非综合征型多数牙先天缺失家系中PAX9新突变的研究及PAX9突变导致非综合征型先天缺牙基因型—表型分析

doi:10.7518/hxkq.2024.2024090

华西口腔医学杂志 ›› 2024, Vol. 42 ›› Issue (5): 581-592.doi: 10.7518/hxkq.2024.2024090

非综合征型多数牙先天缺失家系中PAX9新突变的研究及PAX9突变导致非综合征型先天缺牙基因型—表型分析

靳占云¹(), 郭峻嘉¹, 袁云云¹, 孟令强¹, 李慧¹, 赵娅¹, 任嘉宝¹, 马永平², 肖遵胜³, 张红², 杨玲⁴, 窦晨云¹, 王晓雪¹, 王金梅¹, 沈文静¹()

^1.河北医科大学口腔医学院·口腔医院修复科河北省口腔医学重点实验室河北省口腔疾病临床医学研究中心，石家庄 050017
^2.保定市第二医院口腔科，保定 071051
^3.河北省沧州市中心医院口腔科，沧州 061001
^4.衡水市第六人民医院，衡水 053200

收稿日期:2024-03-14 修回日期:2024-06-25 出版日期:2024-10-01 发布日期:2024-09-21
通讯作者: 沈文静 E-mail:jzy000601@163.com;wenjingshen2020@hebmu.edu.cn
作者简介:靳占云，医师，硕士，E-mail：jzy000601@163.com
基金资助:
河北省科技厅卫生健康创新专项(21377716D);河北省自然科学基金精准医学项目(H2022206246);2023年政府资助临床医学优秀人才培养项目(ZF2023011);河北省财政厅老年病项目(361029)

A novel PAX9 variant in a Chinese family with non-syndromic oligodontia and genotype-phenotype analysis of PAX9variants

Jin Zhanyun¹(), Guo Junjia¹, Yuan Yunyun¹, Meng Lingqiang¹, Li Hui¹, Zhao Ya¹, Ren Jiabao¹, Ma Yongping², Xiao Zun-sheng³, Zhang Hong², Yang Ling⁴, Dou Chenyun¹, Wang Xiaoxue¹, Wang Jinmei¹, Shen Wenjing¹()

^1.Dept. of Prosthodontics, School and Hospital of Stomatology, Hebei Medical University, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, Shijiazhuang 050017, China
^2.Dept. of Stomatology, The No. 2 Hospital of Baoding, Baoding 071051, China
^3.Dept. of Stomatology, Cangzhou Central Hospital, Cangzhou 061001, China
^4.Hengshui Sixth People’s Hospital, Hengshui 053200, China

Received:2024-03-14 Revised:2024-06-25 Online:2024-10-01 Published:2024-09-21
Contact: Shen Wenjing E-mail:jzy000601@163.com;wenjingshen2020@hebmu.edu.cn
Supported by:
Special Project of Health Innovation of Hebei Provincial Department of Science and Technology(21377716D);Natural Science Foundation of Hebei Province(H2022206246);2023 Hebei Provincial Government Funded Clinical Medical Talents Training Project(ZF2023011);Geriatric Disease Project of Hebei Provincial Department of Finance(361029);Correspondence: Shen Wenjing, E-mail: wenjingshen2020@hebmu.edu.cn

摘要/Abstract

摘要：

目的在中国多个非综合征型先天缺牙家系中鉴定PAX9突变，并研究PAX9突变导致非综合征型先天缺牙的基因型—表型关系，为先天缺牙基因诊断提供依据。方法收集自2018年至2023年期间于河北医科大学口腔医院就诊的44例非综合征型多数牙缺失患者。采集先证者及其核心家系成员外周血进行全外显子组测序（WES），并用Sanger测序验证其突变，通过生物信息学工具对突变体进行了致病性分析和功能预测。在PubMed等检索出与先天缺牙相关PAX9突变的55篇文章共232例患者，分析PAX9突变基因型—表型关系。结果在中国家庭中发现了一个新的PAX9基因移码突变c.447delG（p.Pro150Argfs*62）和一个已报道的PAX9基因错义突变c.406C>T（p.Gln136*）。通过生物信息学分析和三维结构建模，预测发现该移码突变具有致病性，突变导致PAX9蛋白提前终止，结构与功能受损严重。总结PAX9基因型—表型关系发现，携带PAX9突变的非综合征型先天缺牙患者最容易缺失第二磨牙。结论发现非综合征型先天缺牙新的PAX9基因移码突变c.447delG（p.Pro150Argfs*62），扩展先天缺牙PAX9突变谱。非综合征型先天缺牙PAX9突变最易感牙位为第二磨牙，PAX9突变导致的乳牙缺失均为乳磨牙缺失。

关键词: 非综合征型先天缺牙, PAX9, 全外显子组测序, 基因型—表型

Abstract:

Objective This study aimed to identifyPAX9variants in non-syndromic tooth agenesis families of China, as well as to analyze the genotype⁃phenotype of non-syndromic tooth agenesis caused by PAX9variants, which can provide a basis for the genetic diagnosis of tooth agenesis. Methods We collected the data of 44 patients with non-syndromic oligodontia who underwent treatment at Stomatological Hospital of Hebei Medical University between 2018 and 2023. Whole-exome sequencing was performed on the peripheral blood of the proband and its core family members, and the variants were verified by Sanger sequencing. Pathogenicity analysis and function prediction of the variants were performed using bioinformatics tools. The correlation between the genotype of PAX9 variant and its corresponding phenotype was examined by reviewing 55 publications retrieved from PubMed. The studies involved 232 tooth agenesis patients with PAX9 variants. Results A novel PAX9 c.447delG (p.Pro150Argfs*62) and a reported PAX9 c.406C>T (p.Gln136*) were identified in two Chinese families. Through bioinformatics analysis and three-dimensional structural modeling, we postulated that the frameshift variant was pathogenic. The outcome was the premature cessation of PAX9 protein, which caused severe structural and functional deficiencies. Summarizing the PAX9 genotype-phenotype relationship revealed that patients carrying the PAX9 variant commonly led to loss of the second molars. Conclusion We identified the novel PAX9 c.447delG (p.Pro150Argfs*62) in a Chinese family of non-syndromic oligodontia, expanding the known variant spectrum of PAX9. The most susceptible tooth position for PAX9 variants of tooth agenesis was the second molars and the deciduous molars during the deciduous dentition.

Key words: non-syndromic tooth agenesis, PAX9, whole-exome sequencing, genotype-phenotype

中图分类号:

R781.9

靳占云, 郭峻嘉, 袁云云, 孟令强, 李慧, 赵娅, 任嘉宝, 马永平, 肖遵胜, 张红, 杨玲, 窦晨云, 王晓雪, 王金梅, 沈文静. 非综合征型多数牙先天缺失家系中PAX9新突变的研究及PAX9突变导致非综合征型先天缺牙基因型—表型分析[J]. 华西口腔医学杂志, 2024, 42(5): 581-592.

Jin Zhanyun, Guo Junjia, Yuan Yunyun, Meng Lingqiang, Li Hui, Zhao Ya, Ren Jiabao, Ma Yongping, Xiao Zun-sheng, Zhang Hong, Yang Ling, Dou Chenyun, Wang Xiaoxue, Wang Jinmei, Shen Wenjing. A novel PAX9 variant in a Chinese family with non-syndromic oligodontia and genotype-phenotype analysis of PAX9variants[J]. West China Journal of Stomatology, 2024, 42(5): 581-592.

图/表 11

图 1

图 2

表 1

图 3

图 4

图 5

表 2

图 6

图 7

图 8

表 3

参考文献 71

1	Lan R, Wu YQ, Dai QG, et al. Gene mutations and chromosomal abnormalities in syndromes with tooth agenesis[J]. Oral Dis, 2023, 29(6): 2401-2408.
2	Yu M, Wong SW, Han D, et al. Genetic analysis: Wnt and other pathways in nonsyndromic tooth agenesis[J]. Oral Dis, 2019, 25(3): 646-651.
3	Zhou M, Zhang H, Camhi H, et al. Analyses of oligodontia phenotypes and genetic etiologies[J]. Int J Oral Sci, 2021, 13(1): 32.
4	Ogasawara M, Wada H, Peters H, et al. Developmental expression of Pax1/9 genes in urochordate and hemichordate gills: insight into function and evolution of the pharyngeal epithelium[J]. Development, 1999, 126(11): 2539-2550.
5	Bhol CS, Patil S, Sahu BB, et al. The clinical significance and correlative signaling pathways of paired box gene 9 in development and carcinogenesis[J]. Biochim Biophys Acta Rev Cancer, 2021, 1876(1): 188561.
6	Peters H, Neubüser A, Kratochwil K, et al. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities[J]. Genes Dev, 1998, 12(17): 2735-2747.
7	叶依婷, 刘浩辰, 韩冬, 等. PAX9突变非综合征型先天缺牙患者的缺牙表型分析[J]. 口腔颌面修复学杂志,2019, 20(3): 151-155.
	Ye YT, Liu HC, Han D, et al. PAX9 mutation phenotype analysis in patients with non-syndromic tooth agenesis[J]. Chin J Prosthodont, 2019, 20(3): 151-155.
8	Bonczek O, Balcar VJ, Šerý O. PAX9 gene mutations and tooth agenesis: a review[J]. Clin Genet, 2017, 92(5): 467-476.
9	Fauzi NH, Ardini YD, Zainuddin Z, et al. A review on non-syndromic tooth agenesis associated with PAX9 mutations[J]. Jpn Dent Sci Rev, 2018, 54(1): 30-36.
10	Li R, Chen Z, Yu Q, et al. The function and regulatory network of Pax9 gene in palate development[J]. J Dent Res, 2019, 98(3): 277-287.
11	Cheng N, Wang D, Zhou ZH, et al. Interaction between HCMV infection and PAX9 gene polymorphisms in low birth weight infants[J]. J Matern Fetal Neonatal Med, 2016, 29(12): 2040-2043.
12	王璟, 简繁, 王晟, 等.一个单纯性先天缺牙家系的临床及基因突变分析[J]. 华西口腔医学杂志, 2009, 27(6): 606-609, 613.
	Wang J, Jian F, Wang S, et al. Analysis of clinical features and mutation associated with oligodontia[J]. West China J Stomatol, 2009, 27(6): 606-609, 613.
13	赵计林, 陈扬熙, 鲍朗, 等.中国先天性缺失牙患者PAX9基因的新突变[J]. 中华口腔医学杂志, 2005, 40(4): 266-269.
	Zhao JL, Chen YX, Bao L, et al. Novel mutations of PAX9 gene in Chinese patients with oligodontia[J]. Chin J Stomatol, 2005, 40(4): 266-270.
14	Haldeman-Englert CR, Biser A, Zackai EH, et al. A 223-kb de novo deletion of PAX9 in a patient with oligodontia[J]. J Craniofac Surg, 2010, 21(3): 837-839.
15	Lammi L, Halonen K, Pirinen S, et al. A missense mutation in PAX9 in a family with distinct phenotype of oligodontia[J]. Eur J Hum Genet, 2003, 11(11): 866-871.
16	Thimmegowda U, Prasanna P, Athimuthu A, et al. A nonsyndromic autosomal dominant oligodontia with a novel mutation of PAX9—a clinical and genetic report[J]. J Clin Diagn Res, 2015, 9(6): ZD08-ZD10.
17	Sarkar T, Bansal R, Das P. A novel G to A transition at initiation codon and exon-intron boundary of PAX9 identified in association with familial isolated oligodontia[J]. Gene, 2017, 635: 69-76.
18	Mendoza-Fandino GA, Gee JM, Ben-Dor S, et al. A novel g.-1258G>A mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia[J]. Clin Genet, 2011, 80(3): 265-272.
19	Liang J, Qin CQ, Yue HT, et al. A novel initiation codon mutation of PAX9 in a family with oligodontia[J]. Arch Oral Biol, 2016, 61: 144-148.
20	Zhao JL, Hu QG, Chen YX, et al. A novel missense mutation in the paired domain of human PAX9 causes oligodontia[J]. Am J Med Genet A, 2007, 143A(21): 2592-2597.
21	Jumlongras D, Lin JY, Chapra A, et al. A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia[J]. Hum Genet, 2004, 114(3): 242-249.
22	Frazier-Bowers SA, Guo DC, Cavender A, et al. A novel mutation in human PAX9 causes molar oligodontia[J]. J Dent Res, 2002, 81(2): 129-133.
23	Mostowska A, Biedziak B, Trzeciak WH. A novel mutation in PAX9 causes familial form of molar oligodontia[J]. Eur J Hum Genet, 2006, 14(2): 173-179.
24	Hansen L, Kreiborg S, Jarlov H, et al. A novel nonsense mutation in PAX9 is associated with marked variability in number of missing teeth[J]. Eur J Oral Sci, 2007, 115(4): 330-333.
25	Daw EM, Saliba C, Grech G, et al. A novel PAX9 mutation causing oligodontia[J]. Arch Oral Biol, 2017, 84: 100-105.
26	Zhang TT, Zhao XX, Hou FF, et al. A novel PAX9 mutation found in a Chinese patient with hypodontia via whole exome sequencing[J]. Oral Dis, 2019, 25(1): 234-241.
27	Šerý O, Bonczek O, Hloušková A, et al. A screen of a large Czech cohort of oligodontia patients implicates a novel mutation in the PAX9 gene[J]. Eur J Oral Sci, 2015, 123(2): 65-71.
28	Sarkar T, Ranjan P, Kanathur S, et al. An in vitro and computational validation of a novel loss-of-functional mutation in PAX9 associated with non-syndromic tooth agenesis[J]. Mol Genet Genomics, 2023, 298(1): 183-199.
29	Arte S, Parmanen S, Pirinen S, et al. Candidate gene analysis of tooth agenesis identifies novel mutations in six genes and suggests significant role for WNT and EDA signaling and allele combinations[J]. PLoS One, 2013, 8(8): e73705.
30	Haddaji Mastouri M, de Coster P, Zaghabani A, et al. Characterization of a novel mutation in PAX9 gene in a family with non-syndromic dental agenesis[J]. Arch Oral Biol, 2016, 71: 110-116.
31	Murakami A, Yasuhira S, Mayama H, et al. Characterization of PAX9 variant P20L identified in a Japanese family with tooth agenesis[J]. PLoS One, 2017, 12(10): e0186260.
32	Guala A, Falco V, Breedveld G, et al. Deletion of PAX9 and oligodontia: a third family and review of the literature[J]. Int J Paediatr Dent, 2008, 18(6): 441-445.
33	Sun RQ, Li SY, Xia B, et al. Detection of novel variant and functional study in a Chinese family with nonsyndromic oligodontia[J]. Oral Dis, 2023, 29(5): 2177-2187.
34	Koskinen S, Keski-Filppula R, Alapulli H, et al. Familial oligodontia and regional odontodysplasia associated with a PAX9 initiation codon mutation[J]. Clin Oral Investig, 2019, 23(11): 4107-4111.
35	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.
36	Sun K, Yu M, Yeh I, et al. Functional study of novel PAX9 variants: the paired domain and non-syndromic oligodontia[J]. Oral Dis, 2021, 27(6): 1468-1477.
37	Ren JB, Gan SF, Zheng SS, et al. Genotype-phenotype pattern analysis of pathogenic PAX9 variants in Chinese Han families with non-syndromic oligodontia[J]. Front Genet, 2023, 14: 1142776.
38	Das P, Stockton DW, Bauer C, et al. Haploinsufficiency of PAX9 is associated with autosomal dominant hypo-dontia[J]. Hum Genet, 2002, 110(4): 371-376.
39	Wang Y, Wu H, Wu JF, et al. Identification and functional analysis of two novel PAX9 mutations[J]. Cells Tissues Organs, 2009, 189(1/2/3/4): 80-87.
40	Nieminen P, Arte S, Tanner D, et al. Identification of a nonsense mutation in the PAX9 gene in molar oligodontia[J]. Eur J Hum Genet, 2001, 9(10): 743-746.
41	Tallón-Walton V, Manzanares-Céspedes MC, Arte S, et al. Identification of a novel mutation in the PAX9 gene in a family affected by oligodontia and other dental anomalies[J]. Eur J Oral Sci, 2007, 115(6): 427-432.
42	Bergendal B, Klar J, Stecksén-Blicks C, et al. Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes[J]. Am J Med Genet A, 2011, 155A(7): 1616-1622.
43	Kapadia H, Frazier-Bowers S, Ogawa T, et al. Molecular characterization of a novel PAX9 missense mutation causing posterior tooth agenesis[J]. Eur J Hum Genet, 2006, 14(4): 403-409.
44	Yue HT, Liang J, Song GT, et al. Mutation analysis in patients with nonsyndromic tooth agenesis using exome sequencing[J]. Mol Genet Genomic Med, 2022, 10(10): e2045.
45	Stockton DW, Das P, Goldenberg M, et al. Mutation of PAX9 is associated with oligodontia[J]. Nat Genet, 2000, 24(1): 18-19.
46	Shahid M, Balto HA, Al-Hammad N, et al. Mutations in MSX1, PAX9 and MMP20 genes in Saudi Arabian patients with tooth agenesis[J]. Eur J Med Genet, 2016, 59(8): 377-385.
47	Pawlowska E, Janik-Papis K, Poplawski T, et al. Mutations in the PAX9 gene in sporadic oligodontia[J]. Orthod Craniofac Res, 2010, 13(3): 142-152.
48	Yu P, Yang WL, Han D, et al. Mutations in WNT10B are identified in individuals with oligodontia[J]. Am J Hum Genet, 2016, 99(1): 195-201.
49	Wong SW, Han D, Zhang H, et al. Nine novel PAX9 mutations and a distinct tooth agenesis genotype-phenotype[J]. J Dent Res, 2018, 97(2): 155-162.
50	Suda N, Ogawa T, Kojima T, et al. Non-syndromic oligodontia with a novel mutation of PAX9[J]. J Dent Res, 2011, 90(3): 382-386.
51	Boeira BR Jr, Echeverrigaray S. Novel missense mutation in PAX9 gene associated with familial tooth agenesis[J]. J Oral Pathol Med, 2013, 42(1): 99-105.
52	Das P, Hai M, Elcock C, et al. Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with autosomal dominant hypodontia[J]. Am J Med Genet A, 2003, 118A(1): 35-42.
53	Liang J, Song GT, Li Q, et al. Novel missense mutations in PAX9 causing oligodontia[J]. Arch Oral Biol, 2012, 57(6): 784-789.
54	Mostowska A, Kobielak A, Biedziak B, et al. Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia[J]. Eur J Oral Sci, 2003, 111(3): 272-276.
55	Klein ML, Nieminen P, Lammi L, et al. Novel mutation of the initiation codon of PAX9 causes oligodontia[J]. J Dent Res, 2005, 84(1): 43-47.
56	Wang SK, Chan HC, Makovey I, et al. Novel PAX9 and COL1A2 missense mutations causing tooth agenesis and OI/DGI without skeletal abnormalities[J]. PLoS One, 2012, 7(12): e51533.
57	Ren JB, Zhao Y, Yuan YY, et al. Novel PAX9 compound heterozygous variants in a Chinese family with non-syndromic oligodontia and genotype-phenotype analysis of PAX9 variants[J]. J Appl Oral Sci, 2023, 31: e20220403.
58	Mitsui SN, Yasue A, Masuda K, et al. Novel PAX9 mutations cause non-syndromic tooth agenesis[J]. J Dent Res, 2014, 93(3): 245-249.
59	Mostowska A, Biedziak B, Zadurska M, et al. Nucleotide variants of genes encoding components of the Wnt signalling pathway and the risk of non-syndromic tooth agenesis[J]. Clin Genet, 2013, 84(5): 429-440.
60	Paixão-Côrtes VR, Braga T, Salzano FM, et al. PAX9 and MSX1 transcription factor genes in non-syndromic dental agenesis[J]. Arch Oral Biol, 2011, 56(4): 337-344.
61	Chu KY, Wang YL, Chen JT, et al. PAX9 mutations and genetic synergism in familial tooth agenesis[J]. Ann N Y Acad Sci, 2023, 1524(1): 87-96.
62	Wang J, Jian F, Chen J, et al. Sequence analysis of PAX9, MSX1 and AXIN₂ genes in a Chinese oligodontia family[J]. Arch Oral Biol, 2011, 56(10): 1027-1034.
63	Jiang CL, Yu K, Shen YH, et al. The phenotype and genotype of PAX9 mutations causing tooth agenesis[J]. Clin Oral Investig, 2023, 27(8): 4369-4378.
64	Mitscherling J, Sczakiel HL, Kiskemper-Nestorjuk O, et al. Whole genome sequencing in families with oligodontia[J]. Oral Dis, 2023. doi: 10.1111/odi.14816 .
65	Mostowska A, Zadurska M, Rakowska A, et al. Novel PAX9 mutation associated with syndromic tooth agenesis[J]. Eur J Oral Sci, 2013, 121(5): 403-411.
66	Zhu JX, Yang X, Zhang CY, et al. A novel nonsense mutation in PAX9 is associated with sporadic hypodontia[J]. Mutagenesis, 2012, 27(3): 313-317.
67	Chen XX, Li YH, Paiboonrungruang C, et al. PAX9 in cancer development[J]. Int J Mol Sci, 2022, 23(10): 5589.
68	Eberhard D, Jiménez G, Heavey B, et al. Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family[J]. EMBO J, 2000, 19(10): 2292-2303.
69	Intarak N, Tongchairati K, Termteerapornpimol K, et al. Tooth agenesis patterns and variants in PAX9: a systematic review[J]. Jpn Dent Sci Rev, 2023, 59: 129-137.
70	Sun RQ, Li SY, Xia B, et al. Detection of novel variant and functional study in a Chinese family with nonsyndromic oligodontia[J]. Oral Dis, 2023, 29(5): 2177-2187.
71	Chi N, Epstein JA. Getting your Pax straight: Pax proteins in development and disease[J]. Trends Genet, 2002, 18(1): 41-47.

PAX9	氨基酸数目	相对分子质量	理论等电点	负电残基数	正电残基数	消光系数	半衰期/h	不稳定性指数	脂溶指数	亲水性平均值
野生型	341	36 310.12	9.39	21	11	42 860	30	50.20	77.86	-0.279
p.Pro150Argfs*62	210	23 208.74	11.00	30	33	24 325	30	63.61	73.81	-0.571

序号	核苷酸改变	氨基酸改变	突变类型	缺失乳牙	参考文献
1	c.175C>T	p.Arg59*	无义突变	65	41
2	c.175C>T	p.Arg59*	无义突变	75	41
3	c.218_219insG	p.Ser74Glnfs*243	移码突变	75、85	45
4	c.330_331insGT+c.1010C>A	p.T337K+p.D113Afs*9	错义突变+移码突变	55、65、74、75、85	57
5	c.330_331insGT+c.1010C>A	p.T337K+p.D113Afs*9	错义突变+移码突变	55、65、75、85	57
6	c.340A>T	p.Lys114*	无义突变	55、65、75、85	40
7	c.406C>T	p.Gln136*	无义突变	55、65、75、85	/
8	c.447delG	p.Pro150Argfs*62	移码突变	55、65、75、85	/
9	44-100 kb deletion including entire PAX9	p.？	缺失	54、55、64、65、74、75、84、85	38
10	223kb de novo heterozyrous deletion including 1 copy of entire PAX9 gene， and partial SLC25A21 gene	p.？	缺失	55、65、74、75、84、85	14

非综合征型多数牙先天缺失家系中PAX9新突变的研究及PAX9突变导致非综合征型先天缺牙基因型—表型分析

A novel PAX9 variant in a Chinese family with non-syndromic oligodontia and genotype-phenotype analysis of PAX9variants

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 11

参考文献 71

相关文章 1

编辑推荐

Metrics

本文评价

先证者	核苷酸改变	氨基酸改变	突变类型	SIFT	Polyphen2	Mutation Taster	致病性分类（ACMG）
1	c.447delG	p.Pro150Argfs*62	移码突变	—	—	D	可能致病（PVS1+PM2）
2	c.406C>T	p.Gln136*	无义突变	—	—	A	致病（PVS1+PM2+PP3）