Journal
GENETICS IN MEDICINE
Volume 21, Issue 10, Pages 2275-2284Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41436-019-0505-2
Keywords
X chromosome; primary ovarian insufficiency; high-resolution copy-number map; X-linked disease; fertility
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Funding
- National Institute of Child Health and Human Development [R01HD070647, R21HD074278]
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Purpose: Sex-biased expression of genes on the X chromosome is accomplished by a complex mechanism of dosage regulation that leads to anatomical and physiological differences between males and females. Copy-number variations (CNVs) may impact the human genome by either affecting gene dosage or disturbing a chromosome structural and/or functional integrity. Methods: We performed a high-resolution CNV profiling to investigate the X chromosome integrity in cohorts of 269 fertile females and 111 women affected with primary ovarian insufficiency (POI) and assessed CNVs impact into functional and nonfunctional genomic elements. Results: In POI patients, we observed a 2.5-fold enrichment for rare CNVs comprising ovary-expressed genes, and genes implicated in autoimmune response and apoptotic signaling. Moreover, there was a higher prevalence of deletions encompassing genes that escape X inactivation, noncoding RNAs, and intergenic DNA sequences among POI females, highlighting structural differences between X chromosomes of fertile and POI females. Furthermore, we discovered a similar to 4% carrier incidence for X-linked disorders among fertile women. onclusion: We constructed a high-resolution map of female-specific CNVs that provides critical insights into the spectrum of human genetic variation, sex-specific disease risk factors, and reproductive potential. We discovered novel CNVs associated with ovarian dysfunction and support polygenic models for POI.
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