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<p>Alport syndrome (AS) is a prevalent inherited kidney disorder mainly caused by mutations in <i>COL4A3</i>, <i>COL4A4</i>, and <i>COL4A5</i> genes. To elucidate the genetic variants of AS, we implemented a sequential sequencing strategy within a Chinese cohort of 555 patients, comprising whole-exome sequencing (WES) for all participants, followed by whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and nanopore long-read sequencing (NLR-seq) for selected individuals. We identify 431 distinct variants in 509 (91.7%) patients, with 42.2% being novel. Beyond WES, additional sequencing approaches resolve 23 patients with noncoding, copy number, or structural variants. Notably, noncoding variants account for 16.2% of detected variants and exhibit ethnic-specific mutagenesis patterns. More interestingly, NLR-seq uncovers two novel types of structural variants, namely large insertions in intronic regions and complex duplication-inversion variants. This study provides deeper insights into the genetic architecture of AS and proposes a research paradigm for improving the genetic diagnosis of inherited diseases.</p>

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Sequential sequencing reveals the architecture and complexity of genomic variants in patients with Alport syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Hongling Di,
  • Zhen You,
  • Ling Wang,
  • QingRong Sun,
  • Jiahui Zhang,
  • Qi Lv,
  • Pei Wang,
  • Ze Lai,
  • Gang Wang,
  • Chunxia Zheng,
  • Liang Gong,
  • Zhihong Liu

摘要

Alport syndrome (AS) is a prevalent inherited kidney disorder mainly caused by mutations in COL4A3, COL4A4, and COL4A5 genes. To elucidate the genetic variants of AS, we implemented a sequential sequencing strategy within a Chinese cohort of 555 patients, comprising whole-exome sequencing (WES) for all participants, followed by whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and nanopore long-read sequencing (NLR-seq) for selected individuals. We identify 431 distinct variants in 509 (91.7%) patients, with 42.2% being novel. Beyond WES, additional sequencing approaches resolve 23 patients with noncoding, copy number, or structural variants. Notably, noncoding variants account for 16.2% of detected variants and exhibit ethnic-specific mutagenesis patterns. More interestingly, NLR-seq uncovers two novel types of structural variants, namely large insertions in intronic regions and complex duplication-inversion variants. This study provides deeper insights into the genetic architecture of AS and proposes a research paradigm for improving the genetic diagnosis of inherited diseases.