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 L Gropman; Brett H 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

Cinthya J. Zepeda-Mendoza, Jonas Ibn-Salem, Tammy Kammin, David J. Harris, Debra Rita, Karen W Gripp, Jennifer J MacKenzie, Andrea L Gropman, Brett H 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-NavarroPeter N. Robinson, Cynthia C. Morton^*

^*Corresponding author for this work

Division of Evolution, Infection and Genomics

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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.

Original language	English
Journal	American Journal of Human Genetics
Early online date	20 Jul 2017
DOIs	https://doi.org/10.1016/j.ajhg.2017.06.011
Publication status	Published - 2017

Keywords

Balanced chromosomal rearrangement
Chromatin conformation
Chromosomal rearrangement
Chromosomal translocation
Clinical genetics
Cytogenetics
Diagnosis
Distal effect
HPO
Long-range effect

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10.1016/j.ajhg.2017.06.011

PredictionPosEffecNonCodRearr_AJHG_CZetal_revision_70717Accepted author manuscript, 185 KB

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Zepeda-Mendoza, C. J., Ibn-Salem, J., Kammin, T., Harris, D. J., Rita, D., Gripp, K. W., MacKenzie, J. J., Gropman, A. L., Graham, B. H., Shaheen, R., Alkuraya, F. S., Brasington, C. K., Spence, E. J., Masser-Frye, D., Bird, L. M., Spiegel, E., Sparkes, R. L., Ordulu, Z., Talkowski, M. E., ... Morton, C. C. (2017). Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements. American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2017.06.011

@article{e252b2070b274e0c8b5f2aa2f7c89ced,

title = "Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements",

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 = "Balanced chromosomal rearrangement, Chromatin conformation, Chromosomal rearrangement, Chromosomal translocation, Clinical genetics, Cytogenetics, Diagnosis, Distal effect, HPO, Long-range effect",

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

year = "2017",

doi = "10.1016/j.ajhg.2017.06.011",

language = "English",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

}

Zepeda-Mendoza, CJ, Ibn-Salem, J, Kammin, T, Harris, DJ, Rita, D, Gripp, KW, MacKenzie, JJ, Gropman, AL, Graham, BH, Shaheen, R, Alkuraya, FS, Brasington, CK, Spence, EJ, Masser-Frye, D, Bird, LM, Spiegel, E, Sparkes, RL, Ordulu, Z, Talkowski, ME, Andrade-Navarro, MA, Robinson, PN & Morton, CC 2017, 'Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements', American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2017.06.011

TY - JOUR

T1 - Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements

AU - Zepeda-Mendoza, Cinthya J.

AU - Ibn-Salem, Jonas

AU - Kammin, Tammy

AU - Harris, David J.

AU - Rita, Debra

AU - Gripp, Karen W

AU - MacKenzie, Jennifer J

AU - Gropman, Andrea L

AU - Graham, Brett H

AU - Shaheen, Ranad

AU - Alkuraya, Fowzan S.

AU - Brasington, Campbell K.

AU - Spence, Edward J.

AU - Masser-Frye, Diane

AU - Bird, Lynne M.

AU - Spiegel, Erica

AU - Sparkes, Rebecca L.

AU - Ordulu, Zehra

AU - Talkowski, Michael E

AU - Andrade-Navarro, Miguel A.

AU - Robinson, Peter N.

AU - Morton, Cynthia C.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Balanced chromosomal rearrangement

KW - Chromatin conformation

KW - Chromosomal rearrangement

KW - Chromosomal translocation

KW - Clinical genetics

KW - Cytogenetics

KW - Diagnosis

KW - Distal effect

KW - HPO

KW - Long-range effect

UR - http://www.scopus.com/inward/record.url?scp=85025477550&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2017.06.011

DO - 10.1016/j.ajhg.2017.06.011

M3 - Article

AN - SCOPUS:85025477550

SN - 0002-9297

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

ER -

Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements

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Keywords

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Manchester Centre for Audiology and Deafness (ManCAD)

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Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements

Abstract

Keywords

Access to Document

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Manchester Centre for Audiology and Deafness (ManCAD)

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