Whole exome sequencing reveals novel COL4A3 and COL4A4 mutations and resolves diagnosis in Chinese families with kidney disease.
Whole exome sequencing reveals novel COL4A3 and COL4A4 mutations and resolves diagnosis in Chinese families with kidney disease.
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DOI：
10.1186/1471-2369-15-175
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发表时间：
2014-11-07
期刊：
影响因子：
2.3
通讯作者：
Gale DP
中科院分区：
文献类型：
--
作者：
Lin F;Bian F;Zou J;Wu X;Shan J;Lu W;Yao Y;Jiang G;Gale DP
iv型胶原相关肾病，包括基底膜薄肾病和Alport综合征（AS），是由COL4A3、COL4A4和COL4A5基因缺陷引起的。这些疾病的诊断可能会因外显率和非特异性临床或病理特征的存在而受阻。从中国上海招募了三个患有不明原因遗传性肾病的家庭。对每个家族的索引病例进行全外显子组测序（WES），并通过Sanger测序检测候选致病突变的共分离。我们鉴定出COL4A4错义变体[c]。G2636A （p.Gly879Glu）和c.C4715T （p.Pro1572Leu）在21岁时被诊断为系膜增生性肾病的1家族男性先证中表达。COL4A4 c.G2636A，一种新的变异，在母系亲属中与肾脏疾病共分离。COL4A4 c.C4715T先前与常染色体隐性遗传AS相关，并遗传自其临床未受影响的父亲。在家族2中，一种新的COL4A3错义突变c.G2290A （p.Gly997Glu）在一名确诊为局灶节段性肾小球硬化症的45岁男性患者中被发现，该突变存在于其所有受影响的家族成员中，其疾病范围从孤立的显微镜下血尿到终末期肾病（ESRD）。在家族3中，ESRD发生在男性和女性中，他们被发现携带已知的引起as的COL4A5供体剪接位点突变（c.687 + 1G > a）。在100名健康的中国人中未检测到这些变异。WES在3个以前无法解释的遗传性肾病家族中发现了2个新的和2个已知的致病性COL4A3/COL4A4/COL4A5突变。这些发现强调了iv型胶原相关肾病的临床范围，并解决了由不典型或不完整的临床/组织学发现引起的诊断混乱，从而提供了适当的咨询和治疗建议。本文的在线版本（doi:10.1186/1471-2369-15-175）包含补充材料，可供授权用户使用。
Collagen IV-related nephropathies, including thin basement membrane nephropathy and Alport Syndrome (AS), are caused by defects in the genes COL4A3, COL4A4 and COL4A5. Diagnosis of these conditions can be hindered by variable penetrance and the presence of non-specific clinical or pathological features. Three families with unexplained inherited kidney disease were recruited from Shanghai, China. Whole exome sequencing (WES) was performed in the index case from each family and co-segregation of candidate pathogenic mutations was tested by Sanger sequencing. We identified COL4A4 missense variants [c.G2636A (p.Gly879Glu) and c.C4715T (p.Pro1572Leu)] in the 21-year-old male proband from family 1, who had been diagnosed with mesangial proliferative nephropathy at age 14. COL4A4 c.G2636A, a novel variant, co-segregated with renal disease among maternal relatives. COL4A4 c.C4715T has previously been associated with autosomal recessive AS and was inherited from his clinically unaffected father. In family 2, a novel COL4A3 missense mutation c.G2290A (p.Gly997Glu) was identified in a 45-year-old male diagnosed with focal segmental glomerulosclerosis and was present in all his affected family members, who exhibited disease ranging from isolated microscopic hematuria to end stage renal disease (ESRD). In family 3, ESRD occurred in both male and females who were found to harbor a known AS-causing COL4A5 donor splice site mutation (c.687 + 1G > A). None of these variants were detected among 100 healthy Chinese individuals. WES identified 2 novel and 2 known pathogenic COL4A3/COL4A4/COL4A5 mutations in 3 families with previously unexplained inherited kidney disease. These findings highlight the clinical range of collagen IV-related nephropathies and resolved diagnostic confusion arising from atypical or incomplete clinical/histological findings, allowing appropriate counselling and treatment advice to be given. The online version of this article (doi:10.1186/1471-2369-15-175) contains supplementary material, which is available to authorized users.
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