以家族性显性遗传型血尿为主要表现的Alport综合征一家系与COL4A4基因突变

A family of Alport syndrome with a novel dominant hereditary hematuria and a mutation in the COL4A4 gene

目的探讨应用全外显子组测序检测COL4A3、COL4A4和COL4A5基因诊断Alport综合征的临床价值并拓宽基因突变谱。方法观察性研究。先证者为一名6岁女孩,4岁时偶然发现镜下血尿。收集患儿的临床资料,采集患儿及其父母、哥哥、姐姐外周静脉血3ml,提取基因组DNA,应用全外显子组测序检测基因的编码区序列,通过突变分析筛选到COL4A4的缺失突变,Sanger测序对筛选到的c.1826delC的突变进行验证。结果全外显子测序未发现患儿存在COL4A3和COL4A5基因突变,但在COL4A4基因(NM_000092)外显子25上检测到c.1826delC(p.Pro609Glnfs*44)杂合突变,经分析,为移码突变。其父亲和姐姐均携带该突变,其母亲和哥哥该位点为野生型。该家系符合常染色体显性遗传型Alport综合征。结论应用全外显子组测序可以对临床疑似Alport综合征患儿明确诊断。本研究中新发现的COL4A4c.1826delC突变,拓宽了COL4A4基因对Alport综合征的突变谱。

ObjectiveAlport syndrome was an inherited kidney disease caused by the mutation of COL4A3,COL4A4,or COL4A5.Whole-exome sequencing was used to detect the mutations on these genes for the molecular diagnosis of Alport syndrome.MethodsA 6-year-old girl found accidentally with microscopic hematuria at the age of 4.The clinical data and blood sample of the family including proband,parents,brothers,and sisters were collected.Whole exome sequencing was conducted using their genomic DNAs.ResultsA novel heterozygous frameshift mutation c.1826delC(p.Pro609Glnfs*44)was found in the exon 25 of the COL4A4(NM_000092)in the proband,the father,and the sister,showing an autosomal dominant inheritance pattern of Alport syndrome.This mutation of COL4A4 was confirmed by mutation analysis,and the mutation of c.1826delC was verified by Sanger sequencing.No mutations on COL4A3 and COL4A5 were detected in this family.And the mother and brother are normal wide-type.ConclusionsThis novel mutation is a valuable addition to the current genetic profile of Alport syndrome,and provide us a better understanding of the disease.Whole-exome sequencing is a power tool to identify the novel mutations of inherited disease and contribute to the molecular diagnosis of disease.