What is KDM5C?

KDM5C is a gene that encodes a protein that regulates how other genes are turned on & off in our bodies. A variant or change in this gene makes a protein that doesn’t function properly. The function of the altered KDM5C protein results in impaired neural function in all parts of the body throughout a person’s lifetime. This makes it challenging to study and difficult to target for therapeutics.

KDM5C controls the expression of a number of genes that are involved in a range of cellular processes including neurodevelopment, inflammation and metabolism. It is expressed in most cells of the body but is particularly important in neurons, where it is needed for developing neural networks.

Genetic variants that disrupt the KDM5C gene result in an array of developmental, behavioral and cognitive changes. These genetic variants can range in severity, with some leading to a small change to the KDM5C protein, while others result in no KDM5C protein being produced. Variants, created by DNA changes within the KDM5C gene,  can be de novo, which means new within the affected individual (e.g. neither parent carries the gene variant), or can be inherited. 

The spectrum of symptoms caused by KDM5C variants is very wide. The impact of KDM5C genetic changes on each individual is very different. Those with a variant in KDM5C that leads to severe symptoms, including intellectual disability, may receive a diagnosis of Claes-Jensen syndrome. However many people with KDM5C variants, especially females, do not meet the criteria for Claes-Jensen diagnosis. 

Males are generally more affected by KDM5C variants than females, because the KDM5C gene is X-linked. KDM5C is expressed from the X chromosomes. Female sex chromosomes are XX, so females have two copies of KDM5C. Male sex chromosomes are XY, so they only have one copy of KDM5C. Thus if males have a variant in KDM5C, they don’t have another unaffected KDM5C gene as backup. But females are affected as well, because the variant KDM5C protein is not functioning as it should. 

Some of the most commonly reported characteristics of a KDM5C genetic variant include:

  • Altered muscle tone

  • Anxiety

  • Attention Deficit Hyperactivity Disorder

  • Autism

  • Challenging behavior

  • Developmental delay

  • Epilepsy

  • Gastrointestinal issues

  • Intellectual disability

  • Motor delays

  • Ocular findings

  • Short stature

  • Sleep issues

  • Speech impairment

A KDM5C variant is diagnosed through genetic sequencing or whole exome sequencing. These tests have only started to become widely accessible in recent years. This means there are likely to be many undiagnosed adults and children living with KDM5C-related conditions. Promoting awareness of KDM5C-related disorders, including Claes-Jensen syndrome, will hopefully lead to more individuals receiving a diagnosis and more research to find strategies to improve the lives of people living with KDM5C variants and their families.