Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE29051 | GEO | 2011/05/06
SECONDARY ACCESSION(S): PRJNA140231
REPOSITORIES: GEO
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Project description:Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. The HSCR phenotype is highly variable with respect to gender, segment length of aganglionosis, familiality and the presence of additional anomalies. By molecular genetic analysis, a minimum of 11 neuro-developmental genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4) are known to harbor rare high-penetrance mutations that confer a large risk to the bearer. In addition, two other genes (RET, NRG1) harbor common low-penetrance polymorphisms that contribute only partially to risk and act as genetic modifiers. To broaden this search, we examined whether a set of 67 proven and candidate HSCR genes harbored additional modifier alleles. In this pilot study, we utilized a custom-designed array CGH with ~33,000 test probes at an average resolution of ~185bp to detect gene-sized or smaller copy number variants (CNVs) within these 67 genes in 18 heterogeneous HSCR patients. Using stringent criteria, we identified CNVs at three loci (MAPK10, ZFHX1B, SOX2) that are novel, involve regulatory and coding sequences of these neuro-developmental genes and show association with HSCR in combination with other congenital anomalies. Two-condition experiment: Patient vs. Control. Sex-matched controls. Technical replicates: 4 were examined twice and 3 were studied in triplicate. Technical replicates: 408.3.1, 408.3.2 Technical replicates: 300.3.1, 300.3.2 Technical replicates: 354.3.1, 354.3.2 Technical replicates: 355.3.1, 355.3.2 Technical replicates: 63.3.1, 63.3.2, 63.3.3 Technical replicates: 122.7.1, 122.7.2, 122.7.3 Technical replicates: 413.3.1, 413.3.2, 413.3.3
2011-05-06 | E-GEOD-29051 | biostudies-arrayexpress
Project description:For most multigenic disorders, clinical manifestation (penetrance) and presentation (expressivity) are likely to be an outcome of genetic interaction between multiple susceptibility genes. Here, using gene knockouts in mice we evaluated genetic interaction between loss of Ret and loss of Sema3d, two Hirschsprung disease (HSCR) susceptibility genes. We intercrossed Ret and Sema3d double null heterozygotes to generate mice with the nine possible genotypes and assessed survival by counting various genotypes, myenteric plexus development by acetylcholinesterase (AchE) staining and embryonic day 12.5 (E12.5) gut transcriptome by RNA-sequencing. Survival rates of Ret wildtype, null heterozygote and null homozygote mice at E12.5, birth and weaning were not influenced by the genotypes at Sema3d locus and vice-versa. Loss of myenteric plexus was observed only in all Ret null homozygotes, irrespective of the genotypes at Sema3d locus, and Sema3d null heterozygote and homozygote mice had normal gut innervation. As compared to wildtype mice gut gene expression, loss of Ret in null homozygotes led to differential expression of ~300 genes, whereas loss of Sema3d in null homozygotes had no major consequence and there was no evidence supporting major interaction between the two genes influencing gut transcriptome. Overall, given the null alleles and phenotypic assays used, we did not find evidence for genetic interaction between Ret and Sema3d affecting survival, myenteric plexus formation or gut transcriptome.
2017-03-28 | GSE89627 | GEO
Project description:The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Pathogenic RET loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.
2021-12-30 | GSE192676 | GEO
Project description:RET/GDNF and ET3/EDNRB regulate cell survival, differentiation and migration of neural crest-derived cells. Many signalling mediators of RET have been characterized but the target genes at the end of the signalling cascade are largely unknown. Since the RET/EDNRB crosstalk has been previously shown, we used a Caenorhabditis elegans knockout strain of Nep-1, a homologue of human ECE1 (endothelin-converting enzyme-1), to identify new target genes. Transcriptome comparison between wild-type and Nep-1 strains at different stages identified vit-3 as a differentially expressed gene. Molecular studies of the vit3 mammalian homologue, Apoliporotein B (APOB), were performed in the murine Neuro2a cell line, a model of ENS development. Apob expression in Neuro2a is specifically activated by the RET/GDNF signalling pathway, since Ret silencing abolished Apob increase, and this effect is induced by MAPK P38 kinase activation. Mouse Apob promoter study revealed that there is a p53-dependent repressor element in the promoter region which blocks Apob expression and we show that actually p53 binds to this region. We demonstrated that RET/GDNF and EDNRB/endothelin 3 (ET-3) cooperate in inducing neuronal differentiation resulting in Apob activation. We also show that Apob expression is downregulated in mouse embryos homozygous for the mutation RetC620R and presenting a severe HSCR phenotype, whereas heterozygous mice, phenotypically normal, present a significant increase in Apob expression. These data suggest that Apob has an important role in RET-mediated neuronal development and APOB decrease may have an impact in human disorders where RET absence has been already identified, such as HSCR and Parkinson disease. Gene expression analysis using Affymetrix GeneChip C. elegans arrays in order to identify genes up- or down-regulated in nep-1 strains, homologue of human ECE1 (endothelin-converting enzyme 1). Comparison of the transcriptomes between wt and nep-1 strains in larval stage L3 and adult C. elegans.
2011-09-23 | E-GEOD-32339 | biostudies-arrayexpress
Project description:RET/GDNF and ET3/EDNRB regulate cell survival, differentiation and migration of neural crest-derived cells. Many signalling mediators of RET have been characterized but the target genes at the end of the signalling cascade are largely unknown. Since the RET/EDNRB crosstalk has been previously shown, we used a Caenorhabditis elegans knockout strain of Nep-1, a homologue of human ECE1 (endothelin-converting enzyme-1), to identify new target genes. Transcriptome comparison between wild-type and Nep-1 strains at different stages identified vit-3 as a differentially expressed gene. Molecular studies of the vit3 mammalian homologue, Apoliporotein B (APOB), were performed in the murine Neuro2a cell line, a model of ENS development. Apob expression in Neuro2a is specifically activated by the RET/GDNF signalling pathway, since Ret silencing abolished Apob increase, and this effect is induced by MAPK P38 kinase activation. Mouse Apob promoter study revealed that there is a p53-dependent repressor element in the promoter region which blocks Apob expression and we show that actually p53 binds to this region. We demonstrated that RET/GDNF and EDNRB/endothelin 3 (ET-3) cooperate in inducing neuronal differentiation resulting in Apob activation. We also show that Apob expression is downregulated in mouse embryos homozygous for the mutation RetC620R and presenting a severe HSCR phenotype, whereas heterozygous mice, phenotypically normal, present a significant increase in Apob expression. These data suggest that Apob has an important role in RET-mediated neuronal development and APOB decrease may have an impact in human disorders where RET absence has been already identified, such as HSCR and Parkinson disease. Gene expression analysis using Affymetrix GeneChip C. elegans arrays in order to identify genes up- or down-regulated in nep-1 strains, homologue of human ECE1 (endothelin-converting enzyme 1).
2011-09-24 | GSE32339 | GEO
Project description:Chromosomal microarray analysis (CMA) in prenatal diagnosis detects copy number variations (CNVs) in many fetuses; however, the low penetrance and phenotypic diversity of CNVs complicate genetic counseling, resulting in limited understanding of intrauterine ultrasound phenotypes linked to CNVs. In a retrospective analysis of 25,000 cases at Fujian Maternal and Child Health Hospital, 18,000 pregnant women underwent SNP array testing (December 2015 to June 2023).
2024-08-14 | GSE274505 | GEO
Project description:The enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate the neurons and glia that regulate gastrointestinal function. Defects in the migration, colonization or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an unknown genetic diagnosis. Therefore, it’s important to identify new genes, modifiers and environmental factors that regulate ENS development and HSCR. We discovered that retinol dehydrogenase 10 (Rdh10) loss-of-function mouse embryos exhibit total intestinal aganglionosis, the most severe form of HSCR. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, RA, and is therefore a central regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. Rdh10 is highly expressed in the mesenchyme surrounding the entrance to the foregut and we demonstrate that paracrine retinoid signaling is essential between E7.5-E9.5 for NCC entry into the gut. Vagal NCC form and migrate in Rdh10 mutant embryos but fail to enter the foregut. Comparative RNA-sequencing revealed Ret-Gdnf-Gfra1-signaling which is critical for vagal NCC chemotaxis is downregulated in Rdh10 mutants and furthermore that the composition of the extracellular matrix through which NCC migrate is altered, particularly by increased collagen deposition. Collectively this restricts NCC entry into the gut, demonstrating that Rdh10-mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of HSCR.
2022-02-01 | GSE166625 | GEO
Project description:Objective: Chromosomal 1q21.1 deletions and duplications are genomic disorders which are usually diagnosed postnatally. However, the genotype-phenotype correlations of 1q21.1 copy number variants (CNVs) during prenatal period are still not clear. This study aimed to provide a systematical summary of prenatal phenotypes for such genomic disorders. Methods: Twenty-six prenatal amniotic fluid samples diagnosed with 1q21.1 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed for all cases simultaneously. The pregnancy outcomes and health conditions after birth for all cases were followed up. Meanwhile, prenatal cases with 1q21.1 microdeletions or microduplications in the literature were retrospectively collected. Results: Eleven pregnancies (11/8252, 0.13%) with 1q21.1 microdeletions and fifteen (15/8252, 0.18%) with 1q21.1 microduplications were identified. Among these 1q21.1 CNVs, four cases covered thrombocytopenia-absent radius (TAR) region, sixteen cases covered 1q21.1 recurrent microdeletion/microduplication region, and six cases covered all regions mentioned above. The prenatal abnormal ultrasound findings were recorded in four participants with 1q21.1 deletions and seven participants with 1q21.1 duplications. Finally, three cases with 1q21.1 deletions and five with 1q21.1 duplications terminated their pregnancies. Conclusion: 1q21.1 microdeletions were associated with increased nuchal translucency (NT), anomalies of urinary system and cardiovascular abnormalities, and 1q21.1 microduplications were correlated with cardiovascular malformations, nasal bone dysplasia and increased NT in prenatal setting. In addition, cerebral ventriculomegaly might be correlated with 1q21.1 microduplications. Considering the variable expressivity and incomplete penetrance of 1q21.1 CNVs, long term follow up after birth should be carried out for these cases. We identified 26 fetuses carrying the 1q21.1 microdeletions and microduplications using chromosomal microarray analysis. And diverse prenatal phenotypes and the critical genes involved in the deleted/duplicated regions were described in this study.
2023-08-14 | GSE240611 | GEO
Project description:Purpose: Obesity is known to be a multifactorial condition that is highly heritable. There have been ~60 susceptibility loci identified, but they only account for a fraction of cases.. As copy number variations (CNVs) have been implicated in the etiology of a multitude of human disorders including obesity, here, we investigated the contribution of rare CNVs (<0.1% population frequency) in pediatric cases of obesity. Methods: We genotyped 67 pediatric patients presenting with obesity, including 22 with co-morbid developmental delay and prioritized rare CNVs at known associated loci, as well as, those impacting genes involved in energy homeostasis or related processes. Results: We identified clinically relevant or potentially clinically-relevant CNVs in 15% (10/67) of individuals. Of these, 4% (3/67) had 16p11.2 microdeletions encompassing the known obesity risk gene SH2B1. Notably, we identified two unrelated probands harboring different 6p22.2 microduplications encompassing SCGN, a potential novel candidate gene for obesity. Further, we identified other biologically relevant candidate genes for pediatric obesity including ARID5B, GPR39, PTPRN2, and HNF4G. Conclusion: We found previously reported candidate loci for obesity, and new ones, suggesting CNV analysis may assist in the diagnosis of pediatric obesity.
2018-07-12 | GSE101416 | GEO
Project description:Purpose: Obesity is known to be a multifactorial condition that is highly heritable. There have been ~60 susceptibility loci identified, but they only account for a fraction of cases. As copy number variations (CNVs) have been implicated in the etiology of a multitude of human disorders including obesity, here, we investigated the contribution of rare CNVs (<0.1% population frequency) in pediatric cases of obesity. Methods: We genotyped 67 pediatric patients presenting with obesity, including 22 with co-morbid developmental delay and prioritized rare CNVs at known associated loci, as well as, those impacting genes involved in energy homeostasis or related processes. Results: We identified clinically relevant or potentially clinically-relevant CNVs in 15% (10/67) of individuals. Of these, 4% (3/67) had 16p11.2 microdeletions encompassing the known obesity risk gene SH2B1. Notably, we identified two unrelated probands harboring different 6p22.2 microduplications encompassing SCGN, a potential novel candidate gene for obesity. Further, we identified other biologically relevant candidate genes for pediatric obesity including ARID5B, GPR39, PTPRN2, and HNF4G. Conclusion: We found previously reported candidate loci for obesity, and new ones, suggesting CNV analysis may assist in the diagnosis of pediatric obesity.
2018-07-12 | GSE101414 | GEO