ArticleGenome biology2017
Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.
Article in Genome biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 91 citations in OpenAlex.
- Vinculin influences essential processes in enteric nervous system development and Hirschsprung disease pathogenesis.The Journal of clinical investigation · 2026Article
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- Refining the Sox10Animal models and experimental medicine · 2025Article
- EMB is essential for enteric nervous system development mediated by PI3K signaling.Genome medicine · 2025Article
- The Hallmarks of Aneuploidy in Cancer and Congenital Syndromes.Annual review of genomics and human genetics · 2025Review
- A Rapid F0 CRISPR Screen in Zebrafish to Identify Regulator Genes of Neuronal Development in the Enteric Nervous System.Neurogastroenterology and motility · 2025Article
- Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants.American journal of human genetics · 2025Article
- Variability in proliferative and migratory defects in Hirschsprung disease-associatedbioRxiv : the preprint server for biology · 2024Article
- Genetic regulation of enteric nervous system development in zebrafish.Biochemical Society transactions · 2024Review
- The role of Down syndrome cell adhesion molecule in Down syndrome.Medical review (2021) · 2024Review
- High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung's disease.Pediatric surgery international · 2024Article
- A targeted CRISPR-Cas9 mediated F0 screen identifies genes involved in establishment of the enteric nervous system.PloS one · 2024Article
- Association between gut microbiota and Hirschsprung disease: a bidirectional two-sample Mendelian randomization study.Frontiers in microbiology · 2024Article
- A targeted CRISPR-Cas9 mediated F0 screen identifies genes involved in establishment of the enteric nervous system.bioRxiv : the preprint server for biology · 2023Article
- Hirschsprung disease.Nature reviews. Disease primers · 2023Review
- A crowdsourcing database for the copy-number variation of the Spanish population.Human genomics · 2023Article
- Genetics of Hirschsprung's disease.Pediatric surgery international · 2023Review
- Article
- Review
- Predicting embryonic aneuploidy rate in IVF patients using whole-exome sequencing.Human genetics · 2022Article
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Authors and funding
40 authors at 16 institutions in 9 countries.
Funding
Abstract
backgroundHirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human.
resultsWe performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS.
conclusionsOur data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.
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