Gly213Ser and c.1009G>T/p.Val337Phe)in a patient with NSTA were identified, with the c.1009G>T mutation being novel. Polyphen-2, CADD, and fathmm predicted both mutations to be deleterious; Mutation Taster predicted c.637G>A to be benign and c.1009G>T to be deleterious. Conservation analysis showed that both mutation sites(213Gly and 337Val)were highly conserved through evolution, and three-dimensional structure analysis of the proteins indicated that the amino acid changes(p.Gly213Ser and p.Val337Phe)affected protein function. 142 cases of NSTA caused by WNT10A mutations were reviewed, and it is found that tooth loss was bilaterally symmetrical. The most frequently missing tooth positions were the mandibular second premolar(60.2%), maxillary second premolar(58.5%), and maxillary lateral incisor(53.9%); the least frequently missing tooth positions were the maxillary central incisor(2.1%), mandibular first molar(12.0%), and maxillary first molar(12.3%). Conclusion This study identified compound heterozygous mutations in WNT10A(c.637G>A/p.Gly213Ser and c.1009G>T/p.Val337Phe)in a Chinese patient with NSTA, with the c.1009G>T(p.Val3337Phe)variant being reported for the first time, thus expanding the mutation spectrum of the WNT10A gene. In addition, phenotypic analysis of WNT10A-related NSTA provides valuable insights for clinical diagnosis, treatment, and genetic counseling.

Key words: Non-syndromic tooth agenesis, Gene mutation, WNT10A, Genotype-phenotype analysis, Genetic counseling

中图分类号:

R574

丁婷婷,刘浩辰. WNT10A双等位基因突变导致非综合征型先天缺牙1例的遗传学分析及文献复习[J]. 山东大学学报 (医学版), 2025, 63(3): 92-98.

DING Tingting, LIU Haochen. Genetic analysis and literature review of a case of non-syndromic tooth agenesis caused by compound heterozygous mutations in WNT10A[J]. Journal of Shandong University (Health Sciences), 2025, 63(3): 92-98.

参考文献

[1] 刘浩辰, 冯海兰. 先天缺牙遗传学病因机制研究进展[J]. 口腔生物医学, 2017, 8(1): 37-43.
[2] 张晓霞, 冯海兰. 多个牙先天缺失的病例分析及临床分型[J]. 中华口腔医学杂志, 2003, 38(4): 266-268. ZHANG Xiaoxia, FENG Hailan. Cases analysis and clinical classification of oligodontia[J]. Chinese Journal of Stomatology, 2003, 38(4): 266-268.
[3] 丁婷婷, 邹东, 刘浩辰. 一个非综合征型先天缺牙家系的MSX1基因突变分析[J]. 山东大学学报(医学版), 2019, 57(4): 97-100. DING Tingting, ZOU Dong, LIU Haochen. An analysis of the mutation of MSX1 gene in a non-syndromic tooth agenesis family[J]. Journal of Shandong University(Health Science), 2019, 57(4): 97-100.
[4] Zhang J, Liu HC, Lyu X, et al. Prevalence of tooth agenesis in adolescent Chinese populations with or without orthodontics[J]. Chin J Dent Res, 2015, 18(1): 59-65.
[5] Cammarata-Scalisi F, Willoughby CE, El-Feghaly JR, et al. Main genetic entities associated with tooth agenesis[J]. Clin Oral Investig, 2024, 29(1): 9. doi:10.1007/s00784-024-05941-7
[6] Juuri E, Balic A. The biology underlying abnormalities of tooth number in humans[J]. J Dent Res, 2017, 96(11): 1248-1256.
[7] Liu HC, Liu HB, Su LX, et al. Four novel PAX9 variants and the PAX9-related non-syndromic tooth agenesis patterns[J]. Int J Mol Sci, 2022, 23(15): 8142.
[8] Prasad MK, Geoffroy V, Vicaire S, et al. A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement[J]. J Med Genet, 2016, 53(2): 98-110.
[9] van den Boogaard MJ, Créton M, Bronkhorst Y, et al. Mutations in WNT10A are present in more than half of isolated hypodontia cases[J]. J Med Genet, 2012, 49(5): 327-331.
[10] Cluzeau C, Hadj-Rabia S, Jambou M, et al. Only four genes(EDA1, EDAR, EDARADD, and WNT10A)account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases[J]. Hum Mutat, 2011, 32(1): 70-72.
[11] Arzoo PS, Klar J, Bergendal B, et al. WNT10A mutations account for of population-based isolated oligodontia and show phenotypic correlations[J]. Am J Med Genet A, 2014, 164(2): 353-359.
[12] Abid MF, Simpson MA, Barbosa IA, et al. WNT10A mutation results in severe tooth agenesis in a family of three sisters[J]. Orthod Craniofac Res, 2018. doi:10.1111/ocr.12231
[13] Yu M, Liu Y, Liu HC, et al. Distinct impacts of bi-allelic WNT10A mutations on the permanent and primary dentitions in odonto-onycho-dermal dysplasia[J]. Am J Med Genet A, 2019, 179(1): 57-64.
[14] Liu HC, Lin BC, Liu HB, et al. Dose dependence effect in biallelic WNT10A variant-associated tooth agenesis phenotype[J]. Diagnostics, 2022, 12(12): 3087.
[15] Park H, Song JS, Shin TJ, et al. WNT10A mutations causing oligodontia[J]. Arch Oral Biol, 2019, 103: 8-11. doi:10.1016/j.archoralbio.2019.05.007
[16] Song SJ, Zhao RY, He HY, et al. WNT10A variants are associated with non-syndromic tooth agenesis in the general population[J]. Hum Genet, 2014, 133(1): 117-124.
[17] Machida J, Goto H, Tatematsu T, et al. WNT10A variants isolated from Japanese patients with congenital tooth agenesis[J]. Hum Genome Var, 2017, 4: 17047. doi:10.1038/hgv.2017.47
[18] Yin W, Bian Z. The gene network underlying hypodontia[J]. J Dent Res, 2015, 94(7): 878-885. doi: 10.1177/0022034515583999
[21] Medina JL, Brooks EG, Chaparro A, et al. Mycoplasma pneumoniae CARDS toxin elicits a functional IgE response in Balb/c mice[J]. PLoS One, 2017, 12(2): e0172447. doi:10.1371/journal.pone.0172447
[22] Tsai TA, Tsai CK, Kuo KC, et al. Rational stepwise approach for Mycoplasma pneumoniae pneumonia in children[J]. J Microbiol Immunol Infect, 2021, 54(4): 557-565.
[23] Yin SS, Ma FL, Gao X. Association of Mycoplasma pneumoniae infection with increased risk of asthma in children[J]. Exp Ther Med, 2017, 13(5): 1813-1819.
[24] 王英媛, 蔡栩栩, 尚云晓,等. 肺炎支原体感染对哮喘儿童呼出气一氧化氮及肺功能影响的研究[J]. 国际儿科学杂志, 2017, 44(7): 491-494. WANG Yingyuan, CAI Xuxu, SHANG Yunxiao, et al. The effects of Mycoplasma pneumoniae infection on the exhaled nitric oxide level and lung function in asthma children [J]. International Journal of Pediatrics, 2017, 44(7): 491-494.
[25] 韩红, 安红, 高超, 等. 呼出气一氧化氮与血清hs-CRP、 sB7-H3联合检测在儿童肺炎支原体肺炎中的诊断价值[J]. 河北医科大学学报, 2020, 41(7): 838-840.
[26] Hagman K, Nilsson AC, Hedenstierna M, et al. Outcomes of adjunctive corticosteroid treatment on hypoxemic adults hospitalised for Mycoplasma pneumoniae pneumonia: a retrospective cohort study[J]. Clin Infect Dis, 2024: ciae451. doi:10.1093/cid/ciae451

相关文章 15

[1]	陈倩,仇一帆,陈世龙,王超,董亮,孙丛丛. 成人囊性纤维化1例并文献复习[J]. 山东大学学报 (医学版), 2024, 62(7): 42-47.
[2]	王一丹,杜润璇,石雪冬,赵兵依,高健. NF1新突变致Ⅰ型神经纤维瘤病的遗传学分析[J]. 山东大学学报 (医学版), 2024, 62(4): 120-124.
[3]	曹广磊,李季,闫飞,林鹏,侯为开,侯新国,陈丽. 甲状腺激素抵抗综合征伴高泌乳素血症1例[J]. 山东大学学报 (医学版), 2023, 61(6): 113-116.
[4]	包瑾瑾,刘庆燕,孙甜甜,陈青,刘佳. 糖尿病相关抗体阳性合并MODY14相关APPL1基因突变1例[J]. 山东大学学报 (医学版), 2023, 61(12): 113-118.
[5]	刘馨,侯新国,刘继东,赵红霞. 伴TSHR基因突变促甲状腺激素抵抗综合征1例[J]. 山东大学学报 (医学版), 2023, 61(10): 113-116.
[6]	薛美娟,石艳,邵琳琳,王琳,张昀,张阿敏. 遗传性血栓性血小板减少性紫癜1例并文献复习[J]. 山东大学学报 (医学版), 2022, 60(3): 121-124.
[7]	亓梦雨,周敏然,孙洺山,李世洁,陈春燕. T大颗粒淋巴细胞白血病合并原发性骨髓纤维化1例[J]. 山东大学学报 (医学版), 2022, 60(2): 118-120.
[8]	潘鹏飞,徐立升,纪坤乾,王得翔,李玉. 以呼吸衰竭起病的线粒体肌病1例及文献回顾[J]. 山东大学学报 (医学版), 2022, 60(2): 54-59.
[9]	史本康,陈守臻,曲思凤,王勇,刘磊. 临床常见快速进展前列腺癌临床特点及研究进展[J]. 山东大学学报 (医学版), 2021, 59(9): 110-116.
[10]	孙宇,陈娜,马爱华. SLC35A2基因突变致先天性糖基化障碍1例[J]. 山东大学学报 (医学版), 2021, 59(4): 113-116.
[11]	黄秀丽,刘丙菊,孙立锋. PIK3CD基因突变致PI3Kδ过度活化综合征1例并文献复习[J]. 山东大学学报 (医学版), 2021, 59(3): 107-112.
[12]	王正阳,夏艳,师凯旋,陶琨,王小杰. 曲美替尼在卵巢癌中对PAX8的表达作用[J]. 山东大学学报 (医学版), 2021, 59(10): 25-31.
[13]	刘娜,刘奇迹,牟凯,程翠云. EBF3基因杂合突变导致1例神经发育障碍综合征[J]. 山东大学学报 (医学版), 2020, 58(4): 105-109.
[14]	丁婷婷,邹东,刘浩辰. 一个非综合征型先天缺牙家系的MSX1基因突变分析[J]. 山东大学学报 (医学版), 2019, 57(4): 97-100.
[15]	窦春慧,邵建华,董学斌,张凌,陈萍,赵红玉,顾琳萍,孙琳,解杰,王敏,王娟,李娜,李凡,李大启. 骨髓增生异常综合征患者基因突变对地西他滨临床疗效的影响[J]. 山东大学学报 (医学版), 2019, 57(3): 42-48.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed