Rafiee Maryam, Razipour Masoumeh, Keramatipour Mohammad, Roozbeh Jamshid, Entezam Mona
Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
J Appl Genet. 2025 Feb 14. doi: 10.1007/s13353-024-00937-1.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder, primarily caused by mutations in the PKD1 and PKD2. Genetic testing is valuable for the diagnosis, prognosis, and clinical management of ADPKD. Next-generation sequencing (NGS) techniques can overcome the limitations of traditional Sanger sequencing for the genetic diagnosis of ADPKD. This study included 18 Iranian ADPKD families. Long-range PCR and Sanger sequencing were used to analyze PKD1 and PKD2. Subsequently, NGS-based gene panel testing and whole-exome sequencing (WES) were also performed in selected families. Pathogenic/likely pathogenic variants were identified in 13/18 families (72.2%), including 9 in PKD1 and 4 in PKD2. Five novel variants were discovered (c.10016C > A, c.2096_2097 + 4del, c.12138 + 5G > C in PKD1; c.2359-8_2373del, c.180_181delGC in PKD2). Additionally, WES revealed a pathogenic PKD1 frameshift deletion (c.11376delG) in one genetically unresolved family, likely missed by initial Sanger sequencing due to allelic dropout. This study expands the mutational spectrum of PKD1/PKD2 with five novel variants. The findings demonstrate the advantages of NGS over conventional Sanger sequencing methods. The genetically unresolved cases suggest the potential involvement of variants within non-coding regions, large copy number variations, or novel genes in ADPKD pathogenesis. Whole-genome sequencing is warranted to investigate these unresolved cases further.
常染色体显性多囊肾病（ADPKD）是最常见的遗传性肾脏疾病，主要由PKD1和PKD2基因突变引起。基因检测对ADPKD的诊断、预后和临床管理具有重要价值。新一代测序（NGS）技术可以克服传统桑格测序在ADPKD基因诊断方面的局限性。本研究纳入了18个伊朗ADPKD家系。采用长距离PCR和桑格测序法分析PKD1和PKD2。随后，对部分家系还进行了基于NGS的基因panel检测和全外显子测序（WES）。在13/18个家系（72.2%）中鉴定出致病/可能致病变异，其中PKD1有9个，PKD2有4个。发现了5个新变异（PKD1中的c.10016C＞A、c.2096_2097+4del、c.12138+5G＞C；PKD2中的c.2359-8_2373del、c.180_181delGC）。此外，WES在一个基因未明确的家系中发现了一个致病的PKD1移码缺失（c.11376delG），可能由于等位基因脱失而被最初的桑格测序遗漏。本研究通过5个新变异扩展了PKD1/PKD2的突变谱。研究结果证明了NGS相对于传统桑格测序方法的优势。基因未明确的病例提示非编码区变异、大片段拷贝数变异或新基因可能参与ADPKD的发病机制。有必要进行全基因组测序以进一步研究这些未明确的病例。
