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Review
. 2023 Jul;19(7):644-651.
doi: 10.1007/s12519-023-00686-x. Epub 2023 Mar 1.

Comprehensive characterization of the genetic landscape of familial Hirschsprung's disease

Jun Xiao  1   2 , Lu-Wen Hao  3 , Jing Wang  1   2 , Xiao-Si Yu  1   2 , Jing-Yi You  1   2 , Ze-Jian Li  1   2 , Han-Dan Mao  1   2 , Xin-Yao Meng  4   5 , Jie-Xiong Feng  6   7
Affiliations
Review

Comprehensive characterization of the genetic landscape of familial Hirschsprung's disease

Jun Xiao et al. World J Pediatr. 2023 Jul.

Abstract

Background: Hirschsprung's disease (HSCR) is one of the most common congenital digestive tract malformations and can cause stubborn constipation or gastrointestinal obstruction after birth, causing great physical and mental pain to patients and their families. Studies have shown that more than 20 genes are involved in HSCR, and most cases of HSCR are sporadic. However, the overall rate of familial recurrence in 4331 cases of HSCR is about 7.6%. Furthermore, familial HSCR patients show incomplete dominance. We still do not know the penetrance and genetic characteristics of these known risk genes due to the rarity of HSCR families.

Methods: To find published references, we used the title/abstract terms "Hirschsprung" and "familial" in the PubMed database and the MeSH terms "Hirschsprung" and "familial" in Web of Science. Finally, we summarized 129 HSCR families over the last 40 years.

Results: The male-to-female ratio and the percentage of short segment-HSCR in familial HSCR are much lower than in sporadic HSCR. The primary gene factors in the syndromic families are ret proto-oncogene (RET) and endothelin B receptor gene (EDNRB). Most families show incomplete dominance and are relevant to RET, and the RET mutation has 56% penetrance in familial HSCR. When one of the parents is a RET mutation carrier in an HSCR family, the offspring's recurrence risk is 28%, and the incidence of the offspring does not depend on whether the parent suffers from HSCR.

Conclusion: Our findings will help HSCR patients obtain better genetic counseling, calculate the risk of recurrence, and provide new insights for future pedigree studies.

Keywords: Genetic characteristics; Hirschsprung’s disease; Penetrance; Recurrence risk; Ret proto-oncogene (RET).

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Conflict of interest statement

No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Author Jie-Xiong Feng is a member of the Editorial Board for World Journal of Pediatrics. The paper was handled by the other Editor and has undergone rigorous peer review process. Author Jie-Xiong Feng was not involved in the journal's review of, or decisions related to, this manuscript. The authors have no conflict of interest to declare.

Figures

Fig. 1
Fig. 1
Preferred Reporting Items for Systematic Review and Meta-Analysis 2020 flow diagram for new systematic reviews that included searches of databases and registers only. HSCR Hirschsprung’s Disease
Fig. 2
Fig. 2
Number of different transmission patterns in RET mutation carriers. RET ret proto-oncogene
See this image and copyright information in PMC

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