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

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_1820D72F7FFD
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.
Périodique
Genome medicine
Auteur(s)
Loviglio M.N., Beck C.R., White J.J., Leleu M., Harel T., Guex N., Niknejad A., Bi W., Chen E.S., Crespo I., Yan J., Charng W.L., Gu S., Fang P., Coban-Akdemir Z., Shaw C.A., Jhangiani S.N., Muzny D.M., Gibbs R.A., Rougemont J., Xenarios I., Lupski J.R., Reymond A.
ISSN
1756-994X (Electronic)
ISSN-L
1756-994X
Statut éditorial
Publié
Date de publication
2016
Peer-reviewed
Oui
Volume
8
Numéro
1
Pages
105
Langue
anglais
Résumé
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.

Mots-clé
Chromatin conformation, Diagnostic, Disease network, Intellectual disability, Text mining
Pubmed
Open Access
Oui
Création de la notice
28/11/2016 14:53
Dernière modification de la notice
20/08/2019 12:48
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