title: Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.
authors: Maria Nicla
authors: MN
authors: Loviglio
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Christine R
authors: CR
authors: Beck
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Janson J
authors: JJ
authors: White
authors: School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne), 1015, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
authors: Marion
authors: M
authors: Leleu
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Tamar
authors: T
authors: Harel
authors: Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
authors: Nicolas
authors: N
authors: Guex
authors: Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
authors: Anne
authors: A
authors: Niknejad
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Weimin
authors: W
authors: Bi
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Edward S
authors: ES
authors: Chen
authors: Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
authors: Isaac
authors: I
authors: Crespo
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.|Laboratory Medicine Program, UHN, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5G 2C4, Canada.
authors: Jiong
authors: J
authors: Yan
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Wu-Lin
authors: WL
authors: Charng
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Shen
authors: S
authors: Gu
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.|Present address: WuXiNextCODE, 101Main Street, Cambridge, MA, 02142, USA.
authors: Ping
authors: P
authors: Fang
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Zeynep
authors: Z
authors: Coban-Akdemir
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Chad A
authors: CA
authors: Shaw
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Shalini N
authors: SN
authors: Jhangiani
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Donna M
authors: DM
authors: Muzny
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
authors: Richard A
authors: RA
authors: Gibbs
authors: School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne), 1015, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
authors: Jacques
authors: J
authors: Rougemont
authors: Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), 1015, Lausanne, Switzerland.
authors: Ioannis
authors: I
authors: Xenarios
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.|Texas Children's Hospital, Houston, TX, 77030, USA.
authors: James R
authors: JR
authors: Lupski
authors: Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland. Alexandre.Reymond@unil.ch.
authors: Alexandre
authors: A
authors: Reymond
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059472:Exome / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058496:Smith-Magenis Syndrome / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*; D059467:Transcriptome
chemical_list: C431552:RAI1 protein, human; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors
keywords: Chromatin conformation; Diagnostic; Disease network; Intellectual disability; Text mining