Sex chromosome aneuploidy impacts on human gene expression and regulation: a systematic review

TL;DR

This paper reviews how extra or missing sex chromosomes affect gene expression and regulation, identifying key genes and networks involved in these disorders.

Contribution

The study systematically identifies dosage-sensitive genes and chromatin-related networks impacted by sex chromosome aneuploidy.

Findings

A core set of dosage-sensitive genes is recurrently impacted by SCAs across multiple tissues.

Three protein-protein interaction networks enriched for chromatin remodeling are identified as potential drivers of phenotypes.

Recent research has expanded beyond commonly studied SCAs and tissues, but gaps remain in karyotype and tissue diversity.

Abstract

Sex chromosome aneuploidies (SCAs) are collectively common genetic disorders that impact diverse body systems. The molecular mechanisms by which an extra or missing sex chromosome increases clinical risk are not fully understood, but they likely involve imbalances in expression and regulation of dosage-sensitive genes. There has been a recent surge in transcriptomic and epigenomic studies on genomic effects of SCAs - making it an opportune time to: (i) map existing knowledge of SCA impacts on gene expression and regulation; (ii) resolve consensus findings on SCA dosage-sensitive genes; and (iii) define gaps and high priority areas for future research.

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (protocol registered on the international Prospective Register of Systematic Reviews PROSPERO CRD42024473984), we searched nine databases and screened the titles and abstracts of 2421 records, thoroughly evaluated 161 full-text articles, and identified 57 eligible studies for abstraction of methodological features and results.

Our review spans 18 years of research and encompasses samples from 930 individuals with SCAs and 2192 euploidic controls. The recent acceleration in publication rates outstrips that for biomedical research as a whole. Studies have only recently started to diversify away from the most studied SCAs (47,XXY and 45,X karyotypes), tissue types (blood-derived, gonadal) and measurement methods (transcriptomic analysis by RNAseq). We identify a core set of dosage-sensitive genes that are recurrently impacted by SCAs across multiple tissues. These genes concentrate in 3 protein-protein interaction networks that are predominantly enriched for chromatin remodelling, and represent candidate drivers of downstream phenotypes.

This systematic review of SCA impacts on the human genome helps to target the future research efforts that are now needed to (i) address existing knowledge gaps by diversifying the karyotypes, tissues and genomic features analyzed, and (ii) test the causal role for recurrently dysregulated genes. Meeting these goals would provide a molecular foundation to drive both basic and clinical understanding of sex chromosome influences on human phenotypic variation.

The online version contains supplementary material available at 10.1186/s10020-025-01404-1.

Figures