A Novel Mitochondrial Phenotype in a Patient with SYNGAP1 Encephalopathy

Background: The SYNGAP1 gene encodes a brain-specific synaptic Ras GTPase activating protein localised in the dendritic spines of cortical pyramidal neurons. The Syngap1 protein suppresses signalling pathways linked to NMDA receptor-mediated synaptic plasticity and AMPA receptor membrane insertion. Defects in the SYNGAP1 gene lead to neurodevelopmental disorders characterised by developmental delay, intellectual disability, autism spectrum disorder, and epilepsy in patients.

Methods: Comprehensive analyses of the mitochondrial (mtDNA) and nuclear genomes were performed by massively parallel sequencing (MitoNGS) and whole exome sequencing (WES), respectively. A skin biopsy was used for genetic and metabolic analyses using the Seahorse technology.

Results: This is a case study of a 3-year-old male born full-term but lethargic at birth. His initial clinical manifestations included seizures with drop attacks, developmental motor and sensory delays accompanied by speech delay and social issues. The MitoGS analysis did not detect mitochondrial pathogenic variants or large deletions, while WES revealed the pathogenic heterozygous nuclear variant c.1783del (p.L595Cfs*55) in the SYNGAP1 gene causing a frameshift variant located in exon 11 of 19. The proband’s fibroblasts exhibited deficient oxidative phosphorylation responsible for mitochondrial ATP synthesis.

Discussion/Conclusion: Our clinical case study provides the first evidence of dysregulated mitochondrial energy metabolism associated with SYNGAP1 encephalopathy.