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.

中文翻译：

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COL4A3/COL4A4 杂合致病变异个体是否存在显性失活效应？

奥尔波特综合征（AS）表现出广泛的表型谱，从孤立性镜下血尿（MH）到终末期肾病（ESKD）。COL4A3 / COL4A4的单等位基因变异与常染色体显性遗传性 AS (ADAS) 相关，双等位基因变异与常染色体隐性遗传性 AS (ARAS) 相关。本研究的目的是分析COL4A3 / COL4A4致病变异个体中可能的基因型-表型相关性的临床和遗传数据。招募了89 名携带至少一种COL4A3 / COL4A4变体的个体，根据美国医学遗传学学院指南和当前修正案，该变体被归类为（可能）致病性。收集有关 MH、蛋白尿、ESKD 和肾外表现首次报告表现的患病率和年龄的临床数据。与具有单等位基因截短变异的个体相比，具有单等位基因非截短变异的个体报告 MH 和蛋白尿的患病率显着更高且更早诊断。具有双等位基因变异的个体比具有单等位基因变异的个体受到更严重的影响。那些具有双等位基因截短变体的人比那些具有复合杂合非截短/截短变体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，与截断变体相比，杂合非截断COL4A3 / COL4A4变体与更严重的表型之间的关联可能表明潜在的显性负效应，作为对此观察结果的解释。ARAS 患者的结果支持了文献中仍然稀缺的数据。