Identification and characterisation of a novel homozygous KDM5A variant associated with severe axial hypotonia, seizures, and cardiac anomalies

KDM5A is a critical chromatin-modifying enzyme with lysine-specific demethylase activity and is highly expressed in brain tissues. Biallelic pathogenic variants in KDM5A are linked to KDM5A-related neurodevelopmental disorders, a rare disorder involving significant cognitive and motor impairments. We conducted a clinical and genetic evaluation of a patient with severe neurodevelopmental delay. Exome sequencing was performed to identify the genetic aetiology, followed by quantitative expression analysis to assess the functional impact of the identified variant on KDM5A mRNA levels. A novel homozygous KDM5A c.2836 C > T p.(Gln946Ter) variant was identified in the proband. Quantitative analysis showed a reduction in KDM5A expression. However, this decrease was not statistically significant. The patients displayed neuromotor developmental delay, severe axial hypotonia, absence of head control and mild upper-extremity spasticity. Additional findings included a history of seizures, facial dysmorphism and congenital heart disease. These findings expand the known clinical spectrum of El Hayek-Chahrour neurodevelopmental disorder (OMIM #620820), specifically highlighting severe motor impairment and complex cardiac involvement, including major aortopulmonary collateral artery, as previously undescribed features of this condition. The non-significant decrease in expression suggests that pathogenicity may arise from altered protein function rather than transcript depletion. Our findings underscore the importance of exome sequencing in delineating phenotypic variability in rare neurodevelopmental syndromes.