Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements

Cinthya J Zepeda-Mendoza; Jonas Ibn-Salem; Tammy Kammin; David J Harris; Debra Rita; Karen W Gripp; Jennifer J MacKenzie; Andrea Gropman; Brett Graham; Ranad Shaheen; Fowzan S Alkuraya; Campbell K Brasington; Edward J Spence; Diane Masser-Frye; Lynne M Bird; Erica Spiegel; Rebecca L Sparkes; Zehra Ordulu; Michael E Talkowski; Miguel A Andrade-Navarro; Peter N Robinson; Cynthia C Morton

doi:10.1016/j.ajhg.2017.06.011

Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements

Am J Hum Genet. 2017 Aug 3;101(2):206-217. doi: 10.1016/j.ajhg.2017.06.011. Epub 2017 Jul 20.

Authors

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

Affiliations

¹ Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
² Johannes Gutenberg University, Mainz 55122, Germany.
³ Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ Harvard Medical School, Boston, MA 02115, USA; Boston Children's Hospital, Boston, MA 02115, USA.
⁵ Cytogenetics Lab, ACL laboratories, Rosemont, IL 60018, USA.
⁶ Nemours Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA.
⁷ Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁸ Children's National Medical Center, Washington, DC 20010, USA.
⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia.
¹¹ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
¹² Clinical Genetics Division, Department of Pediatrics, Levine Children's Hospital at Carolinas Medical Center, Charlotte, NC 28203, USA.
¹³ Genetics and Dysmorphology, Rady Children's Hospital San Diego, San Diego, CA 92123, USA.
¹⁴ Genetics and Dysmorphology, Rady Children's Hospital San Diego, San Diego, CA 92123, USA; University of California, San Diego, La Jolla, CA 92093, USA.
¹⁵ Maternal Fetal Medicine, Columbia University Medical Center, New York, NY 10032, USA.
¹⁶ Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
¹⁷ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁸ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Neurology and Psychiatry and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹⁹ Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
²⁰ Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston, MA 02115, USA; Johannes Gutenberg University, Mainz 55122, Germany; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Evolution and Genomic Science, School of Biological Sciences, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. Electronic address: [email protected].

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.

Keywords: HPO; balanced chromosomal rearrangement; chromatin conformation; chromosomal rearrangement; chromosomal translocation; clinical genetics; cytogenetics; diagnosis; distal effect; long-range effect.

MeSH terms

Chromosomal Position Effects / genetics*
Chromosome Breakpoints
Chromosome Mapping*
Chromosomes, Human / genetics*
Gene Expression Regulation / genetics
Gene Rearrangement / genetics*
Genetic Predisposition to Disease / genetics*
Genetic Variation / genetics
Genome, Human / genetics*
Humans
In Situ Hybridization, Fluorescence
Karyotype
Phenotype
Translocation, Genetic / genetics

Abstract

MeSH terms

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