KDM5C-Related Neurodevelopmental Disorder

Disease Overview

Summary

KDM5C-related neurodevelopmental disorder is a rare genetic condition caused by changes (variants) in the KDM5C gene.^1,2 People with KDM5C variants typically start showing signs and symptoms of the condition when they are babies or young children. These may include intellectual disability, speech and motor delays, behavioral challenges, altered muscle tone, epilepsy and distinctive physical traits.

KDM5C-related neurodevelopmental disorder is an X-linked condition. While no cure exists, supportive therapies can help to manage symptoms and improve quality of life.

Introduction

KDM5C-related neurodevelopmental disorder was previously known as X-linked intellectual disability, Claes-Jensen type, named after researchers who first described the condition.^1,2,5 Through genetic testing and finding more people with the condition, it is known that there is a broad spectrum of symptoms and severity.

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Synonyms

• Claes-Jensen syndrome
• intellectual developmental disorder, X-linked, syndromic, Claes-Jensen type; MRXSCJ
• intellectual developmental disorder, X-linked, syndromic 16; MRXS16
• intellectual disability, X-linked, syndromic 16
• X-linked syndromic intellectual disability 16
• X-linked intellectual disability, Claes-Jensen type
• JARID1C
• SCMX
• Claes-Jensen type X-linked syndromic intellectual developmental disorder
• KDM5C-related syndromic X-linked intellectual disability

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Signs & Symptoms

People with KDM5C-related neurodevelopmental disorder may have the following symptoms:^1-8

• Global developmental delay which includes delays in several areas including:
  • Gross motor skills like crawling and walking
  • Fine motor skills like using utensils or crayons
  • Speech and language
    • Some people have limited or absent speech but often use alternate ways of communicating like sign language or assistive communication devices
  • Intellectual disability or cognitive abnormalities
    • Children can have a harder time with learning or functioning independently
  • Abnormal muscle tone
    • Children can have low muscle tone (hypotonia), increased muscle tone (hypertonia) or a combination of both in different parts of the body
  • Behavioral problems
    • Impulsivity
    • Short attention span
    • Aggressive behavior
    • Emotional dysregulation
    • Autism or autistic-like behavior
    • Anxiety
    • Hyperactivity
    • Attention deficit/hyperactivity disorder (ADHD)
    • Repetitive stereotypic behaviors
  • Seizures
  • Growth problems
    • Short stature is most common, but some people have been reported to be overweight or have general overgrowth
  • Vision problems
    • Crossed eyes (strabismus)
    • Farsightedness
  • Gastrointestinal issues
    • Constipation is common
    • Feeding difficulties
  • Sleep difficulties
  • Other problems including:
    • Slowly progressive paralysis that affects the lower body, typically causing loss of movement and sensation in the legs and feet (paraplegia)
    • Distinctive face with small chin (maxillary hypoplasia or micrognathia), small forehead, prominent projection of the jaw (prognathism), reduced muscle tone in the facial muscles (facial hypotonia), flat area between the upper lip and the nose (philtrum), thin upper lip, high, narrow roof of the mouth (palate), small, deep-set eyes and large ears
    • Small feet

Most people with this condition are males, but some females have signs and symptoms that are usually milder than those seen in males. Studies have shown that the most common signs reported in females include variable degrees of developmental delay/intellectual disability (from none to moderate), language delay, language problems, physical features (facial appearance and short stature are the most frequent), as well as behavioral issues such as aggressive behavior, low frustration tolerance, anxiety and social disability.⁸

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Causes

KDM5C-related neurodevelopmental disorder is caused by disease-causing (pathogenic) variants in the KDM5C gene, which encodes a protein involved in chromatin remodeling and gene regulation. The dysfunction of this gene affects neuronal development and cognitive function.¹ At least 80 variants in KDM5C have been reported to cause symptoms.⁷

Inheritance

KDM5C-related neurodevelopmental disorder follows an X-linked inheritance pattern.^1-7 Males with a disease-causing (pathogenic) variant in KDM5C are typically more severely affected than females because males have only one X chromosome. Females with a KDM5C variant may have variable symptoms because in females, one of the two X chromosomes is naturally “switched off” in each cell through a process called X-chromosome inactivation.

Some people have KDM5C-related neurodevelopmental disorder as the result of a new (de novo) KDM5C variant that is not inherited. Other people have KDM5C-related neurodevelopmental disorder due to a variant inherited from a mother who does not have features of the condition or did not know she had the variant.^3,5-7

Females with KDM5C-related neurodevelopmental disorder may have biological children and can pass this variant to their children. There is a 50% chance for each of her children, male or female, to inherit the variant. If the variant is passed to a son, he will have KDM5C-related neurodevelopmental disorder and is expected to have many of the features described above. If the variant is passed to a daughter, it is not possible to predict how she will be affected.

Most males with KDM5C-related neurodevelopmental disorder do not have biological children. However, if they do, all their daughters and none of their sons would inherit the variant.

It is common for genetic conditions, including KDM5C, to have intrafamilial variability, meaning that people in the same family with the same variant can have different symptoms. It is still not possible to predict what features a person with a KDM5C gene variant will have, but researchers are trying to correlate signs and symptoms with specific variants.⁷

There is also the possibility of a phenomenon called germline or gonadal mosaicism. This means that the variant is only found in the father’s sperm or mother’s eggs, so they do not have the disorder, but can pass the gene variant on to their children. Taking this possibility into account, the chance for two parents who test negative for a KDM5C gene variant to have another child with KDM5C-related neurodevelopmental disorder is around 1%.

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Affected populations

The exact prevalence of KDM5C-related neurodevelopmental disorder is unknown. It is considered a rare disorder and has been reported in individuals from various ethnic backgrounds around the world. This disorder has been primarily identified in males, but females can also have symptoms to varying degrees.

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Disorders with Similar Symptoms

There is an overlap in symptoms with other rare neurodevelopmental disorders which is an ever-increasing group of conditions characterized by developmental delay and intellectual disability with or without seizures caused by pathogenic variants in different genes. The characteristics of KDM5C-related disorder can be similar to these other disorders as well as other conditions:

Cerebral palsy can appear similar to KDM5C-related disorder in children who present with motor impairments such as spasticity or hypotonia. Both conditions may involve intellectual disability and seizures. However, cerebral palsy typically results from a static brain injury around birth and is not progressive, whereas KDM5C-related disorder is genetic and may involve ongoing developmental challenges over time.

Autism spectrum disorder shares features with KDM5C-related disorder, especially when social communication challenges and repetitive behaviors are present. Both may include sensory sensitivities and cognitive impairment. Autism is diagnosed behaviorally and is associated with variants in many different genes. Sometimes the cause is unknown. Additionally, KDM5C is more likely to involve motor delays and seizures, which are not core features of autism.

Rett syndrome, particularly in females, can present with developmental regression, speech loss, seizures and repetitive hand movements, as well as intellectual disability and neurologic symptoms. Rett syndrome may be caused by variants in the MECP2 gene, located on the X chromosome, and it typically affects females because these gene variants are often lethal in males. KDM5C-related disorder can also affect females but tends to be milder due to X-inactivation and males are often more severely affected.

Angelman syndrome overlaps with KDM5C-related disorder through shared symptoms like severe intellectual disability, little or no speech, ataxic gait and a generally happy demeanor. Both conditions may involve seizures and behavioral features, but Angelman syndrome is characterized by a more consistent clinical picture including distinct EEG findings, and these children tend to have very limited verbal abilities compared to speech development in children with KDM5C-related disorder.

Fragile X syndrome has similar symptoms such as intellectual disability, behavioral issues such as anxiety and hyperactivity, and physical traits like a long face or large ears. Both conditions are X-linked but the specific cognitive and behavioral characteristics differ. Boys with fragile X syndrome may have delayed language development, poor articulation and sometimes repetitive speech patterns, whereas boys with KDM5C-related disorder may have more general language delay and broader variability in motor and neurological symptoms.

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Diagnosis

KDM5C-related neurodevelopmental disorder may be suspected in early childhood based on the associated signs and symptoms such as developmental delay, eye (ocular) findings, seizures and/or muscle/motor issues. The diagnosis is confirmed with genetic testing, usually through a gene panel, whole exome sequencing, or whole genome sequencing. The only way to know for sure if someone has a KDM5C-related neurodevelopmental disorder is through genetic testing.

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Standard Therapies

Currently, there is no cure or specific treatment. Each person’s care is based on their symptoms. People with KDM5C-related neurodevelopmental disorder may need to be cared for by several specialists who need to work together as a team in a coordinated way. The specialists and therapies that might be included in a person’s multidisciplinary care may include:

• Neurology
• Developmental pediatrics
• Gastroenterology
• Endocrinology
• Ophthalmology
• Sleep medicine
• Physical medicine and rehabilitation
• Orthopedics
• Genetics
• Feeding therapy
• Physical therapy
• Speech therapy
• Occupational therapy
• Behavioral therapy

These specialists and therapies can be discussed with the doctor who made the diagnosis to see if they are appropriate. Not every person will need all of these.

It is highly recommended that people with KDM5C-related neurodevelopmental disorder and their families meet with a medical geneticist and/or genetic counselor to discuss testing for relatives and to learn more about risks for future children.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Online Mendelian Inheritance in Man (OMIM). Entry- #300534. INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CLAES-JENSEN TYPE; MRXSCJ. Updated: 03/31/2025. https://omim.org/entry/300534 Accessed June 5, 2025.
2. Jensen L, Amende M, Gurok U, et al. Mutations in the JARID1C Gene, Which Is Involved in Transcriptional Regulation and Chromatin Remodeling, Cause X-Linked Mental Retardation. American Journal of Human Genetics. 2005;76(2):227-236. doi: https://doi.org/10.1086/427563
3. Carmignac V, Nambot S, Lehalle D, et al. Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature. Clinical Genetics. 2020;98(1):43-55. doi: https://doi.org/10.1111/cge.13755
4. Santos-Rebouças CB, Fintelman-Rodrigues N, Jensen LR, et al. A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay. Neuroscience Letters. 2011;498(1):67-71. doi: https://doi.org/10.1016/j.neulet.2011.04.065
5. Hatch H, O’Neil MH, Marion RW, Secombe J, Shulman LH. Caregiver‐reported characteristics of children diagnosed with pathogenic variants in KDM5C. American Journal of Medical Genetics Part A. 2021;185(10):2951-2958. doi: https://doi.org/10.1002/ajmg.a.62381
6. Leonardi E, Aspromonte MC, Drongitis D, et al. Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants. European Journal of Human Genetics. 2022;31(2):202-215. doi: https://doi.org/10.1038/s41431-022-01233-4
7. Ghasemi M, Esmaeilizadeh Z, Tehrani Fateh S, et al. 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. 2025;13(1). doi: https://doi.org/10.1002/mgg3.70057
8. Lintas C, Bottillo I, Sacco R, et al. Expanding the Spectrum of KDM5C Neurodevelopmental Disorder: A Novel De Novo Stop Variant in a Young Woman and Emerging Genotype-Phenotype Correlations. Genes (Basel). 2022;13(12):2266. Published 2022 Dec 1. doi:10.3390/genes13122266

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Programs & Resources

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