Medicine:KDM5C-related neurodevelopmental disorder
| KDM5C-related neurodevelopmental disorder | |
|---|---|
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| A boy pictured smiling with unique facial features including deep-set eyes and strabismus, characteristics of KDM5C-related neurodevelopmental disorder | |
| Specialty | Neurology, medical genetics, gastroenterology, ophthalmology |
| Symptoms | Intellectual disability, language delay, hypotonia, hypertonia, autism, ADHD, seizures, short stature, strabismus, farsightedness, gastrointestinal issues, sleep disturbances, craniofacial differences |
| Usual onset | At conception |
| Duration | Lifelong |
| Causes | X-linked genetic mutation |
| Diagnostic method | Genetic testing |
KDM5C-related neurodevelopmental disorder (also known as Claes-Jensen syndrome) is a rare genetic condition caused by variants in the KDM5C gene, located on the X chromosome. The disorder primarily affects neurodevelopment and cognition, leading to a spectrum of intellectual, behavioral, and physical features that vary widely among affected individuals.
Presentation
The features of KDM5C-related neurodevelopmental disorder vary considerably, even among individuals with the same variant.[1] Commonly reported findings include:[2][1]
- Global developmental delay and intellectual disability
- Speech and language delay
- Hypotonia/hypertonia
- Behavioral differences(autism spectrum ADHD)
- Seizures
- Short stature
- Ocular findings(strabismus or farsightedness)
- Gastrointestinal issues
- Sleep disturbances
- Distinctive craniofacial features
KDM5C is an X-linked gene, meaning that males—who have one X chromosome—are typically more severely affected than females, who have two copies.[3] Males with pathogenic variants generally exhibit moderate to severe intellectual disability and multiple associated features. Females may present with milder symptoms, ranging from subtle cognitive differences to moderate developmental delay, or they may be asymptomatic carriers.[1]
Cause
KDM5C-related neurodevelopmental disorder follows an X-linked inheritance pattern. Males with a pathogenic KDM5C variant will pass the variant to all of their daughters and none of their sons. Females with one variant have a 50% chance of transmitting it to each child, regardless of sex.[4] Some cases arise de novo, meaning the variant occurs spontaneously and is not inherited from either parent. Rarely, germline mosaicism may explain recurrence in unaffected parents.[citation needed]
Molecular mechanism
KDM5C encodes a lysine-specific histone demethylase that regulates transcription by modifying histone H3 at lysine 4 (H3K4), a process critical for gene expression and chromatin organization.[5][6] The protein plays an important role in neurons, where it contributes to synaptic development, dendritic spine morphology, and neural network formation.[7]
Pathogenic variants in KDM5C can disrupt this regulation, resulting in widespread changes in gene expression that affect neuronal differentiation, metabolism, and plasticity.[8][9]
Diagnosis
Diagnosis requires genetic testing, typically through targeted gene panels, whole exome sequencing, or whole genome sequencing.[4]
Management
There is no cure for KDM5C-related neurodevelopmental disorder. Treatment focuses on managing individual symptoms through a multidisciplinary approach that may include:[4]
- Neurology (seizures or tone abnormalities)
- Speech, occupational, and physical therapy
- Behavioral and psychological interventions
- Gastroenterology (feeding or digestive issues)
- Ophthalmology and sleep medicine
Society and culture
Families and researchers affected by KDM5C-related conditions are supported by the KARES Foundation, a nonprofit organization that promotes awareness, supports research, and connects families worldwide. KARES also coordinates annual conferences and data-sharing initiatives with platforms such as RARE-X to accelerate understanding and therapeutic development.[10]
History
The condition was first described in the early 2000s by Dr. Stephan Claes and Dr. Lars Jensen, based on studies of males with X-linked intellectual disability and shared clinical characteristics.[11] It was initially termed Claes-Jensen syndrome, but as more individuals with KDM5C variants have been identified—particularly females and those with milder phenotypes—the broader and more inclusive term KDM5C-related neurodevelopmental disorder has become preferred.[1]
The KDM5C gene has also been referred to in earlier literature as JARID1C or SMCX.[12]
Research
Ongoing studies are exploring how KDM5C regulates gene expression in neurons and how its dysfunction leads to disease. Recent publications have highlighted its roles in WNT signaling, ribosomal gene regulation, and mitochondrial metabolism, all of which influence cognitive development.[9][13] Research is also examining potential therapeutic strategies targeting chromatin modifiers and histone demethylases.[14]
References
- ↑ 1.0 1.1 1.2 1.3 Carmignac, Virginie; Nambot, Sophie; Lehalle, Daphné; Callier, Patrick; Moortgat, Stephanie; Benoit, Valérie; Ghoumid, Jamal; Delobel, Bruno et al. (2020-05-29). "Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature". Clinical Genetics 98 (1): 43–55. doi:10.1111/cge.13755. ISSN 1399-0004. PMID 32279304.
- ↑ Ghasemi, Mohammad-Reza; Esmaeilizadeh, Zahra; Tehrani Fateh, Sahand; Sadeghi, Hossein; Bagheri, Saman; Hashemi-Gorji, Farzad; Sheikhi Nooshabadi, Morteza; Madannezhad, Rasoul et al. (2025-01-21). "Clinical Features and Genetic Characteristics of XLID Patients With KDM5C Gene Mutations: Insights on Phenotype-Genotype Correlations From 175 Previous Cases and Identification of a Novel Variant". Molecular Genetics & Genomic Medicine 13 (1). doi:10.1002/mgg3.70057. ISSN 2324-9269. PMID 39835750.
- ↑ Simensen, R. J.; Rogers, R. C.; Collins, J. S.; Abidi, F.; Schwartz, C. E.; Stevenson, R. E. (2012). "Short-term memory deficits in carrier females with KDM5C mutations". Genetic Counseling (Geneva, Switzerland) 23 (1): 31–40. ISSN 1015-8146. PMID 22611640.
- ↑ 4.0 4.1 4.2 "KDM5C-Related Neurodevelopmental Disorder - Symptoms, Causes, Treatment | NORD" (in en-US). https://rarediseases.org/rare-diseases/kdm5c-related-neurodevelopmental-disorder/.
- ↑ Iwase, Shigeki; Lan, Fei; Bayliss, Peter; de la Torre-Ubieta, Luis; Huarte, Maite; Qi, Hank H.; Whetstine, Johnathan R.; Bonni, Azad et al. (2007-03-23). "The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases". Cell 128 (6): 1077–1088. doi:10.1016/j.cell.2007.02.017. ISSN 0092-8674. PMID 17320160.
- ↑ Secombe, Julie; Li, Ling; Carlos, Leni; Eisenman, Robert N. (2007-03-01). "The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth". Genes & Development 21 (5): 537–551. doi:10.1101/gad.1523007. ISSN 0890-9369. PMID 17311883.
- ↑ Hatch, Hayden A. M.; Secombe, Julie (2021-09-29). "Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes-Jensen syndrome". The FEBS Journal 289 (24): 7776–7787. doi:10.1111/febs.16204. ISSN 1742-4658. PMID 34536985.
- ↑ Brookes, Emily; Laurent, Benoit; Õunap, Katrin; Carroll, Renee; Moeschler, John B.; Field, Michael; Schwartz, Charles E.; Gecz, Jozef et al. (2015-05-15). "Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity". Human Molecular Genetics 24 (10): 2861–2872. doi:10.1093/hmg/ddv046. ISSN 1460-2083. PMID 25666439.
- ↑ 9.0 9.1 Karwacki-Neisius, Violetta; Jang, Ahram; Cukuroglu, Engin; Tai, Albert; Jiao, Alan; Predes, Danilo; Yoon, Joon; Brookes, Emily et al. (2024-02-21). "WNT signalling control by KDM5C during development affects cognition". Nature 627 (8004): 594–603. doi:10.1038/s41586-024-07067-y. ISSN 1476-4687. PMID 38383780. Bibcode: 2024Natur.627..594K.
- ↑ "KARES Foundation - KDM5C Advocacy, Research, Education, & Support - Home" (in en-US). https://kares.foundation/.
- ↑ Claes, S.; Devriendt, K.; Van Goethem, G.; Roelen, L.; Meireleire, J.; Raeymaekers, P.; Cassiman, J. J.; Fryns, J. P. (2000-09-04). "Novel syndromic form of X-linked complicated spastic paraplegia". American Journal of Medical Genetics 94 (1): 1–4. doi:10.1002/1096-8628(20000904)94:1<1::aid-ajmg1>3.0.co;2-v. ISSN 0148-7299. PMID 10982473.
- ↑ Jensen, Lars Riff; Amende, Marion; Gurok, Ulf; Moser, Bettina; Gimmel, Verena; Tzschach, Andreas; Janecke, Andreas R.; Tariverdian, Gholamali et al. (2004-12-07). "Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation". American Journal of Human Genetics 76 (2): 227–236. doi:10.1086/427563. ISSN 0002-9297. PMID 15586325.
- ↑ Yheskel, Matanel; Hatch, Hayden A. M.; Pedrosa, Erika; Terry, Bethany K.; Siebels, Aubrey A.; Zheng, Xiang Yu; Blok, Laura E. R.; Fencková, Michaela et al. (2024-06-24). "KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism in neurons". Nucleic Acids Research 52 (11): 6201–6219. doi:10.1093/nar/gkae261. ISSN 1362-4962. PMID 38597673.
- ↑ Han, Jingjing; Hong, Rui; Cao, Cong; Zhang, Lina; Sun, Ao; Li, Yufei; Chi, Yinxiu; Zhang, Linlin et al. (2025-04-01). "Suppression of KDM5C mitigates the symptoms of Alzheimer's disease by up-regulating BDNF expression". Neurochemistry International 186. doi:10.1016/j.neuint.2025.105975. ISSN 1872-9754. PMID 40180246.
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