Abstract
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.
Highlights
Epileptic encephalopathies (EEs) are a group of complex brain disorders characterized by intractable and early-onset epilepsy with or without developmental delays, which are highly genetically heterogeneous (Berg et al, 2010; Scheffer et al, 2017)
It is important to note that a mean of 87.49% of the target regions was covered at 20× and that more than 90% of the exonic regions were sequenced at 10× coverage (Supplementary Table S1)
We confirmed that two de novo mutations (DNMs) and a compound heterozygous mutation were present among the three trios
Summary
Epileptic encephalopathies (EEs) are a group of complex brain disorders characterized by intractable and early-onset epilepsy with or without developmental delays, which are highly genetically heterogeneous (Berg et al, 2010; Scheffer et al, 2017). The development of next-generation sequencing techniques, such as whole-exome sequencing (WES), has greatly facilitated gene discovery in EEs, and these approaches have been widely used to detect pathogenic mutations (Dimassi et al, 2016; Jin et al, 2018). Recent genetic studies have used trio exome sequencing to confirm that many pathogenetic de novo mutations (DNMs) are critical genetic components in the pathogenesis underlying EEs (Claes et al, 2001; Carvill et al, 2013; Epi4K Consortium and Epilepsy Phenome/Genome Project, 2013). Most genes with pathogenetic DNMs in EE encode voltage-gated ion channels or receptors associated with neurotransmitter, including sodium channels, potassium channels, GABA receptors, glutamate receptors and NMDA receptors (Fukata and Fukata, 2017; He et al, 2019), and are often involved in a variety of functional pathways related to neuronal excitability or synaptic and neuronal connectivity (Pardo et al, 2014)
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