6533b86ffe1ef96bd12cde3f
RESEARCH PRODUCT
Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements.
Lynne M. BirdLynne M. BirdFowzan S. AlkurayaJennifer MackenzieRebecca SparkesAndrea L. GropmanCinthya J. Zepeda-mendozaCinthya J. Zepeda-mendozaBrett H. GrahamCampbell K. BrasingtonDiane Masser-fryeZehra OrduluDebra RitaKaren W. GrippEdward J. SpenceJonas Ibn-salemErica SpiegelRanad ShaheenMichael E. TalkowskiTammy KamminCynthia C. MortonMiguel A. Andrade-navarroPeter N. RobinsonDavid J. HarrisDavid J. Harrissubject
0301 basic medicineCandidate genediagnosis030105 genetics & heredityMedical and Health SciencescytogeneticsTranslocation Geneticchromosomal translocationChromosome Breakpointschromatin conformationbalanced chromosomal rearrangement2.1 Biological and endogenous factorsChromosomes HumanGenetics(clinical)AetiologyGenetics (clinical)In Situ HybridizationIn Situ Hybridization Fluorescencelong-range effectGeneticsGenetics & HeredityGene RearrangementGenomeChromosome MappingBiological SciencesChromatinPosition effectPhenotypeMedical geneticsHPOHumandistal effectmedicine.medical_specialtyChromosome engineeringchromosomal rearrangement/dk/atira/pure/subjectarea/asjc/1300/1311KaryotypeTranslocationChromosomal rearrangementBiologyChromosomesFluorescenceArticleChromosomal Position Effects03 medical and health sciencesGeneticClinical ResearchmedicineGeneticsHumansGenetic Predisposition to DiseaseGeneGenome HumanHuman GenomeGenetic Variation/dk/atira/pure/subjectarea/asjc/2700/2716030104 developmental biologyGene Expression RegulationHuman genomeclinical geneticsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-08-01 | American journal of human genetics |