Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling
Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling
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DOI：
10.1093/ndt/17.7.1218
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发表时间：
2002-07-01
影响因子：
6.1
通讯作者：
Weber, M
中科院分区：
文献类型：
--
作者：
Gross, O;Netzer, KO;Weber, M
背景Alport综合征（AS）是一种以进行性肾功能衰竭为特征的遗传性肾病。听力损失和眼部病变。已经描述了编码IV型胶原α链的COL 4A 5基因的许多突变。确定AS的分子病因本研究的目的是确定基因型-表型相关性，这对临床咨询有帮助。分析了267例男性COL 4A 5突变，其中包括23个德国Alport家族。PCR扩增COL 4A 5基因的外显子，并通过Southern印迹、直接测序或变性梯度凝胶电泳进行筛选。表型通过问卷调查获得或从44篇文献中提取，2数据采用Kaplan-Meier统计卡方检验和Kruskal沃利斯检验进行分析。报告了23个德国Alport家族的基因型表型数据。对这些数据和文献中发表的突变分析表明，突变类型是终末期肾衰竭（ESRF）年龄的重要预测因子。患者的肾脏表型可分为三组：（1）大重排，框架衬衫，无意义。剪接供体突变的ESRF发病年龄平均为19.8 ± 5.7岁;（2）非甘氨酸或3'甘氨酸错义突变、框内缺失插入和剪接受体突变的ESRF发病年龄平均为25.7 ± 7.2岁，肾外症状较少;（3）5'甘氨酸取代的ESRF发病年龄平均为30.1 ± 7.2岁。甘氨酸取代从头发生的频率低于所有其他突变（5.5% vs 13.9%）。哦艾弗这是由于它们的中等表型的进化优势。它们是最常见的突变。单个突变的家族内表型与耳聋、圆锥晶状体和ESRU的发病时间点非常一致。对突变的了解增加了关于X连锁AS男性患者肾脏和肾外疾病进展的重要信息。我们认为，患者的基因型的预后相关性相当大，应包括在分类的Alport表型。
Background. Alport syndrome (AS) is a hereditary nephropathy characterized by progressive renal failure. hearing loss and ocular lesions. Numerous mutations of he COL4A5 gene encoding the alpha-chain of type IV collagen have been described. establishing the molecular cause of AS. The goal of the present Study was to identify the genotype- phenotype correlations that are helpful in clinical counseling. COL4A5-mutations (n = 267) in males were analysed including 23 German Alport families.Methods. Exons of the COL4A5 gene were PCR-amplified and screened by Southern blot, direct sequencing or denaturing gradient gel electrophoresis. Phenotypes were obtained by questionnaires or extracted from 44 publications in the literature, 2 Data were analysed by Kaplan-Meier statistics chi(2) and Kruskal Wallis tests.Results. Genotype phenotype data for 23 German Alport families are reported. Analysis or these data and Of Mutations published in the literature showed the type of mutation being it significant predictor of end-stage renal failure (ESRF) age. The patients' renal phenotypes could be grouped into three cohorts: (1) large rearrangements, frame shirt, nonsense. and splice donor mutations had a mean ESRF age of 19.8+/-5.7 years, (2) non-glycine- or 3' glycine-missense mutations, in-frame deletions insertions and splice acceptor mutations had a mean ESRF age of 25.7 +/- 7.2 years and fewer extrarenal symptoms: (3) 5' glycine substitutions had an evert later onset of ESRF at 30.1 +/- 7.2 years. Glycine-substitutions Occurred less commonly de novo than all other mutations (5.5% vs 13.9%). Ho,Aever. due to the evolutionary advantage of their moderate phenotype. they were the most common mutations. The intrafamilial phenotype of an individual mutation Was found to be very consistent with regards to the manifestation of deafness, lenticonus and the time point of onset of ESRU.Conclusions. Knowledge of the Mutation adds significant information about the progress of renal and extrarenal disease in males with X-linked AS. We suggest that the considerable prognostic relevance of a patient's genotype should be included in the classification of the Alport phenotype.