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Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (S...

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Autores principales: Bogenschutz, Eric L., Fox, Zac D., Farrell, Andrew, Wynn, Julia, Moore, Barry, Yu, Lan, Aspelund, Gudrun, Marth, Gabor, Yandell, Mark, Shen, Yufeng, Chung, Wendy K., Kardon, Gabrielle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703690/
https://www.ncbi.nlm.nih.gov/pubmed/33263113
http://dx.doi.org/10.1016/j.xhgg.2020.100008
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author Bogenschutz, Eric L.
Fox, Zac D.
Farrell, Andrew
Wynn, Julia
Moore, Barry
Yu, Lan
Aspelund, Gudrun
Marth, Gabor
Yandell, Mark
Shen, Yufeng
Chung, Wendy K.
Kardon, Gabrielle
author_facet Bogenschutz, Eric L.
Fox, Zac D.
Farrell, Andrew
Wynn, Julia
Moore, Barry
Yu, Lan
Aspelund, Gudrun
Marth, Gabor
Yandell, Mark
Shen, Yufeng
Chung, Wendy K.
Kardon, Gabrielle
author_sort Bogenschutz, Eric L.
collection PubMed
description The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple individuals and mutated genes are incompletely penetrant. This suggests that multiple genetic variants in combination, other not-yet-investigated classes of variants, and/or nongenetic factors contribute to CDH etiology. However, no studies have comprehensively investigated in affected individuals the contribution of all possible classes of variants throughout the genome to CDH etiology. In our study, we used a unique cohort of four individuals with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood and deep whole-genome sequencing to assess germline and somatic de novo and inherited SNVs, indels, and SVs. In each individual we found a different mutational landscape that included germline de novo and inherited SNVs and indels in multiple genes. We also found in two individuals a 343 bp deletion interrupting an annotated enhancer of the CDH-associated gene GATA4, and we hypothesize that this common SV (found in 1%–2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.
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spelling pubmed-77036902020-11-30 Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias Bogenschutz, Eric L. Fox, Zac D. Farrell, Andrew Wynn, Julia Moore, Barry Yu, Lan Aspelund, Gudrun Marth, Gabor Yandell, Mark Shen, Yufeng Chung, Wendy K. Kardon, Gabrielle HGG Adv Article The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple individuals and mutated genes are incompletely penetrant. This suggests that multiple genetic variants in combination, other not-yet-investigated classes of variants, and/or nongenetic factors contribute to CDH etiology. However, no studies have comprehensively investigated in affected individuals the contribution of all possible classes of variants throughout the genome to CDH etiology. In our study, we used a unique cohort of four individuals with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood and deep whole-genome sequencing to assess germline and somatic de novo and inherited SNVs, indels, and SVs. In each individual we found a different mutational landscape that included germline de novo and inherited SNVs and indels in multiple genes. We also found in two individuals a 343 bp deletion interrupting an annotated enhancer of the CDH-associated gene GATA4, and we hypothesize that this common SV (found in 1%–2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial. Elsevier 2020-08-14 /pmc/articles/PMC7703690/ /pubmed/33263113 http://dx.doi.org/10.1016/j.xhgg.2020.100008 Text en © 2020 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Bogenschutz, Eric L.
Fox, Zac D.
Farrell, Andrew
Wynn, Julia
Moore, Barry
Yu, Lan
Aspelund, Gudrun
Marth, Gabor
Yandell, Mark
Shen, Yufeng
Chung, Wendy K.
Kardon, Gabrielle
Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
title Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
title_full Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
title_fullStr Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
title_full_unstemmed Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
title_short Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
title_sort deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703690/
https://www.ncbi.nlm.nih.gov/pubmed/33263113
http://dx.doi.org/10.1016/j.xhgg.2020.100008
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