De Novo Germline Mutations in SEMA5A Associated With Infantile Spasms

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.

Integration of epigenomic and transcriptome analyses of neural tube defects reveals methylation driver lncRNAs and mRNAs

“…Previous studies showed that Sema5a was associated with autism spectrum disorder and mental health development disorders [37]. We also found Ppp1r9a targeted by lncRNAs Gm15521 and Gm13974; Sema5a targeted by lncRNA 4933406K04Rik.…”

Autism Spectrum Disorder- and/or Intellectual Disability-Associated Semaphorin-5A Exploits the Mechanism by Which Dock5 Signalosome Molecules Control Cell Shape

“…Classical transcriptome analysis indicates that some transcripts, including the gene, are downregulated in some individuals with autism [25]. This deleted region includes the gene and some other genes, with studies associating it with causing infantile epilepsy [29,30]. Importantly, the respective mutations of Arg-676 and Ser-951 of Sema5A are critically associated with ASD and/or ID, probably depending on individual patients [27,28], suggesting that Sema5A is actually the responsible gene product of ASD and/or ID.…”

“…Analyses using genetically modified mice have demonstrated that Sema5A is involved in connections between different neurons in certain brain regions [31,32]. Herein, we report that neurite-like process elongation induced by the ASD-and ID-associated Arg676-to-Cys (R676C) mutation [30] within the TSP domain of Sema5A is mediated by a signalosome, including Rac1 guanine-nucleotide exchange factor (GEF) Dock5 as the Rac1 activator, in the N1E-115 cell line [33][34][35][36]. This provides evidence for a unique group of molecules involved in potential therapeutic target pathways in Sema5A-related ASD at the molecular and cellular experimental levels.…”

“…The gene is strongly associated with ASD [25][26][27][28] and intellectual disability (ID) primarily during the developmental period [25][26][27][28]. Certain mutations of the gene are associated with ASD and/or epilepsy [29,30]. Analyses using genetically modified mice have demonstrated that Sema5A is involved in connections between different neurons in certain brain regions [31,32].…”

Risk factors for, and genetic association with, intestinal atresia in dairy calves

“…None of the genes in the 18 genomic regions that were significantly associated with intestinal atresia in the Holstein‐Friesian population have been previously implicated in this phenotype, although USH2A has been associated with microtia‐atresia in humans (Wang, Wang, et al, 2019). Several genes have been associated with other congenital defects in humans (Delmaghani & El‐Amraoui, 2022; Fedick et al, 2015; Jaworek et al, 2013; Mégarbané et al, 2016; Pfendner & Lucky, 1993; Wang, Liu, et al, 2019; Zhang et al, 2016). Interestingly, several of these defects relate to ciliopathies.…”