先天性巨结肠遗传学研究进展、问题与展望  

Research progress, problems, and prospects in the genetic study of Hirschsprung disease

作　　者：高雅 姜茜[1,2] Ya Gao;Qian Jiang(Department of Medical Genetics,Capital Institute of Pediatrics,Beijing 100020,China;Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment(2021RU015),Chinese Academy of Medical Sciences,Beijing 100005,China)

机构地区：[1]首都儿科研究所遗传室,北京100020 [2]中国医学科学院小儿外科微创诊疗创新单元2021RU015,北京100005

出　　处：《科学通报》2024年第4期542-552,共11页Chinese Science Bulletin

基　　金：国家自然科学基金(82070532,81771620);中国医学科学院小儿外科微创诊疗创新单元(2021RU015)资助。

摘　　要：先天性巨结肠(hirschsprung disease,HSCR)又称肠无神经节细胞症,是引起儿童肠梗阻最常见的消化系统疾病,以肠神经嵴细胞增殖、迁移、分化障碍导致远端肠组织中神经节细胞缺失为主要病理特征.基因变异导致的功能缺陷和基因-环境交互作用分别在疾病发生中扮演不同角色.得益于遗传学研究方法的快速发展及普及应用,目前多数家族性患者及部分散发病例的致病基因及疾病遗传结构已被解析.本文首先对遗传及非遗传因素的疾病发生贡献进行了概述,然后重点阐述了肠组织特异性基因相互作用与复杂调控网络、多变异协同致病、肠神经系统发育调控分子以及嵌合体变异作为该病潜在遗传机制的主要研究进展,并围绕“遗传力丢失”、现有分析手段统计效力不足、针对弱效基因变异组合的检测模型缺乏及临床转化应用中面临的主要瓶颈问题进行了论述,最后展望了基于基因编辑技术的疾病研究模型构建、干细胞移植治疗及多组学整合的未来研究方向与应用前景.Hirschsprung disease (HSCR), also known as aganglionosis, is the most common cause of colonic obstruction in children.It is a neurocristopathy characterized by the absence of enteric ganglia along a variable length of the intestine, and when thegut fails to be innervated, it loses motility. The disease was named after Dr. Harald Hirschsprung, who comprehensivelydescribed two unrelated infants who died from abdominal distension as a consequence of the dilatation and hypertrophy ofthe colon in 1888. In clinical practice, HSCR patients often present with delayed meconium passage, abdominal distension,vomiting, severe constipation, predisposition to bowel inflammation (enterocolitis), and even early death. According to theextent of aganglionosis, HSCR can be classified into four main types: Short-segment HSCR (S-HSCR), in which theaganglionic segment is limited to the rectal and distal sigmoid colon;long-segment HSCR (L-HSCR), in which theaganglionosis extends proximal to the sigmoid colon;total colonic aganglionosis (TCA), in which the entire colon isaffected;and total colonic and small-colon aganglionosis (TCSA). HSCR has an incidence of approximately 1 in every5000 newborns of European ancestry and is twice as common in Asians, with a high heritability (>80%) and marked sexdifferences (male:female ratio, 4:1). Although the disease occurs as an isolated disorder in approximately 70% of patients,it can also manifest with chromosomal abnormalities, additional congenital anomalies, or recognized syndromes.Over the last several decades, surgical treatment has effectively decreased the mortality and morbidity of HSCR,allowing for the emergence of familial cases. As a classic developmental disorder of the enteric nervous system (ENS),HSCR is attributed to defective proliferation, migration and differentiation of enteric neural crest cells resulting fromdysregulated gene functions and gene‒environment interactions. Genetic defects play a major role in HSCR pathogenesis,including gene mutations, cytogenetic abnormalities

关 键 词：先天性巨结肠 遗传力 外显率 基因调控网络 嵌合体变异 干细胞移植 

分 类 号：R725.7[医药卫生—儿科]