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A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome

The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matte...

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Autores principales: Pastor, Steven, Tran, Oanh, McGinn, Daniel E., Crowley, T. Blaine, Zackai, Elaine H., McDonald-McGinn, Donna M., Emanuel, Beverly S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498844/
https://www.ncbi.nlm.nih.gov/pubmed/36140835
http://dx.doi.org/10.3390/genes13091668
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author Pastor, Steven
Tran, Oanh
McGinn, Daniel E.
Crowley, T. Blaine
Zackai, Elaine H.
McDonald-McGinn, Donna M.
Emanuel, Beverly S.
author_facet Pastor, Steven
Tran, Oanh
McGinn, Daniel E.
Crowley, T. Blaine
Zackai, Elaine H.
McDonald-McGinn, Donna M.
Emanuel, Beverly S.
author_sort Pastor, Steven
collection PubMed
description The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matters, it is not well represented in the human reference genome. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo, hemizygous deletion approximately 3 Mbp in size occurring by non-allelic homologous recombination (NAHR) mediated by the LCR22s. The ability to fully delineate an individual’s 22q11.2 regional structure will likely be important for studies designed to assess an unaffected individual’s risk for generating rearrangements in germ cells, potentially leading to offspring with 22q11.2DS. Towards understanding these risk factors, optical mapping has been previously employed to successfully elucidate the structure and variation of LCR22s across 30 families affected by 22q11.2DS. The father in one of these families carries a t(11;22)(q23;q11) translocation. Surprisingly, it was determined that he is the parent-of-deletion-origin. NAHR, which occurred between his der(22) and intact chromosome 22, led to a 22q11.2 deletion in his affected child. The unaffected sibling of the proband with 22q11.2DS inherited the father’s normal chromosome 22, which did not aberrantly recombine. This unexpected observation definitively shows that haplotypes that engage in NAHR can also be inherited intact. This study is the first to identify all structures involving a rearranged chromosome 22 that also participates in NAHR leading to a 22q11.2 deletion.
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spelling pubmed-94988442022-09-23 A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome Pastor, Steven Tran, Oanh McGinn, Daniel E. Crowley, T. Blaine Zackai, Elaine H. McDonald-McGinn, Donna M. Emanuel, Beverly S. Genes (Basel) Article The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matters, it is not well represented in the human reference genome. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo, hemizygous deletion approximately 3 Mbp in size occurring by non-allelic homologous recombination (NAHR) mediated by the LCR22s. The ability to fully delineate an individual’s 22q11.2 regional structure will likely be important for studies designed to assess an unaffected individual’s risk for generating rearrangements in germ cells, potentially leading to offspring with 22q11.2DS. Towards understanding these risk factors, optical mapping has been previously employed to successfully elucidate the structure and variation of LCR22s across 30 families affected by 22q11.2DS. The father in one of these families carries a t(11;22)(q23;q11) translocation. Surprisingly, it was determined that he is the parent-of-deletion-origin. NAHR, which occurred between his der(22) and intact chromosome 22, led to a 22q11.2 deletion in his affected child. The unaffected sibling of the proband with 22q11.2DS inherited the father’s normal chromosome 22, which did not aberrantly recombine. This unexpected observation definitively shows that haplotypes that engage in NAHR can also be inherited intact. This study is the first to identify all structures involving a rearranged chromosome 22 that also participates in NAHR leading to a 22q11.2 deletion. MDPI 2022-09-17 /pmc/articles/PMC9498844/ /pubmed/36140835 http://dx.doi.org/10.3390/genes13091668 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pastor, Steven
Tran, Oanh
McGinn, Daniel E.
Crowley, T. Blaine
Zackai, Elaine H.
McDonald-McGinn, Donna M.
Emanuel, Beverly S.
A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome
title A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome
title_full A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome
title_fullStr A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome
title_full_unstemmed A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome
title_short A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome
title_sort novel non-allelic homologous recombination event in a parent with an 11;22 reciprocal translocation leading to 22q11.2 deletion syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9498844/
https://www.ncbi.nlm.nih.gov/pubmed/36140835
http://dx.doi.org/10.3390/genes13091668
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