Identification of rare de novo epigenetic variations in congenital disorders

Autor: Bruce D. Gelb, Silvia De Rubeis, Ricky S. Joshi, Nihir Patel, William S. Gibson, Han G. Brunner, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Hui Mei, Corey T. Watson, Joseph D. Buxbaum, Gabriela Soares, Mafalda Barbosa, Fátima Lopes, Patrícia Maciel, Bharati Jadhav, Lisa Edelmann, Alejandro Martin-Trujillo, Jennifer Reichert, Dorothy E. Grice, Chloe Tessereau, Paras Garg, Kelsey Chetnik, Andrew J. Sharp
Přispěvatelé: Universidade do Minho, MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Epigenomics
Male
General Physics and Astronomy
Datasets as Topic
Genome
Epigenesis
Genetic
Cohort Studies
0302 clinical medicine
Loss of Function Mutation
lcsh:Science
Child
Epigenesis
Genetics
0303 health sciences
education.field_of_study
Multidisciplinary
LYNCH SYNDROME
Middle Aged
3. Good health
GENOME ANALYSIS
030220 oncology & carcinogenesis
Child
Preschool
DNA methylation
EPIMUTATIONS
Adult
Adolescent
Sequence analysis
Science
Population
Genomics
HEART-DISEASE
Biology
General Biochemistry
Genetics and Molecular Biology
Article
Congenital Abnormalities
03 medical and health sciences
Young Adult
All institutes and research themes of the Radboud University Medical Center
Genetic variation
Humans
Epigenetics
education
Gene
030304 developmental biology
EPIGENOME-WIDE ASSOCIATION
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
Science & Technology
MUTATIONS
Genome
Human
Sequence Analysis
RNA
Point mutation
Infant
Newborn
Infant
General Chemistry
Sequence Analysis
DNA
DNA Methylation
GENE
Human genetics
INDIVIDUALS
030104 developmental biology
Neurodevelopmental Disorders
Case-Control Studies
CGG-REPEAT
Human genome
lcsh:Q
Zdroj: Nature Communications, 9, pp.
Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018)
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação
instacron:RCAAP
Nature Communications, 9:2064. Nature Publishing Group
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
Nature Communications
Nature Communications, 9,
ISSN: 2041-1723
Popis: Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.
The authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.
The authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.
Databáze: OpenAIRE
Externí odkaz: