The Role of Cilia and the Complex Genetics of Congenital Heart Disease
<p dir="ltr">Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse chemical mutagenesis screen for mutations causing CHD yielded a preponde...
محفوظ في:
| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , |
| منشور في: |
2024
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| _version_ | 1864513522516361216 |
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| author | George C. Gabriel (11469982) |
| author2 | Madhavi Ganapathiraju (14244737) Cecilia W. Lo (10689741) |
| author2_role | author author |
| author_facet | George C. Gabriel (11469982) Madhavi Ganapathiraju (14244737) Cecilia W. Lo (10689741) |
| author_role | author |
| dc.creator.none.fl_str_mv | George C. Gabriel (11469982) Madhavi Ganapathiraju (14244737) Cecilia W. Lo (10689741) |
| dc.date.none.fl_str_mv | 2024-05-09T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1146/annurev-genom-121222-105345 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/The_Role_of_Cilia_and_the_Complex_Genetics_of_Congenital_Heart_Disease/31444072 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Cardiovascular medicine and haematology complex genetics cilia congenital heart disease |
| dc.title.none.fl_str_mv | The Role of Cilia and the Complex Genetics of Congenital Heart Disease |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse chemical mutagenesis screen for mutations causing CHD yielded a preponderance of cilia-related genes, pointing to a central role for cilia in CHD pathogenesis. The genes uncovered by the screen included genes that regulate ciliogenesis and cilia-transduced cell signaling as well as many that mediate endocytic trafficking, a cell process critical for both ciliogenesis and cell signaling. The clinical relevance of these findings is supported by whole-exome sequencing analysis of CHD patients that showed enrichment for pathogenic variants in ciliome genes. Surprisingly, among the ciliome CHD genes recovered were many that encoded direct protein–protein interactors. Assembly of the CHD genes into a protein–protein interaction network yielded a tight interactome that suggested this protein–protein interaction may have functional importance and that its disruption could contribute to the pathogenesis of CHD. In light of these and other findings, we propose that an interactome enriched for ciliome genes may provide the genomic context for the complex genetics of CHD and its often-observed incomplete penetrance and variable expressivity.</p><h2 dir="ltr">Other Information</h2><p dir="ltr">Published in: Annual Review of Genomics and Human Genetics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1146/annurev-genom-121222-105345" target="_blank">https://dx.doi.org/10.1146/annurev-genom-121222-105345</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_2ad746a2936ee0dfa4dd194c20bef1d8 |
| identifier_str_mv | 10.1146/annurev-genom-121222-105345 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/31444072 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | The Role of Cilia and the Complex Genetics of Congenital Heart DiseaseGeorge C. Gabriel (11469982)Madhavi Ganapathiraju (14244737)Cecilia W. Lo (10689741)Biological sciencesGeneticsBiomedical and clinical sciencesCardiovascular medicine and haematologycomplex geneticsciliacongenital heart disease<p dir="ltr">Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse chemical mutagenesis screen for mutations causing CHD yielded a preponderance of cilia-related genes, pointing to a central role for cilia in CHD pathogenesis. The genes uncovered by the screen included genes that regulate ciliogenesis and cilia-transduced cell signaling as well as many that mediate endocytic trafficking, a cell process critical for both ciliogenesis and cell signaling. The clinical relevance of these findings is supported by whole-exome sequencing analysis of CHD patients that showed enrichment for pathogenic variants in ciliome genes. Surprisingly, among the ciliome CHD genes recovered were many that encoded direct protein–protein interactors. Assembly of the CHD genes into a protein–protein interaction network yielded a tight interactome that suggested this protein–protein interaction may have functional importance and that its disruption could contribute to the pathogenesis of CHD. In light of these and other findings, we propose that an interactome enriched for ciliome genes may provide the genomic context for the complex genetics of CHD and its often-observed incomplete penetrance and variable expressivity.</p><h2 dir="ltr">Other Information</h2><p dir="ltr">Published in: Annual Review of Genomics and Human Genetics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1146/annurev-genom-121222-105345" target="_blank">https://dx.doi.org/10.1146/annurev-genom-121222-105345</a></p>2024-05-09T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1146/annurev-genom-121222-105345https://figshare.com/articles/journal_contribution/The_Role_of_Cilia_and_the_Complex_Genetics_of_Congenital_Heart_Disease/31444072CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/314440722024-05-09T06:00:00Z |
| spellingShingle | The Role of Cilia and the Complex Genetics of Congenital Heart Disease George C. Gabriel (11469982) Biological sciences Genetics Biomedical and clinical sciences Cardiovascular medicine and haematology complex genetics cilia congenital heart disease |
| status_str | publishedVersion |
| title | The Role of Cilia and the Complex Genetics of Congenital Heart Disease |
| title_full | The Role of Cilia and the Complex Genetics of Congenital Heart Disease |
| title_fullStr | The Role of Cilia and the Complex Genetics of Congenital Heart Disease |
| title_full_unstemmed | The Role of Cilia and the Complex Genetics of Congenital Heart Disease |
| title_short | The Role of Cilia and the Complex Genetics of Congenital Heart Disease |
| title_sort | The Role of Cilia and the Complex Genetics of Congenital Heart Disease |
| topic | Biological sciences Genetics Biomedical and clinical sciences Cardiovascular medicine and haematology complex genetics cilia congenital heart disease |