Turco A E, Bresin E, Rossetti S, Peterlin B, Morandi R, Pignatti P F
Institute of Genetics, The University of Verona School of Medicine, University Hospital Polyclinic B. Roma, Italy.
Am J Kidney Dis. 1997 Aug;30(2):174-9. doi: 10.1016/s0272-6386(97)90050-0.
Alport's syndrome (AS) is a clinically and genetically heterogeneous progressive inherited glomerulonephritis characterized by hematuria, sensorineural hearing loss, ocular lesions, and specific alterations of the glomerular basement membrane. Typically, AS shows an X-linked dominant pattern of inheritance, with mutations affecting the collagen type IV alpha5 chain gene (COL4A5) at Xq22. Rarely, AS is caused in some families by mutations of the COL4A3/A4 genes on chromosome 2q, showing an autosomal recessive transmission. Very few families have been described with possible autosomal dominant AS, but no mutations in any of the COL4 genes have been found. We describe three unrelated families affected with a severe AS phenotype in which DNA-based prenatal diagnosis by linkage analysis was made in fetuses at risk for the disease. In two families, the pedigree structure and the clinical picture were consistent with typical X-linked dominant AS. In these families, autosomal inheritance was also ruled out molecularly. In one family, despite careful clinical and molecular evaluation, the mode of transmission could not be firmly established. We used tightly linked and intragenic COL4A5 markers, as well as COL4A3/A4-linked markers. A chromosome Y-specific marker for fetal sex determination was simultaneously used. In all the families, before the fetal analysis, the putative at-risk X haplotype was identified with high diagnostic accuracy. We diagnosed a healthy male fetus in one family, and female but carrier fetuses in the other two kindreds, who decided not to terminate their pregnancies. We used rapid nonisotopic polymerase chain reaction-based methods, and the results were available within 2 to 3 days. The genetic results significantly affected the reproductive decisions of the parents. This report illustrates the application of genetic linkage analysis as an additional tool for molecular diagnosis in AS, and also addresses the issue of the attitudes of the families toward prenatal testing. To our knowledge, prenatal diagnosis of AS using a genetic linkage approach has not been previously reported.
奥尔波特综合征（AS）是一种临床和遗传异质性的进行性遗传性肾小球肾炎，其特征为血尿、感音神经性听力损失、眼部病变以及肾小球基底膜的特定改变。通常，AS呈X连锁显性遗传模式，突变影响位于Xq22的IV型胶原α5链基因（COL4A5）。在一些家族中，AS很少由2号染色体上COL4A3/A4基因的突变引起，呈常染色体隐性遗传。仅有极少数家族被描述可能为常染色体显性AS，但尚未在任何COL4基因中发现突变。我们描述了三个患有严重AS表型的无关家族，在这些家族中，对有患病风险的胎儿进行了基于DNA的连锁分析产前诊断。在两个家族中，家系结构和临床表现与典型的X连锁显性AS一致。在这些家族中，也通过分子方法排除了常染色体遗传。在一个家族中，尽管进行了仔细的临床和分子评估，但遗传方式仍无法明确确定。我们使用了紧密连锁的COL4A5基因内标记以及与COL4A3/A4连锁的标记。同时使用了一种用于确定胎儿性别的Y染色体特异性标记。在所有家族中，在进行胎儿分析之前，以高诊断准确性确定了假定的有风险X单倍型。我们在一个家族中诊断出一名健康的男性胎儿，在另外两个家族中诊断出为女性但为携带者的胎儿，他们决定不终止妊娠。我们使用了基于快速非同位素聚合酶链反应的方法，结果在2至3天内即可获得。遗传结果显著影响了父母的生育决策。本报告说明了遗传连锁分析作为AS分子诊断额外工具的应用，同时也探讨了家族对产前检测的态度问题。据我们所知，此前尚未有使用遗传连锁方法对AS进行产前诊断的报道。
