Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Medical Genetics, University of Siena, Siena, Italy.
Transplantation. 2020 Nov;104(11):2360-2364. doi: 10.1097/TP.0000000000003104.
Alport syndrome is a hereditary nephropathy caused by mutations in collagen IV genes and characterized by ultrastructural lesions of the glomerular basement membrane. Some patients have a negative family history with apparently de novo mutations. Although somatic mosaicism has been postulated, as cryptic mosaicism cannot be detected from mutational screening on peripheral blood samples, cases in kidney-confined mosaic form have been missed.
We report the case of a 24-year-old male patient with X-linked Alport syndrome diagnosis due to a COL4A5 pathogenic mutation (c.3334_3337dup [p.Gly1113Alafs25]). The same mutation had not been previously detected on a peripheral blood sample of maternal DNA. However, the mother, who was undertaking a clinical re-evaluation to take in consideration the possibility of a living-kidney transplantation, had experienced persistent microhematuria since the age of 10 years.
A next-generation sequencing approach performed on maternal DNA from both peripheral blood sample and urine-derived podocyte-lineage cells unmasked the COL4A5 mutation only in the podocyte-lineage cells.
This finding unveils an early postzygotic event which can explain both the renal involvement and germline mosaicism. It changes the inheritance risk for each pregnancy raising it to 50% and underlines the need for different clinical management in the mother. This seems to indicate that a case-by-case more cautious approach is needed with mother-to-son kidney transplants.
Alport 综合征是一种遗传性肾病，由胶原 IV 基因突变引起，其特征为肾小球基底膜的超微结构病变。一些患者有阴性家族史，表现为明显的新生突变。虽然已经提出了体细镶嵌现象，但由于外周血样本的突变筛查无法检测到隐匿性镶嵌现象，因此错过了局限于肾脏的镶嵌形式的病例。
我们报告了一例 24 岁男性患者，因 COL4A5 致病性突变（c.3334_3337dup [p.Gly1113Alafs25]）诊断为 X 连锁 Alport 综合征。此前在外周血母源性 DNA 的样本中未检测到相同的突变。然而，这位母亲正在接受临床再评估，以考虑活体肾脏移植的可能性，她从 10 岁起就一直持续出现镜下血尿。
对来自外周血样本和尿源性足细胞系细胞的母源性 DNA 进行下一代测序揭示了 COL4A5 突变仅存在于足细胞系细胞中。
这一发现揭示了一个早期的合子后事件，可解释肾脏受累和种系镶嵌现象。它改变了每个妊娠的遗传风险，使其提高到 50%，并强调了母亲需要不同的临床管理。这似乎表明，对于母子间的肾脏移植，需要进行个案更谨慎的处理。
