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Molecular Cytogenetics

, 7:4

First Online: 10 January 2014Received: 03 October 2013Accepted: 16 December 2013

Abstract

BackgroundMicroarray analysis has been used as the first-tier genetic testing to detect chromosomal imbalances and copy number variants CNVs for pediatric patients with intellectual and developmental disabilities ID-DD. To further investigate the candidate genes and underlying dosage-sensitive mechanisms related to ID, cytogenomic mapping of critical regions and bioinformatic mining of candidate brain-expressed genes BEGs and their functional interactions were performed. Critical regions of chromosomal imbalances and pathogenic CNVs were mapped by subtracting known benign CNVs from the Databases of Genomic Variants DGV and extracting smallest overlap regions with cases from DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources DECIPHER. BEGs from these critical regions were revealed by functional annotation using Database for Annotation, Visualization, and Integrated Discovery DAVID and by tissue expression pattern from Uniprot. Cross-region interrelations and functional networks of the BEGs were analyzed using Gene Relationships Across Implicated Loci GRAIL and Ingenuity Pathway Analysis IPA.

ResultsOf the 1,354 patients analyzed by oligonucleotide array comparative genomic hybridization aCGH, pathogenic abnormalities were detected in 176 patients including genomic disorders in 66 patients 37.5%, subtelomeric rearrangements in 45 patients 25.6%, interstitial imbalances in 33 patients 18.8%, chromosomal structural rearrangements in 17 patients 9.7% and aneuploidies in 15 patients 8.5%. Subtractive and extractive mapping defined 82 disjointed critical regions from the detected abnormalities. A total of 461 BEGs was generated from 73 disjointed critical regions. Enrichment of central nervous system specific genes in these regions was noted. The number of BEGs increased with the size of the regions. A list of 108 candidate BEGs with significant cross region interrelation was identified by GRAIL and five significant gene networks involving cell cycle, cell-to-cell signaling, cellular assembly, cell morphology, and gene expression regulations were denoted by IPA.

ConclusionsThese results characterized ID related cross-region interrelations and multiple networks of candidate BEGs from the detected genomic imbalances. Further experimental study of these BEGs and their interactions will lead to a better understanding of dosage-sensitive mechanisms and modifying effects of human mental development.

KeywordsIntellectual disability Critical regions Brain expressed genes Cross-region gene interrelation Functional network AbbreviationsaCGHArray comparative genomic hybridization

BEGsBrain-expressed genes

CNVCopy number variant pCNV, pathogenic

bCNVBenign

VOUSVariant of uncertain clinical significance

DDDevelopmental disability

IDIntellectual disability

LCRsLow copy number repeats

MCAMultiple congenital anomalies.

Electronic supplementary materialThe online version of this article doi:10.1186-1755-8166-7-4 contains supplementary material, which is available to authorized users.

Fang Xu, Lun Li contributed equally to this work.

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Autor: Fang Xu - Lun Li - Vincent P Schulz - Patrick G Gallagher - Bixia Xiang - Hongyu Zhao - Peining Li

Fuente: https://link.springer.com/







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