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

doi:10.7518/hxkq.2024.2024090

Abstract

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

CLC Number:

R781.9

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.

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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）

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