{"doi":"10.1093/hmg/ddab221","title":"X-factors in human disease: impact of gene content and dosage regulation","abstract":"The gene content of the X and Y chromosomes has dramatically diverged during evolution. The ensuing dosage imbalance within the genome of males and females has led to unique chromosome-wide regulatory mechanisms with significant and sex-specific impacts on X-linked gene expression. X inactivation or silencing of most genes on one X chromosome chosen at random in females profoundly affects the manifestation of X-linked diseases, as males inherit a single maternal allele, while females express maternal and paternal alleles in a mosaic manner. An additional complication is the existence of genes that escape X inactivation and thus are ubiquitously expressed from both alleles in females. The mosaic nature of X-linked gene expression and the potential for escape can vary between individuals, tissues, cell types and stages of life. Our understanding of the specialized nature of X-linked genes and of the multilayer epigenetic regulation that influence their expression throughout the organism has been helped by molecular studies conducted by tissue-specific and single-cell-specific approaches. In turn, the definition of molecular events that control X silencing has helped develop new approaches for the treatment of some X-linked disorders. This review focuses on the peculiarities of the X chromosome genetic content and epigenetic regulation in shaping the manifestation of congenital and acquired X-linked disorders in a sex-specific manner.","journal":"Human Molecular Genetics","year":2021,"id":170237,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9472,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":317050,"name":"Xinxian Deng","orcid":"0000-0002-5007-218X","position":1,"is_corresponding":false},{"id":90408,"name":"Christine M. Distèche","orcid":"0000-0002-5433-495X","position":2,"is_corresponding":false},{"id":317048,"name":"He Fang","orcid":"0000-0001-9036-8092","position":0,"is_corresponding":true}],"reference_count":139,"raw_metadata":null,"created_at":"2026-07-18T23:46:19.728805Z","pmid":"34387327","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}