The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications
Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500–5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbin...
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| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2021.638093/full |
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| author | Anwarul Karim Clara Sze-Man Tang Clara Sze-Man Tang Paul Kwong-Hang Tam Paul Kwong-Hang Tam |
| author_facet | Anwarul Karim Clara Sze-Man Tang Clara Sze-Man Tang Paul Kwong-Hang Tam Paul Kwong-Hang Tam |
| author_sort | Anwarul Karim |
| collection | DOAJ |
| description | Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500–5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine. |
| first_indexed | 2024-12-19T16:29:05Z |
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| id | doaj.art-7d1ef26a22a84d318e7d41f10bebeff1 |
| institution | Directory Open Access Journal |
| issn | 2296-2360 |
| language | English |
| last_indexed | 2024-12-19T16:29:05Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pediatrics |
| spelling | doaj.art-7d1ef26a22a84d318e7d41f10bebeff12022-12-21T20:14:15ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602021-08-01910.3389/fped.2021.638093638093The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical ApplicationsAnwarul Karim0Clara Sze-Man Tang1Clara Sze-Man Tang2Paul Kwong-Hang Tam3Paul Kwong-Hang Tam4Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaLi Dak-Sum Research Center, The University of Hong Kong—Karolinska Institute Collaboration in Regenerative Medicine, Hong Kong, ChinaDepartment of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaLi Dak-Sum Research Center, The University of Hong Kong—Karolinska Institute Collaboration in Regenerative Medicine, Hong Kong, ChinaHirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500–5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.https://www.frontiersin.org/articles/10.3389/fped.2021.638093/fullHirschsprung diseaseaganglionosisgeneticsgenetic architecturerare variantsGWAS |
| spellingShingle | Anwarul Karim Clara Sze-Man Tang Clara Sze-Man Tang Paul Kwong-Hang Tam Paul Kwong-Hang Tam The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications Frontiers in Pediatrics Hirschsprung disease aganglionosis genetics genetic architecture rare variants GWAS |
| title | The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications |
| title_full | The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications |
| title_fullStr | The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications |
| title_full_unstemmed | The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications |
| title_short | The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications |
| title_sort | emerging genetic landscape of hirschsprung disease and its potential clinical applications |
| topic | Hirschsprung disease aganglionosis genetics genetic architecture rare variants GWAS |
| url | https://www.frontiersin.org/articles/10.3389/fped.2021.638093/full |
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