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Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

BACKGROUND: Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is...

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Autores principales: Jensen, Matthew, Tyryshkina, Anastasia, Pizzo, Lucilla, Smolen, Corrine, Das, Maitreya, Huber, Emily, Krishnan, Arjun, Girirajan, Santhosh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522054/
https://www.ncbi.nlm.nih.gov/pubmed/34657631
http://dx.doi.org/10.1186/s13073-021-00982-z
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author Jensen, Matthew
Tyryshkina, Anastasia
Pizzo, Lucilla
Smolen, Corrine
Das, Maitreya
Huber, Emily
Krishnan, Arjun
Girirajan, Santhosh
author_facet Jensen, Matthew
Tyryshkina, Anastasia
Pizzo, Lucilla
Smolen, Corrine
Das, Maitreya
Huber, Emily
Krishnan, Arjun
Girirajan, Santhosh
author_sort Jensen, Matthew
collection PubMed
description BACKGROUND: Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. METHODS: We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and “second-hit” variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. RESULTS: We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations in deletion carriers. CONCLUSIONS: Our results suggest a potential mechanism for how “second-hit” variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00982-z.
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spelling pubmed-85220542021-10-21 Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion Jensen, Matthew Tyryshkina, Anastasia Pizzo, Lucilla Smolen, Corrine Das, Maitreya Huber, Emily Krishnan, Arjun Girirajan, Santhosh Genome Med Research BACKGROUND: Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. METHODS: We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and “second-hit” variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. RESULTS: We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations in deletion carriers. CONCLUSIONS: Our results suggest a potential mechanism for how “second-hit” variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00982-z. BioMed Central 2021-10-18 /pmc/articles/PMC8522054/ /pubmed/34657631 http://dx.doi.org/10.1186/s13073-021-00982-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Jensen, Matthew
Tyryshkina, Anastasia
Pizzo, Lucilla
Smolen, Corrine
Das, Maitreya
Huber, Emily
Krishnan, Arjun
Girirajan, Santhosh
Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
title Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
title_full Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
title_fullStr Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
title_full_unstemmed Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
title_short Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
title_sort combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522054/
https://www.ncbi.nlm.nih.gov/pubmed/34657631
http://dx.doi.org/10.1186/s13073-021-00982-z
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