TY - JOUR
T1 - Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
AU - Jensen, Matthew
AU - Tyryshkina, Anastasia
AU - Pizzo, Lucilla
AU - Smolen, Corrine
AU - Das, Maitreya
AU - Huber, Emily
AU - Krishnan, Arjun
AU - Girirajan, Santhosh
N1 - Funding Information:
We are grateful to all members of the five families who participated in this study. We also thank Sherryann Wert, Melissa Berkowitz, and Tara Schmidlen (Coriell Institute) for their assistance in the generation of stable LCL lines; Craig Praul and Yuka Imamura (Penn State Genomics Core Facility) for assistance with designing the RNA sequencing strategy; Casey Brown (UPenn), Istvan Albert (Penn State), and Qunhua Li (Penn State) for assistance with statistical analysis of transcriptome data; and Jesse Gillis (CSHL), Dajiang Liu (Penn State), and members of the Girirajan lab for useful discussions and critical reading of the manuscript. We appreciate access to data from the Genotype-Tissue Expression (GTEx) Project, which was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal in January 2020.
Funding Information:
This work was supported by NIH R01-GM121907 and resources from the Huck Institutes of the Life Sciences to S.G. M.J. was supported by NIH T32-GM102057. A.T. was supported by NIH T32-LM012415. L.P. was supported by Fulbright Commission Uruguay-ANII. A.K. was supported by NIH R35-GM128765. The funding bodies had no role in the design of the study, the collection, analysis, and interpretation of data, or in writing the manuscript.
Funding Information:
We are grateful to all members of the five families who participated in this study. We also thank Sherryann Wert, Melissa Berkowitz, and Tara Schmidlen (Coriell Institute) for their assistance in the generation of stable LCL lines; Craig Praul and Yuka Imamura (Penn State Genomics Core Facility) for assistance with designing the RNA sequencing strategy; Casey Brown (UPenn), Istvan Albert (Penn State), and Qunhua Li (Penn State) for assistance with statistical analysis of transcriptome data; and Jesse Gillis (CSHL), Dajiang Liu (Penn State), and members of the Girirajan lab for useful discussions and critical reading of the manuscript. We appreciate access to data from the Genotype-Tissue Expression (GTEx) Project, which was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal in January 2020.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1186/s13073-021-00982-z
DO - 10.1186/s13073-021-00982-z
M3 - Article
C2 - 34657631
AN - SCOPUS:85117330086
VL - 13
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 163
ER -