Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2024-12-19 DOI:10.1038/s41525-024-00452-6
Amali C Mallawaarachchi, Yvonne Hort, Laura Wedd, Kitty Lo, Sarah Senum, Mojgan Toumari, Wenhan Chen, Mike Utsiwegota, Jane Mawson, Scott Leslie, Jerome Laurence, Lyndal Anderson, Paul Snelling, Robert Salomon, Gopala K Rangan, Timothy Furlong, John Shine, Mark J Cowley
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Abstract

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.

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通过对人类肾囊肿进行深度测序发现常染色体显性多囊肾的体细胞突变。
常染色体显性多囊肾病(ADPKD)导致进行性囊肿,导致肾衰竭,是由PKD1或PKD2的杂合种系变异引起的。囊肿的发病机制尚不明确。体细胞二次撞击突变与囊肿发病有关,但技术测序方面的挑战限制了研究。我们使用独特的分子标识符、高深度大规模平行测序和定制分析技术,利用重复样本和正交确认,鉴定了来自6个人类ADPKD肾脏不同区域的24个完整囊肿的体细胞二次命中突变。获得PKD1和PKD2的平均覆盖深度分别为1166个和539个。58%(14/24)的囊肿可检测到PKD1体细胞变异,其中5/6的参与者至少有一个囊肿具有体细胞变异。我们证明在终末期ADPKD人类肾脏的一部分囊肿中可以检测到低频体细胞突变。需要进一步的研究来了解这种体细胞突变的驱动因素。
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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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