Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.
- Loviglio MN Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.
- Beck CR Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- White JJ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Leleu M School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne), 1015, Lausanne, Switzerland.
- Harel T Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Guex N Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
- Niknejad A Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
- Bi W Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Chen ES Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Crespo I Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
- Yan J Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Charng WL Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Gu S Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Fang P Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Coban-Akdemir Z Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Shaw CA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Jhangiani SN Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
- Muzny DM Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
- Gibbs RA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Rougemont J School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne), 1015, Lausanne, Switzerland.
- Xenarios I Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.
- Lupski JR Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Reymond A Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland. Alexandre.Reymond@unil.ch.
- 2016-11-02
Published in:
- Genome medicine. - 2016
Chromatin conformation
Diagnostic
Disease network
Intellectual disability
Text mining
Animals
Embryo, Mammalian
Exome
Female
Gene Regulatory Networks
Genomics
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Phenotype
RNA, Messenger
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Smith-Magenis Syndrome
Transcription Factors
Transcriptome
English
BACKGROUND
Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors.
METHODS
We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes.
RESULTS
Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 -/- mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 -/- mouse model.
CONCLUSIONS
These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.
Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors.
METHODS
We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes.
RESULTS
Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 -/- mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 -/- mouse model.
CONCLUSIONS
These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s13073-016-0359-z
- PMID 27799067
- Persistent URL
- https://sonar.ch/global/documents/20481
Statistics
Document views: 46
File downloads:
- Full-text: 0