Abstract：
Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature.
摘要：
Alport综合征（AS）表现出广泛的表型谱，范围从孤立的显微镜下血尿（MH）到终末期肾病（ESKD）。COL4A3/COL4A4中的单等位基因致病变异与常染色体显性遗传AS(ADAS)和双等位基因变异与常染色体隐性遗传AS(ARAS)相关。这项研究的目的是分析在COL4A3/COL4A4中具有致病变异的个体中可能的基因型-表型相关性的临床和遗传数据。根据美国医学遗传学学会指南和当前修正案，招募了89名携带至少一种COL4A3/COL4A4变异体（可能是致病性的）。有关首次报告的MH的患病率和年龄的临床数据，蛋白尿,ESKD,收集了肾外表现。与具有单等位基因截断变体的个体相比，具有单等位基因非截断变体的个体报告了MH和蛋白尿的患病率和早期诊断。具有双等位基因变体的个体比具有单等位基因变体的个体受到更严重的影响。具有双等位基因截短变体的那些比具有复合杂合非截短/截短变体的那些或具有双等位基因非截短变体的个体受到更严重的影响。在这项研究中，与截短变体相比，杂合非截短COL4A3/COL4A4变体与更严重表型的关联可以显示，表明潜在的显性负效应作为该观察结果的解释。对于有ARAS的个人来说，结果支持，仍然稀缺，文献中的数据。
