PDF(Pubmed)
Abstract：
Disease-causing variants in COL4A3-5 are associated with type-IV-collagen-related nephropathy, a genetically and phenotypically multifaceted disorder comprising Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) and autosomal, X-linked and a proposed digenic inheritance. Initial symptoms of individuals with AS are microscopic hematuria followed by proteinuria leading to kidney failure (90% on dialysis < age 40 years). In contrast, individuals with TBMN, an outdated histology-derived term, present with microscopic hematuria, only some of them develop kidney failure (>50 years of age). An early diagnosis of type-IV-collagen-related nephropathy is essential for optimized therapy and slowing of the disease. Sixty index cases, in whom exome sequencing had been performed and with disease-causing variant(s) in COL4A3-5, were evaluated concerning their clinical tentative diagnosis and their genotype. Of 60 reevaluated individuals with type-IV-collagen-related nephropathy, 72% had AS, 23% TBMN and 5% focal segmental glomerulosclerosis (FSGS) as clinical tentative diagnosis. The FSGS cases had to be re-classified as having type-IV-collagen-related nephropathy. Twelve percent of cases had AS as clinical tentative diagnosis and a monoallelic disease-causing variant in COL4A3/4 but could not be classified as autosomal dominant AS because of limited or conflicting clinical data. This study illustrates the complex clinical and genetic picture of individuals with a type IV-collagen-related nephropathy indicating the need of a refined nomenclature and the more interdisciplinary teamwork of clinicians and geneticists as the key to optimized patient care.
摘要：
COL4A3-5中的致病变异与IV型胶原相关性肾病相关,一种遗传和表型多面性疾病，包括Alport综合征（AS）和薄基底膜肾病（TBMN）和常染色体，X连锁和拟议的双基因遗传。患有AS的个体的初始症状是显微镜下血尿,随后是导致肾衰竭的蛋白尿(透析时90%<40岁)。相比之下,有TBMN的人，一个过时的组织学衍生术语，存在镜下血尿，他们中只有一些发展为肾衰竭（>50岁）。IV型胶原相关性肾病的早期诊断对于优化治疗和减缓疾病至关重要。六十个指标案例，对已进行外显子组测序和在COL4A3-5中存在致病变异的患者进行了临床暂定诊断和基因型评估.在60名IV型胶原相关性肾病患者中，72%有AS，23％的TBMN和5％的局灶节段肾小球硬化（FSGS）作为临床初步诊断。必须将FSGS病例重新分类为IV型胶原相关肾病。12％的病例具有AS作为临床暂定诊断，并且在COL4A3/4中具有单等位基因致病变异，但由于临床数据有限或相互矛盾，因此无法归类为常染色体显性AS。这项研究说明了IV型胶原相关肾病患者的复杂临床和遗传情况，表明需要完善的命名法以及临床医生和遗传学家的跨学科团队合作，这是优化患者护理的关键。
