ArticleMolecular neurobiology2020
Understanding the Landscape of X-linked Variants Causing Intellectual Disability in Females Through Extreme X Chromosome Inactivation Skewing.
Article in Molecular neurobiology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 41 citations in OpenAlex.
- c.7156C > T p.(Gln2386*) variant causes loss-of-function of the USP9X gene in a female-restricted X-linked syndromic intellectual disability: a case report.Journal of medical case reports · 2025Article
- Early-onset Parkinson's disease in a patient with a rare homozygous pathogenic GBA1 variant and no Gaucher disease symptoms.Neurogenetics · 2025Article
- Assessment of XCI skewing and demonstration of XCI escape region based on single-cell RNA sequencing: comparison between female Grave's disease and control.BMC molecular and cell biology · 2025Article
- The roles of TAF1 in neuroscience and beyond.Royal Society open science · 2024Review
- Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders.Disease models & mechanisms · 2024Article
- Co-occurrence of PRKN and SYNJ1 variants in Early-Onset Parkinson's disease.Metabolic brain disease · 2024Article
- Distributed X chromosome inactivation in brain circuitry is associated with X-linked disease penetrance of behavior.Cell reports · 2024Article
- Characteristics and clinical evaluation of X chromosome translocations.Molecular cytogenetics · 2023Article
- Skewed X-inactivation is associated with retinal dystrophy in female carriers ofLife science alliance · 2023Article
- Identification of USP9X as a leukemia susceptibility gene.Blood advances · 2023Article
- A novel quantitative targeted analysis of X-chromosome inactivation (XCI) using nanopore sequencing.Scientific reports · 2023Article
- Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children.Molecular medicine (Cambridge, Mass.) · 2022Article
- A de novo YY1 missense variant expanding the Gabriele-de Vries syndrome phenotype and affecting X-chromosome inactivation.Metabolic brain disease · 2022Article
- Case Report:Frontiers in genetics · 2022Article
- The Impact of X-Chromosome Inactivation on Phenotypic Expression of X-Linked Neurodevelopmental Disorders.Brain sciences · 2021Review
- Missense variant contribution to USP9X-female syndrome.NPJ genomic medicine · 2020Article
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Authors and funding
14 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Intellectual disability (ID) affects 30% more males than females. This sex bias can be attributed to the enrichment of genes on the X chromosome playing essential roles in the central nervous system and their hemizygous state on males. Moreover, as a result of X chromosome inactivation (XCI), most genes on one of the X chromosomes in female somatic cells are epigenetically silenced, so that females carrying X-linked variants are not expected to be so severely affected as males. Consequently, the knowledge about X-linked ID (XLID) in females is still scarce. Herein, we used extreme XCI skewing (≥ 90%) to predict X-linked variants in females with idiopathic ID. XCI profiles from 53 probands were estimated from blood and buccal mucosa through a methylation-sensitive AR/RP2 assay. DNA samples with extreme XCI skewing were then submitted to array-comparative genomic hybridization and whole-exome sequencing. Seven females (13.2%) exhibited extreme XCI skewing, a percentage significantly higher than expected for healthy females in our population. XLID-potentially related variants were identified in five patients with extreme XCI skewing, including one pathogenic rstructural rearrangement [der(X) chromosome from a t(X;2)] and four single nucleotide variants in NLGN4X, HDAC8, TAF1, and USP9X genes, two of which affecting XCI escape genes. XCI skewing showed to be an outstanding approach for the characterization of molecular mechanisms underlying XLID in females. Beyond expanding the spectrum of variants/phenotypes associated with ID, our results pointed to compensatory biological pathways underlying XCI and uncover new insights into the involvement of escape genes on XLID, impacting genetic counseling.
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