<i>EPB</i>41基因突变导致遗传性椭圆形红细胞增多症一家系的分子诊断研究

陈静; 周雯婧; 李云霞; 陈宇宁; 陈华根; 丁显平

doi:10.12182/20200160505

EPB41基因突变导致遗传性椭圆形红细胞增多症一家系的分子诊断研究

Identification of a Novel Mutation of EPB41 Gene in a Family Affected with Hereditary Elliptocytosis

摘要

摘要:
目的对临床诊断为遗传性椭圆形红细胞增多症（HE）的一个家系进行遗传学病因分析。
方法应用靶向捕获及高通量测序技术对先证者和家系中4名成员的外周血基因组DNA进行高通量测序，经过数据分析筛选可能的致病变异，同时使用生物信息学软件对变异进行功能预测，在家系中对检出的可疑致病性变异进行Sanger测序验证。同时对50例健康对照抽取外周血，进行正常人群突变位点检测。
结果高通量测序结果显示临床表现为中度贫血的先证者和其母在EPB41基因第13外显子均存在杂合c.1215G>A（p.Trp405Ter）无义突变，为功能缺失型突变，有极强的致病性（very strong pathogenicity，PVS1）。该位点G碱基突变为A碱基，导致其编码的蛋白质链第405位的色氨酸的密码子变为终止密码子，使蛋白合成提前终止，形成截短蛋白，部分功能区域丧失。该变异在人群中极为罕见，为尚未报道的致病性突变。Sanger测序结果显示先证者外祖母亦携带这一杂合突变，且在此家系中观察到基因型和表型共分离。50例无亲缘关系的健康对照均未检测到突变。
结论 EPB41基因的c.1215G>A突变是本例HE家系的可疑致病原因。首次在中国HE家系中发现了EPB41基因致病性突变。

Abstract:
Objective To analyse potential genetic cause of a family affected with hereditary elliptocytosis （HE）.
Methods Peripheral blood samples from this HE family were collected. Targeted capture and high-throughput sequencing of 4 813 genetic disease-associated genes was performed in four members of the family. Possible causative genetic variation was obtained and further confirmed by Sanger sequencing. Fifty healthy control subjects were recruited for detection of the candidate variation.
Results High-throughput sequencing detected a nonsense mutation c.1215G>A（p.Trp405Ter）in exon 13 of the EPB41 gene in the proband and his mother presenting with moderate anemia. The pathogenicity of this loss-of-function mutation is very strong, because the G→A transition leads to introduce the premature stop codon instead of tryptophan codon at position 405, which producing a truncating protein with loss of important functional domains. This causative mutation is extremely rare in the population, and it has not yet been reported. The grandmother of the proband was heterozygous for the same mutation. Genotype-phenotype cosegregation was observed in this family. This mutation was not found in the 50 unrelated healthy controls.
Conclusion The c.1215G>A mutation of the EPB41 gene probably accounts for the disease in this HE family. This study reports a pathogenic EPB41 mutation in a Chinese HE family for the first time.

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