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Detection and preliminary screening of the human gene expression profile for Hirschsprung's disease.

ABSTRACT: The present study investigated a genome microarray of colorectal lesions (spasm segments) in children with Hirschsprung's disease (HSCR), and analyzed the results. In addition, the present study screened for differentially expressed genes in children with HSCR. Microarray technology was used to examine the human gene expression profiles of the colorectal lesions (spasm segments) of six children with HSCR, and three normal colon tissue samples. The data were analyzed be determining P?values of significance and absolute fold changes. Preliminary screening was performed to identify genes exhibiting significant differential expression in children with HSCR, and these target genes were analyzed in subsequent verification and analytical investigations. Of >20,000 detected human genes, the preliminary screenings demonstrated that 3,850 genes were differentially expressed and upregulated, with P<0.05 and >2?fold absolute changes in expression. In addition, 645 differentially expressed genes with P<0.05 and >2?fold absolute changes were downregulated. Of the upregulated genes, 118 were involved in classic signaling pathways, compared with 11 of the downregulated genes (P<0.001; absolute fold change >2?fold). HSCR etiology is complex and often involves multiple gene changes. Microarray technology can produce large quantities of gene expression data simultaneously, and analyzing this data using various techniques may provide a fast and efficient method for identifying novel gene targets and for investigating the mechanisms underlying HSCR pathogenesis.

SUBMITTER: Wang X

PROVIDER: S-EPMC4686122 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Detection and preliminary screening of the human gene expression profile for Hirschsprung's disease.

Wang Xin X Wang Shiqi S Jin Xianqing X Wang Ning N Luo Yuanyuan Y Teng Yinping Y

Molecular medicine reports 20151201 1

The present study investigated a genome microarray of colorectal lesions (spasm segments) in children with Hirschsprung's disease (HSCR), and analyzed the results. In addition, the present study screened for differentially expressed genes in children with HSCR. Microarray technology was used to examine the human gene expression profiles of the colorectal lesions (spasm segments) of six children with HSCR, and three normal colon tissue samples. The data were analyzed be determining P‑values of si ...[more]

PMID: 26648025

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Project description:BackgroundHirschsprung's disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants. The disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes.MethodsWe genotyped and exome-sequenced samples from 190 patients with Hirschsprung's disease to quantify the genetic burden in patients with this condition. DNA sequence variants, large copy-number variants, and karyotype variants in probands were considered to be pathogenic when they were significantly associated with Hirschsprung's disease or another neurodevelopmental disorder. Novel genes were confirmed by functional studies in the mouse and human embryonic gut and in zebrafish embryos.ResultsThe presence of five or more variants in four noncoding elements defined a widespread risk of Hirschsprung's disease (48.4% of patients and 17.1% of controls; odds ratio, 4.54; 95% confidence interval [CI], 3.19 to 6.46). Rare coding variants in 24 genes that play roles in enteric neural-crest cell fate, 7 of which were novel, were also common (34.7% of patients and 5.0% of controls) and conferred a much greater risk than noncoding variants (odds ratio, 10.02; 95% CI, 6.45 to 15.58). Large copy-number variants, which were present in fewer patients (11.4%, as compared with 0.2% of controls), conferred the highest risk (odds ratio, 63.07; 95% CI, 36.75 to 108.25). At least one identifiable genetic risk factor was found in 72.1% of the patients, and at least 48.4% of patients had a structural or regulatory deficiency in the gene encoding receptor tyrosine kinase (RET). For individual patients, the estimated risk of Hirschsprung's disease ranged from 5.33 cases per 100,000 live births (approximately 1 per 18,800) to 8.38 per 1000 live births (approximately 1 per 120).ConclusionsAmong the patients in our study, Hirschsprung's disease arose from common noncoding variants, rare coding variants, and copy-number variants affecting genes involved in enteric neural-crest cell fate that exacerbate the widespread genetic susceptibility associated with RET. For individual patients, the genotype-specific odds ratios varied by a factor of approximately 67, which provides a basis for risk stratification and genetic counseling. (Funded by the National Institutes of Health.).

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Detection and preliminary screening of the human gene expression profile for Hirschsprung's disease.

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Detection and preliminary screening of the human gene expression profile for Hirschsprung's disease.

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