Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Histone lysine methylation is crucial for gene expression and DNA repair.
• Jumonji C (JmjC) domain proteins, including the KDM5 family, are key histone demethylases.
• KDM5B variants have been previously associated with intellectual disability (ID) and autism spectrum disorder (ASD).

Purpose of the Study:

• To investigate the role of novel de novo splice variants in the KDM5B gene in patients with ID and ASD.
• To elucidate the molecular mechanisms underlying KDM5B-associated neurodevelopmental disorders.

Main Methods:

• Identification and characterization of two novel de novo splice variants (c.808+1G>A and c.576+2T>C) in the KDM5B gene.
• Analysis of KDM5B mRNA expression levels.
• Assessment of H3K4me3 patterns in affected individuals.

Main Results:

• The c.808+1G>A variant led to reduced KDM5B mRNA expression without altering H3K4me3.
• The c.576+2T>C variant resulted in an abnormal transcript, potentially causing loss of the ARID1B domain and increased global H3K4me3.
• KDM5B haploinsufficiency was not implicated in ID; KDM5B disorders with LOF variants appear recessive.

Conclusions:

• KDM5B haploinsufficiency is not the mechanism for ID in these cases.
• KDM5B disorder associated with loss-of-function variants is likely a recessive condition.
• Some KDM5B variants may exert gain-of-function effects, necessitating careful interpretation and further functional studies.