Clinical characteristics and genetic analysis of Desbuquois dysplasia Kim type caused by CANT1 mutation

doi:10.3969/j.issn.1673-8640.2023.02.006

Abstract

Abstract:

Objective By analyzing the clinical and genetic characteristics of a Han patient with Desbuquois dysplasia（DBQD） without abnormal hand appearance，the phenotypic and genetic variation spectrum of DBQD in Chinese population has been further expanded. Methods The clinical data of the patient with DBQD were collected，and the genetic mutations of the patient and his parents were determined by trio-whole exome sequencing（Trio-WES）. Bioinformatics analysis and crystal structure analysis were used to analyze the biohazard of mutation，and Sanger sequencing was used to verify. The clinical characteristics and genetic variation spectrum of DBQD were summarized through literature review. Results The patient had special features（flat round face，exophthalmos and low bridge of nose），growth retardation，scoliosis and foot pain，but the appearance of hands was normal. The results of Trio-WES showed that the homozygous mutation of the CANT1 gene was c.494T>C（ p.Met165Thr），and the parents were heterozygous carriers of the mutation. SIFT，Polyphen-2 and Mutation Taste online softwares predicted that c.494T>C can cause harmful effects on protein or protein products. Sanger sequencing confirmed the existence of mutation. The prediction of crystal structure suggested that c.494T>C（ p.Met165Thr） may lead to the decrease of local structural stability of protein and affect the function of protein. The patient was diagnosed as DBQD-Kim type according to the hand characteristics，clinical phenotypic characteristics and gene determination results. Through literature review and the analysis of 41 patients with DBQD caused by CANT1 gene mutation，32 CANT1 gene mutations were found，including 15 missense mutations，11 frameshift mutations，3 nonsense mutations，3 non-coding mutations and 1 copy number deletion mutation. Among patients with DBQD 1 type，the frequency of arginine mutation（p.Arg300His or p.Arg300Cys） of CANT1 protein 300 was the highest. The Kim type patients were mainly serine 156（p.Ser156Phe） and valine 226（p.Val226Met）. Conclusions The extensive skeletal abnormalities in children with DBQD-Kim type may be caused by homozygous mutation of CANT1 gene. Combined with clinical phenotype and gene determination results，DBQD can be clearly diagnosed and classified.

Key words: CANT1 gene, Desbuquois dysplasia, Trio-whole exome sequencing

CLC Number:

R446.7

WANG Xin, DENG Qian, WANG Juanjuan, CAI Wenjuan, GAO Jian, HAN Yanping, HU Kefei, CHEN Yuqing. Clinical characteristics and genetic analysis of Desbuquois dysplasia Kim type caused by CANT1 mutation[J]. Laboratory Medicine, 2023, 38(2): 130-136.

Figures/Tables 7

References 19

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序号	国家或地区	碱基变异位点	氨基酸变异位点	近亲婚配	DBQD类型	文献
1	斯里兰卡	del2703bp		是	1型	[1]
2	土耳其	c.734delC	p.Pro245ArgfsX3	是	1型	[1]
3	土耳其	c.898C>T	p.Arg300Cys	是	1型	[1]
4	土耳其	c.898C>T	p.Arg300Cys	是	1型	[1]
5	伊朗	c.898C>T	p.Arg300Cys	是	1型	[1]
6	法国	c.899G>A	p.Arg300His	是	1型	[1]
7	阿联酋	c.899G>A	p.Arg300His	是	1型	[1]
8	摩洛哥	c.907_911insGCGCC	p.Ser303AlafsX20	是	1型	[1]
9	巴西	c.374G>A、c.896C>T	p.Trp125X、p.Pro299 Leu	否	1型	[1]
10	巴西	c.374G>A、c.896C>T	p.Trp125X、p.Pro299 Leu	否	1型	[1]
11	澳大利亚	c.228_229insC、c.671T>C	p.Trp77LeufsX13、p.Leu224Pro	否	1型	[2]
12	沙特阿拉伯	c.893_894insGCCGC	p.Phe325fsX	是	1型	[5]
13	中国	c.836-9G>A	p.Gly279ValfsX8	是	1型	[6]
14	高加索地区	c.336C>A	p.Asp112Glu	是	1型	[7]
15	以色列	c.899G>A	p.Arg300His	是	1型	[8]
16	高加索地区	c.228_229insC、c.277_278delCT	p.Leu93ValfsX89、p.Trp77LeufsX13	否	1型	[9]
17	高加索地区	c.228_229insC	p.Trp77LeufsX13	否	1型	[9]
18	日本	c.805delC	p.Leu269CysfsX54	否	1型	[9]
19	中国	c.494T>C、c.848A>G	p.Met165Thr、p.His283Arg	否	1型	[10]
20	中国	c.594G>A、c.734C>T	p.Trp198X、p.Pro245Leu	否	1型	[11]
21	摩洛哥	c.1121T>A	p.Ile374Asn	是	1型	[11]
22	荷兰	c.100delinsTT、c.358delC	p.Ala34PhefsX56、p.Gln120LysfsX10	否	1型	[11]
23	土耳其	c.531_532del>T	p.Thr178LeufsX4	是	1型	[11]
24	也门	c.531_532del>T	p.Thr178LeufsX4	是	1型	[11]
25	孟加拉国	c.100delinsTT、c.277_278delCT	p.Ala34PhefsX56、p.Leu93ValfsX89	否	1型	[11]
26	印度	g.76993427_76993428delAG	p.Leu93fs	是	1型	[12]
27	中国	c.594G>A、c.734C>T	p.Trp198X、p.Pro245Leu	否	1型	[14]
28	中国	c.594G>A、c.734C>T	p.Trp198X、p.Pro245Leu	否	1型	[14]
29	印度	c.898C>T	p.Arg300Cys	是	1型	[15]
30	土耳其	c.375G>C	p.Trp125Cys	是	2型	[2]
31	土耳其	c.909C>G	p.Ser303Arg	是	2型	[8]
32	日本	c.676G>A	p.Val226Met	是	Kim变异型	[2]
33	日本	c.676G>A、c.861C>A	p.Val226Met、p.Cys287X	否	Kim变异型	[2]
34	日本	c.494T>C、c.676G>A	p.Met165Thr、p.Val226Met	否	Kim变异型	[2]
35	韩国	c.676G>A、c.1079C>A	p.Val226Met、p.Ala360Asp	否	Kim变异型	[2]
36	韩国	IVS2-9G>A、c.676G>A	p.Gly279ValfsX8、p.Val226Met	否	Kim变异型	[2]
37	土耳其	c.-342+1G>A		是	Kim变异型	[8]
38	印度	c.467C>T	p.Ser156Phe	是	Kim变异型	[10]
39	印度	c.467C>T	p.Ser156Phe	是	Kim变异型	[10]
40	印度	c.467C>T	p.Ser156Phe	是	Kim变异型	[13]
41	英国	c，551C>G	p.Thr184Arg	是	Kim变异型	[14]

序号	国家或地区	碱基变异位点	氨基酸变异位点	近亲婚配	DBQD类型	文献
1	斯里兰卡	del2703bp		是	1型	[1]
2	土耳其	c.734delC	p.Pro245ArgfsX3	是	1型	[1]
3	土耳其	c.898C>T	p.Arg300Cys	是	1型	[1]
4	土耳其	c.898C>T	p.Arg300Cys	是	1型	[1]
5	伊朗	c.898C>T	p.Arg300Cys	是	1型	[1]
6	法国	c.899G>A	p.Arg300His	是	1型	[1]
7	阿联酋	c.899G>A	p.Arg300His	是	1型	[1]
8	摩洛哥	c.907_911insGCGCC	p.Ser303AlafsX20	是	1型	[1]
9	巴西	c.374G>A、c.896C>T	p.Trp125X、p.Pro299 Leu	否	1型	[1]
10	巴西	c.374G>A、c.896C>T	p.Trp125X、p.Pro299 Leu	否	1型	[1]
11	澳大利亚	c.228_229insC、c.671T>C	p.Trp77LeufsX13、p.Leu224Pro	否	1型	[2]
12	沙特阿拉伯	c.893_894insGCCGC	p.Phe325fsX	是	1型	[5]
13	中国	c.836-9G>A	p.Gly279ValfsX8	是	1型	[6]
14	高加索地区	c.336C>A	p.Asp112Glu	是	1型	[7]
15	以色列	c.899G>A	p.Arg300His	是	1型	[8]
16	高加索地区	c.228_229insC、c.277_278delCT	p.Leu93ValfsX89、p.Trp77LeufsX13	否	1型	[9]
17	高加索地区	c.228_229insC	p.Trp77LeufsX13	否	1型	[9]
18	日本	c.805delC	p.Leu269CysfsX54	否	1型	[9]
19	中国	c.494T>C、c.848A>G	p.Met165Thr、p.His283Arg	否	1型	[10]
20	中国	c.594G>A、c.734C>T	p.Trp198X、p.Pro245Leu	否	1型	[11]
21	摩洛哥	c.1121T>A	p.Ile374Asn	是	1型	[11]
22	荷兰	c.100delinsTT、c.358delC	p.Ala34PhefsX56、p.Gln120LysfsX10	否	1型	[11]
23	土耳其	c.531_532del>T	p.Thr178LeufsX4	是	1型	[11]
24	也门	c.531_532del>T	p.Thr178LeufsX4	是	1型	[11]
25	孟加拉国	c.100delinsTT、c.277_278delCT	p.Ala34PhefsX56、p.Leu93ValfsX89	否	1型	[11]
26	印度	g.76993427_76993428delAG	p.Leu93fs	是	1型	[12]
27	中国	c.594G>A、c.734C>T	p.Trp198X、p.Pro245Leu	否	1型	[14]
28	中国	c.594G>A、c.734C>T	p.Trp198X、p.Pro245Leu	否	1型	[14]
29	印度	c.898C>T	p.Arg300Cys	是	1型	[15]
30	土耳其	c.375G>C	p.Trp125Cys	是	2型	[2]
31	土耳其	c.909C>G	p.Ser303Arg	是	2型	[8]
32	日本	c.676G>A	p.Val226Met	是	Kim变异型	[2]
33	日本	c.676G>A、c.861C>A	p.Val226Met、p.Cys287X	否	Kim变异型	[2]
34	日本	c.494T>C、c.676G>A	p.Met165Thr、p.Val226Met	否	Kim变异型	[2]
35	韩国	c.676G>A、c.1079C>A	p.Val226Met、p.Ala360Asp	否	Kim变异型	[2]
36	韩国	IVS2-9G>A、c.676G>A	p.Gly279ValfsX8、p.Val226Met	否	Kim变异型	[2]
37	土耳其	c.-342+1G>A		是	Kim变异型	[8]
38	印度	c.467C>T	p.Ser156Phe	是	Kim变异型	[10]
39	印度	c.467C>T	p.Ser156Phe	是	Kim变异型	[10]
40	印度	c.467C>T	p.Ser156Phe	是	Kim变异型	[13]
41	英国	c，551C>G	p.Thr184Arg	是	Kim变异型	[14]