Intellectual Disability, X-linked, Claes-Jensen Type via the KDM5C Gene

Intellectual disability, X-linked and syndromic, Claes-Jensen type is characterized by mild to severe intellectual disability, often accompanied by symptoms such as epilepsy, behavioral disturbances, short stature and hyperreflexia (Abidi et al. 2008; Brookes et al. 2015). A KDM5C pathogenic variant has also been reported in autism spectrum disorder, Huntington’s disease and drug addiction (Brookes et al. 2015).

Female carriers have been reported to have mild intellectual disability or learning difficulties (Abidi et al. 2008; Rujirabanjerd et al. 2010).

Pathogenic variants in KDM5C cause intellectual disability, syndromic, Claes-Jensen type which is inherited in an X-linked recessive manner (Abidi et al. 2008; Gonçalves et al. 2014; Brookes et al. 2015). The majority of pathogenic variants reported in KDM5C are missense. Others include nonsense, splicing, small deletions/duplications, as well as a large deletion compassing the KDM5C locus (Human Gene Mutation Database).

The KDM5C gene (also known as JARID1C and SMCX) encodes lysine-specific demethylase 5C which is a histone demethylase. This demethylase removes di- and tri-methylation of histone H3 lysine 4 [H3K4me2/3], leading to modification of the associated gene activation. Malfunction of KDM5C could lead to alterations in chromatin landscape and may contribute to disease (Brookes et al. 2015).

Pathogenic variants in the KDM5C gene account for 1–4% of X-linked intellectual disability (Brookes et al. 2015) and in another study for 0.7% among males with probable X-linked intellectual disability in Latin America (Gonçalves et al. 2014).

A large deletion with several genes, including the KDM5C gene, has been reported (Fieremans et al. 2015). To date, no large cohort study on deletions/duplications of KDM5C has been published.

This test provides full coverage of all coding exons of the KDM5C gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).