Research progress,problems,and prospects in the genetic study of Hirschsprung disease
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 the gut fails to be innervated,it loses motility.The disease was named after Dr.Harald Hirschsprung,who comprehensively described two unrelated infants who died from abdominal distension as a consequence of the dilatation and hypertrophy of the 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 the extent of aganglionosis,HSCR can be classified into four main types:Short-segment HSCR(S-HSCR),in which the aganglionic segment is limited to the rectal and distal sigmoid colon;long-segment HSCR(L-HSCR),in which the aganglionosis extends proximal to the sigmoid colon;total colonic aganglionosis(TCA),in which the entire colon is affected;and total colonic and small-colon aganglionosis(TCSA).HSCR has an incidence of approximately 1 in every 5000 newborns of European ancestry and is twice as common in Asians,with a high heritability(＞80％)and marked sex differences(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 from dysregulated gene functions and gene-environment interactions.Genetic defects play a major role in HSCR pathogenesis,including gene mutations,cytogenetic abnormalities,and abnormal gene expression.In addition,smoking,obesity and maternal use of selective serotonin reuptake inhibitors during pregnancy have been suggested to be associated with the development of HSCR in newborn children.Recent developments in genetic tools and techniques and the implementation of population screening have provided new insights into the causal genes and genetic architecture of most familial cases and some sporadic cases.Here,we outline the latest progress in genetic studies in HSCR,mainly focusing on gut-specific gene-gene interactions and gene regulatory networks,the synergetic effects of common noncoding variants and rare coding mutations,molecular defects related to ENS development and mosaic mutations.Furthermore,we discuss the major problems in this area,including the"missing heritability",insufficient statistical effectiveness,lack of appropriate detection models for combined variants with moderate effects and clinical transformation and application.Finally,we summarize the future research directions and application prospects of gene editing-based disease model construction,stem cell transplantation therapy and multiomics integration studies.
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