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Alport综合征(alport syndrome,AS)又称遗传性进行性肾炎,临床特点是以血尿、蛋白尿及进行性肾功能减退为主,部分病人可合并出现感音神经性耳聋、眼部异常、食管平滑肌瘤等肾外表现,是危及儿童及青少年生命健康的重要疾病之一[1-3]。随着精准医学的发展及各级医疗机构诊疗水平的提高, 其发病率呈逐年上升趋势。根据2008年北美儿童肾脏实验及合作性研究中心的数据显示,AS患儿肾移植占同期儿童肾移植的2.3%, 占同期儿童血液透析的2.3%, 该病活产儿发病率为1:5000[4]。AS为编码Ⅳ型胶原α3、α4、α5链的基因突变所致,其中α3(Ⅳ)、α4(Ⅳ)基因突变所致为常染色体显性或隐性遗传,α5(Ⅳ)基因突变所致为X连锁显性遗传,至今为止已有超出700个基因突变被发现[5]。本研究采用高通量第2代测序技术对1例AS患儿进行检测,结果发现一个新的α5链位点移码突变,为国内外首次报道。
COL4A5基因c.4518_c.4519 insC新突变所致X连锁显性遗传Alport综合征的分子遗传学及临床分析
Molecular genetics and clinical analysis of X-linked dominant Alport syndrome caused by a new mutation of COL4A5 gene c.4518_c.4519 insC
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摘要:
目的通过对胶原蛋白Ⅳ型α5链(collagen type Ⅳ α 5 chain,COL4A5)基因进行分析,为1例X-连锁性遗传性Alport综合征家系的分子诊断和遗传咨询提供依据。探讨Alport综合征COL4A5基因移码突变谱及临床表型。 方法应用全外显子组测序技术进行基因检测,应用Sanger测序法对候选致病变异进行验证。 结果病人肾损害渐进展,出现肉眼血尿、肾病综合征,抗感染治疗后蛋白尿及肉眼血尿可缓解。先证者肾脏病理活检:病理表现为基底膜厚薄不一,致密层增厚,部分呈撕裂状和蛛网状。高通量测序和一代测序结果均提示病人COL4A5基因49号外显子存在c.4518_c.4519 insC(p.Gln1507Profs*14)的杂合变异;病人父母均不携带该变异。 结论首次报道了COL4A5基因该位点的新生变异为病人的发病原因,丰富了COL4A5基因变异谱,为该X-连锁性遗传性肾炎家系的分子诊断及产前诊断提供了依据;对指导家族中母亲及女儿再生育,通过产前基因诊断或胚胎植入前遗传学诊断技术,阻断该疾病有重要意义。 Abstract:ObjectiveTo analyze the collagen type Ⅳ α 5 chain(COL4A5) gene, provide the basis for molecular diagnosis and genetic counseling of a family with X-linked hereditary Alport syndrome, and investigate the COL4A5 gene shift mutation spectrum and clinical phenotype of Alport syndrome. MethodsThe whole exome sequencing was used for gene detection, and Sanger sequencing was used to validate candidate pathogenic variants. ResultsThe renal damage of patient progressed gradually, the gross hematuria and nephrotic syndrome appeared.The proteinuria and gross hematuria could be relieved after anti-infection treatment.The pathological biopsy of the kidney of the proband showed that the thickness of the basement membrane varied, the thickness of the dense layer increased, and parts were torn or cobweb.The results of high-throughput sequencing and first-generation sequencing indicated the exon 49 of COL4A5 gene, c.4518_c.4519 heterozygous variants of insC(p.gln1507profs *14) in patient was found, and neither parent carried the mutation. ConclusionsIt is the first report that the new variation of COL4A5 gene at this locus is the pathogenesis of patient, which enrichs the spectrum of COL4A5 gene variation, and provides the basis for the molecular diagnosis and prenatal diagnosis of this family of X-linked hereditary nephritis.It is of great significance to guide the reproduction of mother and daughter in the family, and prevent the disease through prenatal genetic diagnosis or preimplantation genetic diagnosis. -
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