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Genet Med. 2018 Jul;20(7):770-777. doi: 10.1038/gim.2017.178. Epub 2017 Oct 26.

RET somatic mutations are underrecognized in Hirschsprung disease.

Author information

1
Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China. teaco@126.com.
2
Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China.
3
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
4
Department of Developmental Behavioral Pediatrics, First Hospital of Jilin University, Changchun, China.
5
Department of General Surgery, Capital Institute of Pediatrics Affiliated Children's Hospital, Beijing, China.
6
Department of Pathology, Capital Institute of Pediatrics Affiliated Children's Hospital, Beijing, China.
7
Reproductive Medicine Center, Clinical College of PLA Affiliated Anhui Medical University, Hefei, China.
8
Department of Pathophysiology, School of Preclinical Sciences, Guangxi Medical University, Nanning, China.
9
Obstetrics and Gynecology Hospital, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.
10
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
11
Department of General Surgery, Capital Institute of Pediatrics Affiliated Children's Hospital, Beijing, China. lilong23@126.com.

Abstract

PURPOSE:

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.

METHODS:

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

RESULTS:

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%).

CONCLUSION:

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.

PMID:
29261189
DOI:
10.1038/gim.2017.178
[Indexed for MEDLINE]

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