Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

Genome Medicine

Ioannis Xenarios¹  Alexandre Reymond¹  Maria Nicla Loviglio¹  Edward S. Chen²  Wu-Lin Charng²  Tamar Harel²  Jiong Yan²  Weimin Bi²  James R. Lupski²  Janson J. White²  Christine R. Beck²  Shen Gu²  Ping Fang²  Zeynep Coban-Akdemir²  Richard A. Gibbs²  Chad A. Shaw²  Shalini N. Jhangiani³  Donna M. Muzny³  Marion Leleu⁴  Jacques Rougemont⁴  Anne Niknejad⁵  Isaac Crespo⁵  Nicolas Guex⁵ 

[1] Center for Integrative Genomics, University of Lausanne;Department of Molecular and Human Genetics, Baylor College of Medicine;Human Genome Sequencing Center, Baylor College of Medicine;School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne);Swiss Institute of Bioinformatics (SIB);

关键词: Diagnostic;    Intellectual disability;    Chromatin conformation;    Text mining;    Disease network;   

DOI  :  10.1186/s13073-016-0359-z

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown