Molecular Neurobiology

, Volume 47, Issue 3, pp 957–966 | Cite as

Exome Sequencing Identified NRG3 as a Novel Susceptible Gene of Hirschsprung’s Disease in a Chinese Population

  • Jun Yang
  • Shengyu Duan
  • Rong Zhong
  • Jieyun Yin
  • Jiarui Pu
  • Juntao Ke
  • Xuzai Lu
  • Li Zou
  • Hongmei Zhang
  • Zhidong Zhu
  • Depeng Wang
  • Huasheng Xiao
  • Anyuan Guo
  • Jiahong Xia
  • Xiaoping MiaoEmail author
  • Shaotao TangEmail author
  • Guobin WangEmail author


Hirschsprung’s disease (HSCR) is a complex developmental defect characterized by the absence of enteric ganglia in the gastrointestinal tract. Although the genetic defect of enteric nervous system (ENS) was identified to play a critical role in the progress of HSCR, the systemic genetic dissection of HSCR still needs to be clarified. In this study, we firstly performed exome sequencing of two HSCR patients from a Han Chinese family, including the affected mother and son. After the initial quality filtering (coverage ≥ 5X and SNP quality score ≥ 40) of the raw data, we identified 13,948 and 13,856 single nucleotide variants (SNVs), respectively. We subsequently compared the SNVs against public databases (dbSNP130, HapMap, and 1000 Genome Project) and obtained a total of 15 novel nonsynonymous SNVs in 15 genes, which were shared between these two patients. Follow-up Sanger sequencing and bioinformatics analysis highlighted variant c.853G>A (p.E285K) in NRG3, a gene involved in the development of ENS. In the validation phase, we sequenced all nine exons of NRG3 in 96 additional sporadic HSCR cases and 110 healthy individuals and identified another nonsynonymous variant c.1329G>A (p.M443I) and two synonymous variants c.828G>A (p.T276T) and c.1365T>A (p.P455P) only in the cases. Our results indicated that NRG3 may be a susceptibility gene for HSCR in a Chinese population.


Hirschsprung’s disease (HSCR) Whole exome sequence NRG3 Single nucleotide variants (SNVs) 



This work was supported by the Program for New Century Excellent Talents in University NCET-10-0388, Natural Science Foundation of Hubei 2010CDB03203 and 2011CDB304, and the Fundamental Research Funds for the Central Universities HUST: No. 2010QN005. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors have declared no conflicts of interest.

Supplementary material

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Supplementary Fig. 1

The pedigree of the affected Han Chinese family. Blue color represents HSCR patients. Patient II:3 is the mother and III:3 is the son (JPEG 23 kb)

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High resolution image (TIFF 539 kb)
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Supplementary Fig. 2

The sequence diagram of the identified false positive variants in UNC5C and C22orf42 (JPEG 50 kb)

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Supplementary Fig. 2b

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jun Yang
    • 1
    • 6
  • Shengyu Duan
    • 2
  • Rong Zhong
    • 2
  • Jieyun Yin
    • 2
  • Jiarui Pu
    • 1
  • Juntao Ke
    • 2
  • Xuzai Lu
    • 2
  • Li Zou
    • 2
  • Hongmei Zhang
    • 3
  • Zhidong Zhu
    • 4
  • Depeng Wang
    • 5
  • Huasheng Xiao
    • 4
  • Anyuan Guo
    • 3
  • Jiahong Xia
    • 1
  • Xiaoping Miao
    • 1
    • 2
    Email author
  • Shaotao Tang
    • 1
    Email author
  • Guobin Wang
    • 1
    Email author
  1. 1.Department of Pediatric SurgeryUnion Hospital of Huazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Epidemiology and Biostatistics and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  3. 3.Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
  4. 4.National Engineering Center for Biochip at ShanghaiShanghaiChina
  5. 5.Nextomics Biosciences Co., Ltd.WuhanChina
  6. 6.Department of Pediatric SurgeryWuhan Children’s HospitalWuhanChina

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