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RET somatic mutations are underrecognized in Hirschsprung disease

Genetics in Medicinevolume 20pages770777 (2018) | Download Citation




We aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk.


Targeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation.


We identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35–44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1–28%).


Somatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.

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This work was made possible by a grant from the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-I2M). This study was supported by the National Natural Science Foundation of China (81300266 and 81771620), the Beijing Natural Science Foundation (7142029), the Beijing Excellent Scientist Fund (2013D003034000007), the Beijing Nova Program (Z151100000315091 and Z171100001117125), and the Basic Foundation of the Capital Institute of Pediatrics (FX-2016-02) to Q.J. Q.L. was supported by the Beijing Natural Science Foundation (7154185). X.-L.C. was supported by the National Natural Science Foundation of China (81370708 and 31671310) and the Beijing Natural Science Foundation (7162029). L.L. was supported by grants from the Public Welfare Industry Research Special Foundation of China (201402007) and a Clinical Medicine Development Project of the Beijing Hospital Administration Bureau (ZYLX201306). F.Z. was supported by the National Natural Science Foundation of China (31625015). A.C. was supported by grants from the National Institutes of Health (HD28088). We are grateful to the affected individuals and their family members whose cooperation made this study possible. We thank Qixi Wu, Xiaoxu Yang, and Liping Wei from the National Institute of Biological Sciences for assistance with Bayesian-based mosaic validation, and acknowledge Ashish Kapoor (Johns Hopkins University School of Medicine) and Xue Zhang (Chinese Academy of Medical Sciences) for helpful discussions.

Author information


  1. Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China

    • Qian Jiang PhD
    • , Fang Liu MSc
    •  & Xiaoli Chen PhD
  2. Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China

    • Chunyue Miao PhD
  3. Department of Developmental Behavioral Pediatrics, First Hospital of Jilin University, Changchun, China

    • Chunyue Miao PhD
  4. Department of General Surgery, Capital Institute of Pediatrics Affiliated Children’s Hospital, Beijing, China

    • Qi Li MSc
    • , Zhen Zhang MSc
    •  & Long Li MD, PhD
  5. Department of Pathology, Capital Institute of Pediatrics Affiliated Children’s Hospital, Beijing, China

    • Ping Xiao MSc
  6. Reproductive Medicine Center, Clinical College of PLA Affiliated Anhui Medical University, Hefei, China

    • Lin Su MSc
  7. Department of Pathophysiology, School of Preclinical Sciences, Guangxi Medical University, Nanning, China

    • Kaihui Yu MSc
  8. Obstetrics and Gynecology Hospital, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China

    • Feng Zhang PhD
  9. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    • Aravinda Chakravarti PhD


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The authors declare no conflict of interest.

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Correspondence to Qian Jiang PhD or Long Li MD, PhD.

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