Mallawaarachchi Amali C, Hort Yvonne, Wedd Laura, Lo Kitty, Senum Sarah, Toumari Mojgan, Chen Wenhan, Utsiwegota Mike, Mawson Jane, Leslie Scott, Laurence Jerome, Anderson Lyndal, Snelling Paul, Salomon Robert, Rangan Gopala K, Furlong Timothy, Shine John, Cowley Mark J
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia.
Clinical Genetics Service, Institute of Precision Medicine and Bioinformatics, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
NPJ Genom Med. 2024 Dec 19;9(1):69. doi: 10.1038/s41525-024-00452-6.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) results in progressive cysts that lead to kidney failure, and is caused by heterozygous germline variants in PKD1 or PKD2. Cyst pathogenesis is not definitively understood. Somatic second-hit mutations have been implicated in cyst pathogenesis, though technical sequencing challenges have limited investigation. We used unique molecular identifiers, high-depth massively parallel sequencing and custom analysis techniques to identify somatic second-hit mutations in 24 whole cysts from disparate regions of six human ADPKD kidneys, utilising replicate samples and orthogonal confirmation. Average depth of coverage of 1166 error-corrected reads for PKD1 and 539 reads for PKD2 was obtained. 58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having at least one cyst with a somatic variant. We demonstrate that low-frequency somatic mutations are detectable in a proportion of cysts from end-stage ADPKD human kidneys. Further studies are required to understand the drivers of this somatic mutation.
常染色体显性多囊肾病（ADPKD）会导致渐进性囊肿，进而引发肾衰竭，它由PKD1或PKD2基因的杂合种系变异引起。囊肿发病机制尚未完全明确。尽管技术测序挑战限制了相关研究，但体细胞二次打击突变被认为与囊肿发病机制有关。我们使用独特分子标识符、高深度大规模平行测序和定制分析技术，对来自6例人类ADPKD肾脏不同区域的24个完整囊肿进行体细胞二次打击突变鉴定，并利用重复样本和正交确认。PKD1的平均覆盖深度为1166条纠错读数，PKD2为539条读数。58%（14/24）的囊肿有可检测到的PKD1体细胞变异，6名参与者中有5名至少有一个囊肿存在体细胞变异。我们证明，在晚期ADPKD人类肾脏的部分囊肿中可检测到低频体细胞突变。需要进一步研究以了解这种体细胞突变的驱动因素。
