Wang Haojun, Wen Wen, Yao Mingxi, Yang Tongwang, Chen Dongshan, Wang Wei
Department of Urology, Beijing Chaoyang Hospital Affiliated Capital Medical University, Beijing, China.
State Key Laboratory of Complex Severe and Rare Diseases, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Front Genet. 2024 Jul 23;15:1399604. doi: 10.3389/fgene.2024.1399604. eCollection 2024.
Congenital scoliosis and congenital anomalies of the kidney and urinary tract are distinct genetic disorders with differing clinical manifestations. Clinically, their coexistence is not rare, but the etiologies of these complex diseases remain largely unknown, especially their shared genetic basis.
We sequenced the genomes of 40 individuals diagnosed with both CS and CAKUT, alongside 2,764 controls from a Chinese Han population cohort. Our analyses encompassed gene-based and pathway-based weighted rare variant association tests, complemented by copy number variant association analyses, aiming to unravel the shared genomic etiology underlying these congenital conditions.
Gene-based analysis identified PTPN11 as a pivotal gene influencing both skeletal and urinary system development ( = 1.95E-21), participating in metabolic pathways, especially the MAPK/ERK pathway known to regulate skeletal and urinary system development. Pathway-based enrichment showed a significant signal in the MAPK/ERK pathway ( = 3E-04), reinforcing the potential role of PTPN11 and MAPK/ERK pathway in both conditions. Additionally, CNV analysis pinpointed IGFLR1 haploinsufficiency as a potential influential factor in the combined CS-CAKUT phenotypic spectrum.
This study enriches our understanding of the intricate genomic interplay underlying congenital scoliosis and kidney and urinary tract anomalies, emphasizing the shared genetic foundations between these two disorders.
先天性脊柱侧凸以及肾脏和泌尿系统先天性异常是具有不同临床表现的独特遗传疾病。临床上，它们同时存在并不罕见，但这些复杂疾病的病因在很大程度上仍不清楚，尤其是它们共同的遗传基础。
我们对40名被诊断患有先天性脊柱侧凸（CS）和先天性肾脏和尿路畸形（CAKUT）的个体以及来自中国汉族人群队列的2764名对照进行了全基因组测序。我们的分析包括基于基因和基于通路的加权罕见变异关联测试，并辅以拷贝数变异关联分析，旨在揭示这些先天性疾病潜在的共同基因组病因。
基于基因的分析确定PTPN11是影响骨骼和泌尿系统发育的关键基因（P = 1.95E - 21），参与代谢途径，特别是已知调节骨骼和泌尿系统发育的MAPK/ERK途径。基于通路的富集分析在MAPK/ERK途径中显示出显著信号（P = 3E - 04），进一步证实了PTPN11和MAPK/ERK途径在这两种疾病中的潜在作用。此外，拷贝数变异分析确定IGFLR1单倍体不足是先天性脊柱侧凸合并先天性肾脏和尿路畸形表型谱中的一个潜在影响因素。
本研究丰富了我们对先天性脊柱侧凸与肾脏和尿路异常之间复杂基因组相互作用的理解，强调了这两种疾病之间共同的遗传基础。
