一个X连锁显性遗传Nance-Horan综合征家系致病突变的遗传学研究

doi:10.3877/cma.j.issn.2095-2007.2019.03.006

目的

对中国东北辽宁地区一个三代后极性先天性白内障合并小眼球小角膜家系进行致病变异筛查，为临床明确诊断及遗传咨询提供必要的遗传学依据。

方法

2017年4月采集该家系中2例患者和1例正常对照者的外周静脉血，提取基因组脱氧核糖核酸，对先证者进行眼部检查。通过MiSeq测序平台对4813个临床疾病相关基因进行高通量测序，寻找致病变异位点。

结果

该家系表现为后极性先天性白内障伴有小眼球小角膜，呈X连锁显性遗传。对家系中3个成员基因组脱氧核糖核酸进行测序，发现家系内患者携带X染色体NHS基因无义突变(NHS c．742C>T，p.R248^*)，该突变在家系中与疾病表型共分离。通过查询人类基因突变数据库，该突变为Nance-Horan综合征致病突变，患者临床表现与该综合征相符。

结论

该家系诊断为Nance-Horan综合征，NHS基因c.742C>T(p.R248^*)突变是该家系的致病变异。

关键词: Nance-Horan综合征, NHS基因, 高通量测序

Objective

The aim of this study was to screen the pathogenic mutation of three generation post polar congenital cataract with small eyeball and small cornea, and provide necessary genetic evidence for clinical diagnosis and genetic counseling.

Methods

In April 2017, Peripheral venous blood from 2 patients and a normal control case was collected; genomic deoxyribonucleic acid was extracted, and the ocular examination was done for proband. The 4813 clinical disease related genes were sequenced by high throughput sequencing based on MiSeq sequencing platform for seeking the pathogenic mutation.

Results

The family was characterized by posterior polar congenital cataract with small eyeball and small cornea, which was X dominant inheritance. The genomic deoxyribonucleic acid of 3 members of the family was sequenced, and the patients were found to carry the NHS gene non sense mutation (NHS c. 742C>T, p. R248^*) on the chromosome X, which was co-separated with the disease phenotype in the family. After comparing with Human Gene Mutation Database, the mutation is pathogenic for Nance-Horan syndrome which were consistent with the clinical manifestations of the patients.

Conclusions

The family is diagnosed as Nance-Horan syndrome, and the mutation of NHS gene c. 742C>T (p.R248^*) is the pathogenic variation of this family.

Key words: Nance-Horan syndrome, NHS gene, High throughput sequencing

图1 该家系患者表型、系谱及NHS基因突变位点的Sanger验证结果图　图A示NHS基因突变位点的Sanger验证结果图，上侧为家系内未患病者，下侧为患病者；图B示先证者Ⅲ1的眼部表型，表现为后极性白内障；图C示患者Ⅰ2的面部表型，表现为牙齿异常；图D示患者Ⅱ2的面部表型，表现为脸型较长；图E示该先天性白内障家系系谱图

表1 中国家系中报道的NHS基因突变

突变位点	蛋白改变	突变类型	参考文献
c.322G>T	p.E108^*	无义突变	[42]
c.556G>T	p.E186^*	无义突变	[43]
c.852delG	-	移码突变	[25]
c.853-1G>A	-	剪接位点突变变	[43]
c.1045+2T>A	-	剪接位点突变变	[44]
c.1693C>T	p.R565^*	无义突变	[45]
c.2716_2719delTTAG	-	移码突变	[43]

表1 中国家系中报道的NHS基因突变

突变位点	蛋白改变	突变类型	参考文献
c.322G>T	p.E108^*	无义突变	[42]
c.556G>T	p.E186^*	无义突变	[43]
c.852delG	-	移码突变	[25]
c.853-1G>A	-	剪接位点突变变	[43]
c.1045+2T>A	-	剪接位点突变变	[44]
c.1693C>T	p.R565^*	无义突变	[45]
c.2716_2719delTTAG	-	移码突变	[43]

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Pathogenic mutation in a family with X-linked dominant Nance-Horan syndrome

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Pathogenic mutation in a family with X-linked dominant Nance-Horan syndrome