Insufficient gene expression and lost gene regulatory network may underlie the mechanism of Hirschsprung Disease in 5p–syndrome
Cri-du-chat syndrome (CDC, OMIM 123450) is a rare chromosomal syndrome that results from partial deletions on the short arm of chromosome 5, known as 5p minus. Substantial clinical and genetic heterogeneity were observed in CDC patients. Large efforts have been dedicated to correlating the deleted r...
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Elsevier
2025-02-01
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| Series: | Heliyon |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844025004591 |
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| author | Yizhao Luan Peng Li Yuanyuan Luo Hong Zhang Xiaochun Zhu Yan Zhang Aihua Yin Qiang Wu Chengwei Chai |
| author_facet | Yizhao Luan Peng Li Yuanyuan Luo Hong Zhang Xiaochun Zhu Yan Zhang Aihua Yin Qiang Wu Chengwei Chai |
| author_sort | Yizhao Luan |
| collection | DOAJ |
| description | Cri-du-chat syndrome (CDC, OMIM 123450) is a rare chromosomal syndrome that results from partial deletions on the short arm of chromosome 5, known as 5p minus. Substantial clinical and genetic heterogeneity were observed in CDC patients. Large efforts have been dedicated to correlating the deleted regions on 5p arm with observed symptoms in CDC patients. However, the genetic basis of many specific phenotypes, including the co-occurrence of Hirschsprung Disease (HSCR), have yet been clarified. Here, we conducted a study on two patients with CDC and HSCR using whole genome sequencing (WGS) analyses. Our WGS data confirmed the deletion regions on 5p associated with CDC and indicated potential unknown genetic mechanisms underlying HSCR. On the one hand, leveraging human single-cell atlas for developing enteric nervous system, we demonstrated that some affected genes in these two patients overlapped with those showing expression changes along the development pseudotime of enteric nervous cells (ENC) and overlapped with known HSCR genes including RET, NRG1, ERBB (ERBB2 and ERBB3), ITGB (ITGB1). On the other hand, integrating gene regulatory relationship estimated from single cell chromatin accessibility omics of enteric neurons, we found that the 5p deletion regions contained key cis-regulatory regions for HSCR-related gene GDNF. Taken together, our study reveals the genetic basis of HSCR or intestinal phenotypes in 5p minus patients, highlighting the importance of studying gene regulatory relationships to explain phenotypic heterogeneity. |
| format | Article |
| id | doaj-art-80ea7ccac6fd4fb28e34e8cfdc6d08ad |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Heliyon |
| spelling | doaj-art-80ea7ccac6fd4fb28e34e8cfdc6d08ad2025-01-31T05:12:00ZengElsevierHeliyon2405-84402025-02-01113e42079Insufficient gene expression and lost gene regulatory network may underlie the mechanism of Hirschsprung Disease in 5p–syndromeYizhao Luan0Peng Li1Yuanyuan Luo2Hong Zhang3Xiaochun Zhu4Yan Zhang5Aihua Yin6Qiang Wu7Chengwei Chai8Prenatal Diagnosis Centre, Maternal and Children Metabolic-Genetic Key Laboratory, Guangzhou Key Laboratory of Prenatal Screening and Diagnosis, Guangdong Women and Children Hospital, Guangzhou, 511442, ChinaDepartment of Pediatric General Surgery, Guangdong Women and Children Hospital, Guangzhou, 511442, ChinaDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, ChinaDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, ChinaDepartment of Pediatric General Surgery, Guangdong Women and Children Hospital, Guangzhou, 511442, ChinaPrenatal Diagnosis Centre, Maternal and Children Metabolic-Genetic Key Laboratory, Guangzhou Key Laboratory of Prenatal Screening and Diagnosis, Guangdong Women and Children Hospital, Guangzhou, 511442, ChinaPrenatal Diagnosis Centre, Maternal and Children Metabolic-Genetic Key Laboratory, Guangzhou Key Laboratory of Prenatal Screening and Diagnosis, Guangdong Women and Children Hospital, Guangzhou, 511442, China; Corresponding author.Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China; Corresponding author.Department of Pediatric General Surgery, Guangdong Women and Children Hospital, Guangzhou, 511442, China; Corresponding author.Cri-du-chat syndrome (CDC, OMIM 123450) is a rare chromosomal syndrome that results from partial deletions on the short arm of chromosome 5, known as 5p minus. Substantial clinical and genetic heterogeneity were observed in CDC patients. Large efforts have been dedicated to correlating the deleted regions on 5p arm with observed symptoms in CDC patients. However, the genetic basis of many specific phenotypes, including the co-occurrence of Hirschsprung Disease (HSCR), have yet been clarified. Here, we conducted a study on two patients with CDC and HSCR using whole genome sequencing (WGS) analyses. Our WGS data confirmed the deletion regions on 5p associated with CDC and indicated potential unknown genetic mechanisms underlying HSCR. On the one hand, leveraging human single-cell atlas for developing enteric nervous system, we demonstrated that some affected genes in these two patients overlapped with those showing expression changes along the development pseudotime of enteric nervous cells (ENC) and overlapped with known HSCR genes including RET, NRG1, ERBB (ERBB2 and ERBB3), ITGB (ITGB1). On the other hand, integrating gene regulatory relationship estimated from single cell chromatin accessibility omics of enteric neurons, we found that the 5p deletion regions contained key cis-regulatory regions for HSCR-related gene GDNF. Taken together, our study reveals the genetic basis of HSCR or intestinal phenotypes in 5p minus patients, highlighting the importance of studying gene regulatory relationships to explain phenotypic heterogeneity.http://www.sciencedirect.com/science/article/pii/S2405844025004591 |
| spellingShingle | Yizhao Luan Peng Li Yuanyuan Luo Hong Zhang Xiaochun Zhu Yan Zhang Aihua Yin Qiang Wu Chengwei Chai Insufficient gene expression and lost gene regulatory network may underlie the mechanism of Hirschsprung Disease in 5p–syndrome Heliyon |
| title | Insufficient gene expression and lost gene regulatory network may underlie the mechanism of Hirschsprung Disease in 5p–syndrome |
| title_full | Insufficient gene expression and lost gene regulatory network may underlie the mechanism of Hirschsprung Disease in 5p–syndrome |
| title_fullStr | Insufficient gene expression and lost gene regulatory network may underlie the mechanism of Hirschsprung Disease in 5p–syndrome |
| title_full_unstemmed | Insufficient gene expression and lost gene regulatory network may underlie the mechanism of Hirschsprung Disease in 5p–syndrome |
| title_short | Insufficient gene expression and lost gene regulatory network may underlie the mechanism of Hirschsprung Disease in 5p–syndrome |
| title_sort | insufficient gene expression and lost gene regulatory network may underlie the mechanism of hirschsprung disease in 5p syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2405844025004591 |
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