Genetic Background of Hirschsprung Disease: A Bridge Between Basic Science and Clinical Application

@article{Bahrami2018GeneticBO,
  title={Genetic Background of Hirschsprung Disease: A Bridge Between Basic Science and Clinical Application},
  author={Afsane Bahrami and Marjan Joodi and Mehrdad Moetamani-Ahmadi and Mina Maftouh and Seyed Mahdi Hassanian and Gordon A. Ferns and Amir Avan},
  journal={Journal of Cellular Biochemistry},
  year={2018},
  volume={119}
}
Hirschsprung's disease (HSCR) is a congenital disorder, defined by partial or complete loss of the neuronal ganglion cells in the intestinal tract, which is caused by the failure of neural crest cells to migrate completely during intestinal development during fetal life. HSCR has a multifactorial etiology, and genetic factors play a key role in its pathogenesis; these include mutations within several gene loci. These have been identified by screening candidate genes, or by conducting genome… 
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What is new about the genetic background of Hirschsprung disease?
TLDR
This review summarizes the current knowledge about molecular genetic basis of HSCR and describes a wide spectrum of mutations affecting many different genes that cause the disease.
[Syndromic Hirschsprung′s disease and its mode of inheritance].
TLDR
The clinical manifestations, genetic basis, and genetic modes of different types of syndromic HSCR can be classified into different types according to the length of the affected intestinal canal.
RET compound inheritance in Chinese patients with Hirschsprung disease: lack of penetrance from insufficient gene dysfunction.
TLDR
This study supports the idea that common RET variants can modify the penetrance of rare null RET mutations in HSCR, and the combined high susceptibility allele dosage may constitute the unique raised "risk baseline" among the Chinese population.
A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease
TLDR
This approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of H SCR.
Sequence characterization of RET in 117 Chinese Hirschsprung disease families identifies a large burden of de novo and parental mosaic mutations
TLDR
The findings expand the clinical and molecular spectrum of RET variants in HSCR and reveal a high frequency of RET DNVs in the Chinese population.
NOX5 is expressed aberrantly but not a critical pathogenetic gene in Hirschsprung disease
TLDR
It is shown that NOX5 markedly decreased in the aganglionic segment of HSCR but didn’t involve in the ENS development of zebrafish, which implies that absence of intestinal ganglion cells may lead to down-regulation of NOx5.
Phenotypic spectrum associated with pathogenic mutation in the NRG1 gene in Acadian family
TLDR
Molecular analysis in two brothers of Acadian descent presented with a history of Hirschsprung disease revealed a heterozygous pathogenic mutation in the NGR1 gene (c.235C>T [p.Arg79*]), that was inherited from an unaffected father, expanding knowledge about the phenotypic spectrum associated with pathogenic mutated NRG1 gene with intrafamilial variability and the likely reduced penetrance for the phenotypesic expression.
Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease
TLDR
Data support the idea that PTPRR may ensure a certain number of neural precursor cells by inhibiting ENCC overt differentiation and maintaining ENCC proliferation, which is considered to be the multipotency of ENCCs, and eventually participate in the development of the ENS.
Association between DSCAM polymorphisms and non-syndromic Hirschsprung disease in Chinese population
TLDR
There is an association between DSCAM polymorphisms and non-syndromic HSCR in South Chinese population.
Exome Sequencing Identifies RET Associated Hirschsprung Disease in a Fetus with Echogenic Bowel
TLDR
Exome sequencing done on fetal DNA from amniotic fluid revealed a putative pathogenic heterozygous c.1438G > A variant in exon 7 of RET gene, which was inherited from the asymptomatic mother, which enabled genetic counseling and prenatal diagnosis in subsequent pregnancy.
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References

SHOWING 1-10 OF 53 REFERENCES
Genetic basis of Hirschsprung’s disease
TLDR
This review will focus on the genes known to be involved in HSCR pathology, how they interact, and on how technology advances are being employed to uncover the pathological processes underlying this disease.
Hirschsprung disease, associated syndromes and genetics: a review
TLDR
Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment, which stands as a model for genetic disorders with complex patterns of inheritance.
The contribution of associated congenital anomalies in understanding Hirschsprung’s disease
  • S. Moore
  • Medicine
    Pediatric Surgery International
  • 2006
TLDR
The importance of certain flanking genes of critical areas in the final phenotypic expression of HSCR are explored, appearing to arise from the combined cumulative effects of susceptibility loci at critical genes controlling the mechanisms of cell proliferation, differentiation and maturation.
Studying the genetics of Hirschsprung's disease: unraveling an oligogenic disorder
TLDR
The identification of genes and loci involved in the non‐syndromic common form and syndromic Mendelian forms of Hirschsprung's disease proved to be complex; involvement of multiple loci was demonstrated in a multiplicative model.
Fine mapping of the 9q31 Hirschsprung’s disease locus
TLDR
The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk of disease, supported by the role of IKBkAP in the development of the nervous system.
Fine Mapping of the NRG1 Hirschsprung's Disease Locus
TLDR
A genome-wide association study uncovered a ∼350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1) and investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues and found differences in expression as a function of genotype.
Association Analysis of SLC6A20 Polymorphisms With Hirschsprung Disease
TLDR
The results suggest that SLC6A20 may have roles in HSCR development and in the extent of aganglionic segment during enteric nervous system development.
Novel mutations at RET ligand genes preventing receptor activation are associated to Hirschsprung’s disease
TLDR
It is suggested that the biological consequence of the mutations NTRN F127L and PSPN R91C would be a reduction in the activation of RET-dependent signaling pathways, leading to a defect in the proliferation, migration, and or differentiation process of neural crest cells within the developing gut and thus to the typical aganglionosis of the HSCR phenotype.
Copy Number Variants in Candidate Genes Are Genetic Modifiers of Hirschsprung Disease
TLDR
A role for CNVs in HSCR is suggested and the role of variation in regulatory sequences is emphasizes and a much larger study will be necessary both for replication and for identifying the full spectrum of small CNV effects.
Genetic variants of IL‐11 associated with risk of Hirschsprung disease
  • L. Kim, H. Cheong, H. D. Shin
  • Medicine
    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
  • 2015
TLDR
This work studied associations with HSCR of nine common single nucleotide polymorphisms (SNPs) on IL‐11 and identified a variant of interleukin‐11 (IL‐11) as a potential susceptible locus for H SCR.
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