Infantile spasm (IS) is an early-onset epileptic encephalopathy that usually presents with hypsarrhythmia on an electroencephalogram with developmental impairment or regression. In this study, whole-exome sequencing was performed to detect potential pathogenic de novo mutations, and finally we identified a novel damaging de novo mutation in SEMA5A and a compound heterozygous mutation in CLTCL1 in three sporadic trios with IS. The expression profiling of SEMA5A in the human brain showed that it was mainly highly expressed in the cerebral cortex, during the early brain development stage (8 to 9 post-conception weeks and 0 to 5 months after birth). In addition, we identified a close protein-protein interaction network between SEMA5A and candidate genes associated with epilepsy, autism spectrum disorder (ASD) or intellectual disability. Gene enrichment and function analysis demonstrated that genes interacting with SEMA5A were significantly enriched in several brain regions across early fetal development, including the cortex, cerebellum, striatum and thalamus (q < 0.05), and were involved in axonal, neuronal and synapse-associated processes. Furthermore, SEMA5A and its interacting genes were associated with ASD, epilepsy syndrome and developmental disorders of mental health. Our results provide insightful information indicating that SEMA5A may contribute to the development of the brain and is associated with IS. However, further genetic studies are still needed to evaluate the role of SEMA5A in IS to definitively establish the role of SEMA5A in this disorder.
Keywords: SEMA5A; de novo mutations; epileptic encephalopathy; infantile spasms; whole-exome sequencing.