ArticleEuropean journal of human genetics : EJHG2023
Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes.
Article in European journal of human genetics : EJHG, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 23 citations in OpenAlex.
- Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity.eLife · 2026Article
- OTUD5-related rare X-linked multiple congenital anomalies and neurodevelopmental syndrome: clinical findings and review of the literature.Neurogenetics · 2026Review
- Novel HUWE1-Related Neurodevelopmental Disorder: Genotypic and Phenotypic Expansion.International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience · 2026Article
- Case Report: A female case of X-linked intellectual disability syndrome type 34 caused by a NONO frameshift variant and literature review.Frontiers in pediatrics · 2026Article
- Before hormones: early sex-specific mechanisms shaping nervous system development, function, and postnatal disease susceptibility.Frontiers in behavioral neuroscience · 2026Review
- Lyonization of X-chromosome: New insights.Journal of genetics · 2026Review
- The impact of X chromosome inactivation on human health.Frontiers in genetics · 2026Review
- Hemizygous contiguous gene deletion within Xq28 that includes BCAP31, ABCD1, SRPK3 and SSR4: case report and literature review.Global medical genetics · 2025Article
- Xist condensates: perspectives for therapeutic intervention.Genome biology · 2025Review
- Genetic Investigation of Inherited Variants in a Multiplex Autism Spectrum Disorder (ASD) Family Using Whole-Genome Sequencing (WGS).Iranian journal of public health · 2025Article
- X-linked Deficiency in ELF4 in Females with Skewed X Chromosome Inactivation.Journal of clinical immunology · 2025Article
- Article
- Genomic Landscape of Chromosome X Factor VIII: From Hemophilia A in Males to Risk Variants in Females.Genes · 2024Article
- Emerging X-linked genes associated with neurodevelopmental disorders in females.Current opinion in neurobiology · 2024Review
- DDX3X syndrome: From clinical phenotypes to biological insights.Journal of neurochemistry · 2024Review
- 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
- Stochasticity in genetics and gene regulation.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- 2023 in the European Journal of Human Genetics.European journal of human genetics : EJHG · 2024Article
- Deep phenotyping and population-level data can help resolve genomic variants.European journal of human genetics : EJHG · 2023Article
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Authors and funding
29 authors at 12 institutions in 6 countries.
Funding
Abstract
Despite major advances in genome technology and analysis, >50% of patients with a neurodevelopmental disorder (NDD) remain undiagnosed after extensive evaluation. A point in case is our clinically heterogeneous cohort of NDD patients that remained undiagnosed after FRAXA testing, chromosomal microarray analysis and trio exome sequencing (ES). In this study, we explored the frequency of non-random X chromosome inactivation (XCI) in the mothers of male patients and affected females, the rationale being that skewed XCI might be masking previously discarded genetic variants found on the X chromosome. A multiplex fluorescent PCR-based assay was used to analyse the pattern of XCI after digestion with HhaI methylation-sensitive restriction enzyme. In families with skewed XCI, we re-evaluated trio-based ES and identified pathogenic variants and a deletion on the X chromosome. Linkage analysis and RT-PCR were used to further study the inactive X chromosome allele, and Xdrop long-DNA technology was used to define chromosome deletion boundaries. We found skewed XCI (>90%) in 16/186 (8.6%) mothers of NDD males and in 12/90 (13.3%) NDD females, far beyond the expected rate of XCI in the normal population (3.6%, OR = 4.10; OR = 2.51). By re-analyzing ES and clinical data, we solved 7/28 cases (25%) with skewed XCI, identifying variants in KDM5C, PDZD4, PHF6, TAF1, OTUD5 and ZMYM3, and a deletion in ATRX. We conclude that XCI profiling is a simple assay that targets a subgroup of patients that can benefit from re-evaluation of X-linked variants, thus improving the diagnostic yield in NDD patients and identifying new X-linked disorders.
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