Chunyan Wang, Xiaoshan Tang, Xiuli Wang, Shuzhen Sun, Yuhong Li, Yijin Song, Yue Du, Qingshan Ma, Kaishu Zhao, Dexuan Wang, Qifan Zhu, Xiaoshan Shao, Xiaowen Wang, Lin Huang, Haitao Bai, Yang Yang, Ying Bao, Pei Qian, Shipin Feng, Min Xie, Xinli Han, Rufeng Dai, Jiaojiao Liu, Zhiqing Zhang, Qianfan Miao, Zhiquan Xu, Li Miao, Hui Zhang, Qing Sun, Dandan Xin, Yanyan Guo, Peng Li, Qiang Ma, Mei Han, Xiaojuan Shi, Yan Zhang, Junfeng Liu, Xiaoqing Yang, Wenli Xu, Yuanhan Qin, Fengying Lei, Xiaoyun Jiang, Liping Rong, 党西强, Yongzhen Li, Hongbin Zhu, Ke Wu, Jianxin Wang, Ye Zhang, Taisong Li, Yihui Zhai, Xiaoyan Fang, Jing Chen, Aihua Zhang, Duan Ma, Qian Shen, Hong Xu
Genetic kidney disease (GKD) is a major cause of pediatric chronic kidney disease. Many patients remain genetically unresolved by exome sequencing (ES) and copy number variation (CNV) analysis. Genome sequencing (GS) enables a comprehensive detection of genetic variations. This study evaluates a GS-based sequential strategy to determine the diagnostic yield in pediatric GKD. We recruited families with GKD from a national cohort of 23 centers from 2020 to 2024 through Chinese Children Genetic Kidney Disease Database. This sequential sequencing strategy involved initial trio-ES and Trio-CNV-seq, followed by GS in undiagnosed cases, splicing essays analysis was performed for intronic variants. A total of 735 families were enrolled. Trio-ES and Trio-CNV-seq achieved a diagnostic yield of 39.4% (35.5% from ES and 4.0% from CNV-seq). Subsequent GS identified pathogenic variants in 23 of 445 previously undiagnosed cases (5.2%), including small structural variants (5 cases), intronic variants affecting splicing function (9 cases), and variants in mitochondrion DNA (9 cases). GS showed 14% and 8.8% increase in diagnostic yield in renal tubular disease and CKD of unexplained cause. Syndromic cases exhibited a higher diagnostic yield (10.9%) than isolated cases (4.6%). These findings indicate GS-based sequential strategy improves the diagnostic yield of GKD.