Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.
Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.
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DOI：
10.1038/ki.2014.305
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发表时间：
2014-12
影响因子：
19.6
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中科院分区：
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局灶节段性肾小球硬化症（FSGS）是一种组织学病变，其病因包括遗传性遗传缺陷，临床表现主要为蛋白尿。已知COL4A3和COL4A4突变可引起Alport综合征、薄基底膜肾病，并导致特异性肾小球基底膜异常。已知继发性FSGS在典型Alport综合征的后期阶段发展。在这里，我们提出了7个家庭的罕见或新的变异COL4A3或COL4A4（6个与单一和两个杂合变异）从一个队列的70个家庭诊断为遗传性FSGS。诊断时主要临床表现为蛋白尿伴血尿。在所有7个家庭，有个人肾病范围蛋白尿与FSGS的光镜组织学特征。在一个家庭，电子显微镜显示薄肾小球基底膜，但其他四个家庭的变量不符合经典的Alport肾炎的结果。肾移植后无复发。与疾病分离的COL4A3和COL4A4变异家族占我们队列的10%。因此，COL4A3和COL4A4变异体在解释这些患者的下一代测序数据时应予以考虑。此外，这项研究说明了分子遗传学诊断在澄清肾脏表型中的作用。
Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical findings at diagnosis were proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin glomerular basement membrane, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.