| Literature DB >> 28735859 |
Cinthya J Zepeda-Mendoza1, Jonas Ibn-Salem2, Tammy Kammin3, David J Harris4, Debra Rita5, Karen W Gripp6, Jennifer J MacKenzie7, Andrea Gropman8, Brett Graham9, Ranad Shaheen10, Fowzan S Alkuraya11, Campbell K Brasington12, Edward J Spence12, Diane Masser-Frye13, Lynne M Bird14, Erica Spiegel15, Rebecca L Sparkes16, Zehra Ordulu17, Michael E Talkowski18, Miguel A Andrade-Navarro2, Peter N Robinson19, Cynthia C Morton20.
Abstract
Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects' phenotypes. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements.Entities:
Keywords: HPO; balanced chromosomal rearrangement; chromatin conformation; chromosomal rearrangement; chromosomal translocation; clinical genetics; cytogenetics; diagnosis; distal effect; long-range effect
Mesh：
Year: 2017 PMID： 28735859 PMCID： PMC5544382 DOI： 10.1016/j.ajhg.2017.06.011
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025