Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Mol Genet Genomic Med. 2020 Oct;8(10):e1452. doi: 10.1002/mgg3.1452. Epub 2020 Aug 18.
Alport syndrome is a progressive hereditary kidney disease clinically presenting with haematuria, proteinuria, and early onset end-stage renal disease, and often accompanied by hearing loss and ocular abnormalities. The inheritance is X-linked in the majority of families and caused by sequence variants in the COL4A5 gene encoding the α5-chain of type-IV collagen. The proportion of de novo COL4A5 sequence variants in X-linked Alport syndrome has been reported between 12 and 15% in previous studies.
In the present study we have systematically investigated the mosaic status of asymptomatic parents of six patients with X-linked Alport syndrome using next-generation sequencing of DNA extracted from different tissues. The deleterious COL4A5 sequence variants in these patients were previously assumed to be de novo, based on Sanger sequencing of the parents.
A low-grade (1%) parental mosaicism was detected in only one out of six families (17%). In addition, in one out of six families (17%), we found that the mutational event probably occurred postzygotic.
These findings highlight the importance of testing for mosaicism in unaffected parents of patients with sequence variants considered to be de novo, as it may have implications for the recurrence risk and thereby for the genetic counseling of the family.
Alport 综合征是一种进行性遗传性肾脏疾病，临床上表现为血尿、蛋白尿和早期终末期肾病，常伴有听力损失和眼部异常。大多数家族的遗传方式为 X 连锁，由编码 IV 型胶原α5 链的 COL4A5 基因突变引起。先前的研究报道，X 连锁 Alport 综合征中新生的 COL4A5 序列变异的比例在 12%至 15%之间。
在本研究中，我们使用从不同组织提取的 DNA 进行下一代测序，系统地研究了六名 X 连锁 Alport 综合征患者无症状父母的镶嵌状态。这些患者的有害 COL4A5 序列变异之前基于对父母的 Sanger 测序被假定为新生。
仅在六分之一的家庭（17%）中检测到低级别（1%）的父母镶嵌。此外，在六分之一的家庭（17%）中，我们发现突变事件可能发生在合子后。
这些发现强调了在被认为是新生的患者的未受影响的父母中检测镶嵌的重要性，因为这可能对复发风险有影响，从而对家庭的遗传咨询有影响。
