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High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung’s disease

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Abstract

Purpose

Hirschsprung’s disease (HSCR) is the leading cause of neonatal functional intestinal obstruction, which has been identified in many familial cases. HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We present a genetic investigation of familial HSCR to clarify the genotype–phenotype relationship.

Methods

We performed whole exome sequencing (WES) on Illumina HiSeq X Ten platform to investigate genetic backgrounds of core family members, and identified the possibly harmful mutation genes. Mutation carriers and pedigree relatives were validated by Sanger sequencing for evaluating the gene penetrance.

Results

Four familial cases showed potential disease-relative variants in EDNRB and RET gene, accounting for all detection rate of 57.1%. Three familial cases exhibited strong pathogenic variants as frameshift or missense mutations in EDNRB gene. A novel c.367delinsTT mutation of EDNRB was identified in one family member. The other two EDNRB mutations, c.553G>A in family 2 and c.877delinsTT in family 5, have been reported in previous literatures. The penetrance of EDNRB variants was 33–50% according mutation carries. In family 6, the RET c.1858T>C (C620R) point mutation has previously been reported to cause HSCR, with 28.5% penetrance.

Conclusion

We identified a novel EDNRB (deleted C and inserted TT) mutation in this study using WES. Heterozygote variations in EDNRB gene were significantly enriched in three families and RET mutations were identified in one family. EDNRB variants showed an overall higher incidence and penetrance than RET in southern Chinese families cases.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

We would like to express our gratitude to the numerous patients, their families, and referring physicians who have participated in these studies and to the numerous members of our laboratories for their valuable contributions. We are grateful to Dr. Ma Jian for his valuable advice on this project and thank the Science and Technology Program of Guangzhou for providing financial support.

Funding

This study is financially supported by the Science and Technology Program of Guangzhou, China (Grant number: 202102080069).

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Author notes

  1. Hui-yang Ding and Wen Lei contributed equally to this work.

Authors and Affiliations

  1. Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China

    Hui-yang Ding, Shang-jie Xiao, Li-ke Yuan, Lu Xu, Jia-liang Zhou, Rong Huang, Yuan-long Fang, Qing-yuan Wang, Ying Zhang & Xiao-chun Zhu

  2. Maternal and Child Health Research Institute, Translational Medicine Center, Guangdong Women and Children Hospital, Guangzhou, 511400, China

    Wen Lei, Hua Deng & Liang Zhang

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  1. Hui-yang Ding
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Contributions

Study conception and design: LZ and XCZ. Patients information acquisition: LKY, LX, JLZ, and RH. Sequence experiment: HYD and WL. Analysis and data interpretation: YLF, QYW, and ZY. Drafting of the manuscript: HYD and WL. Critical revision: SJX and HD.

Corresponding authors

Correspondence to Liang Zhang or Xiao-chun Zhu.

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The authors declare no conflict of interest.

Ethical

The study was approved by the Guangdong Women and Children Hospital Ethics Committee (Number: 202001101).

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Ding, Hy., Lei, W., Xiao, Sj. et al. High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung’s disease. Pediatr Surg Int 40, 38 (2024). https://doi.org/10.1007/s00383-023-05620-w

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