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BMC Pediatrics
Published in: BMC Pediatrics 1/2018

Open Access 01-12-2018 | Research article

NRG1 variant effects in patients with Hirschsprung disease

Authors: Gunadi, Nova Yuli Prasetyo Budi, Raman Sethi, Aditya Rifqi Fauzi, Alvin Santoso Kalim, Taufik Indrawan, Kristy Iskandar, Akhmad Makhmudi, Indra Adrianto, Lai Poh San

Published in: BMC Pediatrics | Issue 1/2018

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Abstract

Background

Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 (NRG1) gene have been implicated in some cases of intestinal aganglionosis. This study aims to investigate the contribution of the NRG1 gene to HSCR development in an Indonesian population.

Methods

We analyzed the entire coding region of the NRG1 gene in 54 histopathologically diagnosed HSCR patients.

Results

All patients were sporadic non-syndromic HSCR with 53/54 (98%) short-segment and 1/54 (2%) long-segment patients. NRG1 gene analysis identified one rare variant, c.397G > C (p.V133 L), and three common variants, rs7834206, rs3735774, and rs75155858. The p.V133 L variant was predicted to reside within a region of high mammalian conservation, overlapping with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and potentially altering the AP-4_2, BDP1_disc3, Egr-1_known1, Egr-1_known4, HEN1_2 transcription factor binding motifs. This p.V133 L variant was absent in 92 non-HSCR controls. Furthermore, the rs7834206 polymorphism was associated with HSCR by case–control analysis (p = 0.037).

Conclusions

This study is the first report of a NRG1 rare variant associated with HSCR patients of South-East Asian ancestry and provides further insights into the contribution of NRG1 in the molecular genetic pathogenesis of HSCR.
Appendix
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Literature
1.
Chakravarti A, Lyonnet S. Hirschsprung disease. In: Scriver CR, Beaudet AL, Valle D, et al., editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 6231–55.
2.
Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 2008;45:1–14.CrossRefPubMed
3.
Emison ES, Garcia-Barcelo M, Grice EA, et al. Differential contributions of rare and common, coding and noncoding ret mutations to multifactorial Hirschsprung disease liability. Am J Hum Genet. 2010;87:60–74.CrossRefPubMedPubMedCentral
4.
5.
Gunadi, Dwihantoro A, Iskandar K, Makhmudi A, Rochadi. Accuracy of polymerase chain reaction-restriction fragment length polymorphism for RET rs2435357 genotyping as Hirschsprung risk. J Surg Res. 2016;203:91–4.CrossRefPubMed
6.
Gunadi, Makhmudi A, Agustriani N, Rochadi. Effects of SEMA3 polymorphisms in Hirschsprung disease patients. Pediatr Surg Int. 2016;32:1025–108.CrossRefPubMed
7.
Alves MM, Sribudiani Y, Brouwer RW, et al. Contribution of rare and common variants determine complex diseases-Hirschsprung disease as a model. Dev Biol. 2013;382:320–9.CrossRefPubMed
8.
Tam PK, Garcia-Barceló M. Genetic basis of Hirschsprung's disease. Pediatr Surg Int. 2009;25:543–58.CrossRefPubMed
9.
Garcia-Barcelo MM, Tang CS, Ngan ES, et al. Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease. Proc Natl Acad Sci U S A. 2009;106:2694–9.CrossRefPubMedPubMedCentral
10.
Tang CS, Ngan ES, Tang WK, et al. Mutations in the NRG1 gene are associated with Hirschsprung disease. Hum Genet. 2012;131:67–76.CrossRefPubMed
11.
Luzón-Toro B, Torroglosa A, Núñez-Torres R, et al. Comprehensive analysis of NRG1 common and rare variants in Hirschsprung patients. PLoS One. 2012;7:e36524.CrossRefPubMedPubMedCentral
12.
13.
Gui H, Tang WK, So MT, et al. RET and NRG1 interplay in Hirschsprung disease. Hum Genet. 2013;132:591–600.CrossRefPubMed
14.
Setiadi JA, Dwihantoro A, Iskandar K, Heriyanto DS. Gunadi. The utility of the hematoxylin and eosin staining in patients with suspected Hirschsprung disease. BMC Surg. 2017;17:71.CrossRefPubMedPubMedCentral
15.
Parahita IG, Makhmudi A, Gunadi. Comparison of Hirschsprung-associated enterocolitis following soave and Duhamel procedures. J Pediatr Surg. 2018;53:1351-135.
16.
17.
Gunadi MK, Ohta M, et al. Two novel mutations in the ED1 gene in Japanese families with X-linked hypohidrotic ectodermal dysplasia. Pediatr Res. 2009;65:453–7.CrossRefPubMed
18.
19.
Ghosh R, Oak N, Plon SE. Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines. Genome Biol. 2017;18:225.CrossRefPubMedPubMedCentral
20.
Walters-Sen LC, Hashimoto S, Thrush DL, et al. Variability in pathogenicity prediction programs: impact on clinical diagnostics. Mol Genet Genomic Med. 2015;3:99–110.CrossRefPubMed
21.
22.
Dong C, Wei P, Jian X, et al. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet. 2015;24:2125–37.CrossRefPubMed
23.
Jha P, Lu D, Xu S. Natural selection and functional potentials of human noncoding elements revealed by analysis of next generation sequencing data. PLoS One. 2015;10:e0129023.CrossRefPubMedPubMedCentral
24.
Holmes WE, Sliwkowski MX, Akita RW, et al. Identification of heregulin, a specific activator of p185erbB2. Science. 1992;256:1205–10.CrossRefPubMed
25.
Barlow A, de GVE, Pachnis V. Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET. Neuron. 2003;40:905–16.CrossRefPubMed
26.
Paratore C, Eichenberger C, Suter U, et al. Sox10 haploinsuffciency affects maintenance of progenitor cells in a mouse model of Hirschsprung disease. Hum Mol Genet. 2002;11:3075–85.CrossRefPubMed
27.
Phusantisampan T, Sangkhathat S, Phongdara A, et al. Association of genetic polymorphisms in the RET-protooncogene and NRG1 with Hirschsprung disease in Thai patients. J Hum Genet. 2012;57:286–93.CrossRefPubMed
28.
Kapoor A, Jiang Q, Chatterjee S, et al. Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms. Hum Mol Genet. 2015;24:2997–3003.CrossRefPubMedPubMedCentral
29.
30.
Tajima A, Pan IH, Fucharoen G, et al. Three major lineages of Asian Y chromosomes: implications for the peopling of east and Southeast Asia. Hum Genet. 2002;110:80–8.CrossRefPubMed
Metadata
Title
NRG1 variant effects in patients with Hirschsprung disease
Authors
Gunadi
Nova Yuli Prasetyo Budi
Raman Sethi
Aditya Rifqi Fauzi
Alvin Santoso Kalim
Taufik Indrawan
Kristy Iskandar
Akhmad Makhmudi
Indra Adrianto
Lai Poh San
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Pediatrics / Issue 1/2018
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-018-1265-x

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