Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants
Abstract Background Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown. Methods We applied a combination of systematic experimental and bioinformatic metho...
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doaj-341d24bce7eb47ffb1b6902c15a0ce412020-12-06T12:10:44ZengBMCGenome Medicine1756-994X2019-12-0111111510.1186/s13073-019-0692-0Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variantsSjors Middelkamp0Judith M. Vlaar1Jacques Giltay2Jerome Korzelius3Nicolle Besselink4Sander Boymans5Roel Janssen6Lisanne de la Fonteijne7Ellen van Binsbergen8Markus J. van Roosmalen9Ron Hochstenbach10Daniela Giachino11Michael E. Talkowski12Wigard P. Kloosterman13Edwin Cuppen14Center for Molecular Medicine and Oncode Institute, University Medical Center UtrechtCenter for Molecular Medicine and Oncode Institute, University Medical Center UtrechtDepartment of Genetics, University Medical Center UtrechtCenter for Molecular Medicine and Oncode Institute, University Medical Center UtrechtCenter for Molecular Medicine and Oncode Institute, University Medical Center UtrechtCenter for Molecular Medicine and Oncode Institute, University Medical Center UtrechtCenter for Molecular Medicine and Oncode Institute, University Medical Center UtrechtCenter for Molecular Medicine and Oncode Institute, University Medical Center UtrechtDepartment of Genetics, University Medical Center UtrechtCenter for Molecular Medicine and Oncode Institute, University Medical Center UtrechtDepartment of Genetics, University Medical Center UtrechtMedical Genetics Unit, Department of Clinical and Biological Sciences, University of TorinoCenter for Genomic Medicine, Massachusetts General HospitalDepartment of Genetics, University Medical Center UtrechtCenter for Molecular Medicine and Oncode Institute, University Medical Center UtrechtAbstract Background Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown. Methods We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual disability harboring apparent de novo SVs, most with an inconclusive diagnosis after regular genetic testing. Results In 7 of these cases (18%), whole-genome sequencing analysis revealed disease-relevant complexities of the SVs missed in routine microarray-based analyses. We developed a computational tool to predict the effects on genes directly affected by SVs and on genes indirectly affected likely due to the changes in chromatin organization and impact on regulatory mechanisms. By combining these functional predictions with extensive phenotype information, candidate driver genes were identified in 16/39 (41%) patients. In 8 cases, evidence was found for the involvement of multiple candidate drivers contributing to different parts of the phenotypes. Subsequently, we applied this computational method to two cohorts containing a total of 379 patients with previously detected and classified de novo SVs and identified candidate driver genes in 189 cases (50%), including 40 cases whose SVs were previously not classified as pathogenic. Pathogenic position effects were predicted in 28% of all studied cases with balanced SVs and in 11% of the cases with copy number variants. Conclusions These results demonstrate an integrated computational and experimental approach to predict driver genes based on analyses of WGS data with phenotype association and chromatin organization datasets. These analyses nominate new pathogenic loci and have strong potential to improve the molecular diagnosis of patients with de novo SVs.https://doi.org/10.1186/s13073-019-0692-0Structural variationCopy number variantsNeurodevelopmental disordersIntellectual disabilityMultiple congenital anomaliesDriver genes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sjors Middelkamp Judith M. Vlaar Jacques Giltay Jerome Korzelius Nicolle Besselink Sander Boymans Roel Janssen Lisanne de la Fonteijne Ellen van Binsbergen Markus J. van Roosmalen Ron Hochstenbach Daniela Giachino Michael E. Talkowski Wigard P. Kloosterman Edwin Cuppen |
spellingShingle |
Sjors Middelkamp Judith M. Vlaar Jacques Giltay Jerome Korzelius Nicolle Besselink Sander Boymans Roel Janssen Lisanne de la Fonteijne Ellen van Binsbergen Markus J. van Roosmalen Ron Hochstenbach Daniela Giachino Michael E. Talkowski Wigard P. Kloosterman Edwin Cuppen Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants Genome Medicine Structural variation Copy number variants Neurodevelopmental disorders Intellectual disability Multiple congenital anomalies Driver genes |
author_facet |
Sjors Middelkamp Judith M. Vlaar Jacques Giltay Jerome Korzelius Nicolle Besselink Sander Boymans Roel Janssen Lisanne de la Fonteijne Ellen van Binsbergen Markus J. van Roosmalen Ron Hochstenbach Daniela Giachino Michael E. Talkowski Wigard P. Kloosterman Edwin Cuppen |
author_sort |
Sjors Middelkamp |
title |
Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants |
title_short |
Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants |
title_full |
Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants |
title_fullStr |
Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants |
title_full_unstemmed |
Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants |
title_sort |
prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2019-12-01 |
description |
Abstract Background Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown. Methods We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual disability harboring apparent de novo SVs, most with an inconclusive diagnosis after regular genetic testing. Results In 7 of these cases (18%), whole-genome sequencing analysis revealed disease-relevant complexities of the SVs missed in routine microarray-based analyses. We developed a computational tool to predict the effects on genes directly affected by SVs and on genes indirectly affected likely due to the changes in chromatin organization and impact on regulatory mechanisms. By combining these functional predictions with extensive phenotype information, candidate driver genes were identified in 16/39 (41%) patients. In 8 cases, evidence was found for the involvement of multiple candidate drivers contributing to different parts of the phenotypes. Subsequently, we applied this computational method to two cohorts containing a total of 379 patients with previously detected and classified de novo SVs and identified candidate driver genes in 189 cases (50%), including 40 cases whose SVs were previously not classified as pathogenic. Pathogenic position effects were predicted in 28% of all studied cases with balanced SVs and in 11% of the cases with copy number variants. Conclusions These results demonstrate an integrated computational and experimental approach to predict driver genes based on analyses of WGS data with phenotype association and chromatin organization datasets. These analyses nominate new pathogenic loci and have strong potential to improve the molecular diagnosis of patients with de novo SVs. |
topic |
Structural variation Copy number variants Neurodevelopmental disorders Intellectual disability Multiple congenital anomalies Driver genes |
url |
https://doi.org/10.1186/s13073-019-0692-0 |
work_keys_str_mv |
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