A high-resolution X chromosome copy-number variation map in fertile females and women with primary ovarian insufficiency

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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.


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.


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 ~4% carrier incidence for X-linked disorders among fertile women.


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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We are grateful to the staff of the Pittsburgh Cytogenetics Laboratory for the technical assistance in aCGH studies, and Yu Ren for assistance in RNA sequencing. This work was supported by the National Institute of Child Health and Human Development (R01HD070647, R21HD074278, A.R).

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Correspondence to Svetlana A. Yatsenko MD or Aleksandar Rajkovic MD, PhD.

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The authors declare no conflicts of interest.

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Yatsenko, S.A., Wood-Trageser, M., Chu, T. et al. A high-resolution X chromosome copy-number variation map in fertile females and women with primary ovarian insufficiency. Genet Med 21, 2275–2284 (2019) doi:10.1038/s41436-019-0505-2

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  • X chromosome
  • primary ovarian insufficiency
  • high-resolution copy-number map
  • X-linked disease
  • fertility

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