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KDM5C
lysine demethylase 5C
KDM5C is located on the short (p) arm of chromosome X, at band Xp11.22. Arm ratio per GRCh38 - banding schematic.
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Overview
KDM5C is located on the X chromosome and encodes lysine demethylase 5C, an enzyme that regulates gene expression through chromatin modification. The protein removes methyl groups from lysine 4 of histone H3, a modification associated with active gene transcription. Because KDM5C resides on the X chromosome, pathogenic variants typically affect males more severely than females, who generally have a second, functional copy of the gene. The gene plays a particularly important role during brain development, where precise control of gene expression is essential for neuronal differentiation and connectivity. Variants in KDM5C have been identified in individuals with intellectual disability, developmental delay, and neurological features, leading to its inclusion in multiple NHS genomic medicine panels.
What the gene does
The KDM5C protein functions as a histone demethylase, specifically targeting trimethylated and dimethylated lysine 4 on histone H3 (H3K4me3 and H3K4me2). These histone modifications typically mark gene promoters and enhancers as transcriptionally active. By removing these methyl marks, KDM5C acts as a transcriptional repressor, silencing genes that should not be expressed in particular cell types or developmental stages. The enzyme operates within multiprotein complexes that coordinate chromatin remodelling and gene regulation. In neurons, KDM5C influences the expression of genes involved in synaptic function, neuronal migration, and dendritic spine formation. The protein's catalytic activity depends on iron and alpha-ketoglutarate as cofactors, linking its function to cellular metabolism. Research suggests that KDM5C plays a particularly critical role during early brain development, where it helps establish and maintain appropriate patterns of gene expression in differentiating neural cells. Disruption of this regulatory mechanism can lead to aberrant gene expression programmes that interfere with normal cognitive development.
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Chromosome location
KDM5C is located at position Xp11.22 on the short arm of the X chromosome. This chromosomal region contains numerous genes associated with neurodevelopmental conditions. The gene's position on the X chromosome means that males, who carry only one X chromosome, are hemizygous for KDM5C and therefore more vulnerable to the effects of pathogenic variants. Females carry two X chromosomes, and in cells where the chromosome bearing a pathogenic variant is preferentially active, they may exhibit milder features. The genomic structure spans multiple exons that encode the 1560-amino-acid protein.
Protein structure
The KDM5C protein is organised into several functional domains that coordinate its enzymatic activity and protein interactions. At the N-terminus, a JmjN domain (amino acids 14-55) works in concert with the JmjC domain (amino acids 468-634) to form the catalytic centre responsible for demethylase activity. An ARID domain (amino acids 79-169) mediates DNA binding, allowing the protein to recognise specific genomic regions. The protein contains three zinc finger domains: a PHD-type 1 finger (amino acids 326-372), a C5HC2 zinc finger (amino acids 707-759), and a PHD-type 2 finger (amino acids 1187-1248). These zinc fingers facilitate interactions with modified histones and other chromatin proteins, helping to target the enzyme to appropriate genomic locations. Multiple disordered regions are interspersed throughout the protein (amino acids 197-227, 1161-1181, 1316-1371, and 1444-1560), which often serve as flexible linkers or sites for regulatory post-translational modifications.
Key variants
Pathogenic variants in KDM5C disrupt the protein's ability to regulate gene expression appropriately. Many reported variants affect the catalytic JmjC domain or interfere with the protein's ability to recognise histone substrates. Because the gene follows an X-linked inheritance pattern, males with a single pathogenic variant typically exhibit more pronounced features than heterozygous females. The variant spectrum includes missense changes affecting critical functional residues, nonsense variants leading to truncated proteins, and deletions removing essential domains.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1510G>A | p.Val504Met | Pathogenic/Likely pathogenic | ★★☆☆ | KDM5C-related disorder |
c.1592C>T | p.Pro531Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Syndromic X-linked intellectual disability Claes-Jensen type |
c.1762C>T | p.Gln588Ter | Pathogenic | ★★☆☆ | Spastic paraplegia |
c.202C>T | p.Arg68Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2041C>T | p.Arg681Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.2427_2430del | p.Glu810fs | Pathogenic | ★★☆☆ | Syndromic X-linked intellectual disability Claes-Jensen type |
c.2575C>T | p.Gln859Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2908C>T | p.Gln970Ter | Pathogenic | ★★☆☆ | Syndromic X-linked intellectual disability Claes-Jensen type |
c.3392_3393del | p.Glu1131fs | Pathogenic | ★★☆☆ | Syndromic X-linked intellectual disability Claes-Jensen type |
c.974_975del | p.Tyr325fs | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in KDM5C are associated with a spectrum of neurodevelopmental presentations. Affected individuals may present with intellectual disability of varying severity, developmental delay, speech and language difficulties, and behavioural challenges. Some individuals exhibit features of hereditary spastic paraplegia, characterised by progressive lower-limb spasticity and weakness. Additional features reported in some cases include seizures, growth abnormalities, and dysmorphic facial features. The phenotypic variability likely reflects differences in the specific variant, its effect on protein function, and individual genetic background. Females with pathogenic variants may be asymptomatic or have milder features due to random X-chromosome inactivation, though some heterozygous females do exhibit clinical manifestations.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic KDM5C variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
Within the NHS Genomic Medicine Service, KDM5C appears on multiple nationally approved gene panels with green classification, indicating strong evidence for clinical validity. The gene is included in the Intellectual Disability panel (R29), reflecting its role in cognitive development. It also appears on the Childhood Onset Hereditary Spastic Paraplegia and Hereditary Spastic Paraplegia panels (R61), acknowledging the motor phenotypes observed in some affected individuals. KDM5C is additionally listed on the Fetal Anomalies panel (R21) and the Developmental Disorders Genotype-to-Phenotype (DDG2P) database, supporting its consideration in prenatal and paediatric genomic testing pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
Why are males more severely affected by KDM5C variants?
KDM5C is located on the X chromosome. Males have only one X chromosome, so a pathogenic variant in their single copy of KDM5C eliminates functional protein production. Females have two X chromosomes and often retain some functional protein from their unaffected copy, though the degree of protection varies depending on X-inactivation patterns.
What does a histone demethylase do?
Histone demethylases remove methyl chemical groups from histone proteins, which are the spools around which DNA wraps in cells. Removing these methyl marks changes how tightly DNA is packaged and whether particular genes can be read and activated, thereby controlling gene expression.
Is KDM5C testing available through the NHS?
Yes, KDM5C is included on several NHS Genomic Medicine Service gene panels with green classification, meaning testing may be offered when clinical features align with the associated conditions, such as unexplained intellectual disability or childhood-onset spastic paraplegia. A genetics specialist can determine eligibility based on individual presentation.