Identification and Functional Characterization of a Novel SEMA3A Exon Deletion Variant in Kallmann Syndrome.

backgroundKallmann syndrome (KS) is a genetic disorder characterized by impaired reproductive system and olfactory development. This study aimed to identify a novel variant of SEMA3A in a KS patient and explore its potential pathogenic mechanism.

methodsA gene panel was used to identify potential pathogenic mutations. Wild-type and mutant SEMA3A overexpression plasmids were constructed. Western blotting, RNA sequencing, and cell migration were performed to assess the effects of SEMA3A gene variations on GnRH neuronal migration.

resultsA novel heterozygous mutation in the SEMA3A gene (NM_006080.3: exon 6-9 deletion) was identified in the proband, as well as in his father and sister. The spatial structure of the SEMA3A mutant protein was relatively looser. In vitro experiments revealed that SEMA3A mutation reduced SEMA3A expression and inhibited GnRH neuronal migration. RNAseq analysis revealed that the expression of 76 genes was upregulated and that of 104 genes was downregulated after SEMA3A mutation. The altered gene clusters were enriched mainly in cell migration, male gonad development, motor proteins, and neuron synapses.

conclusionsIn this study, we identified a novel variant of SEMA3A in a KS patient and verified its function. These findings expand the mutation spectrum of the SEMA3A gene and offer a theoretical basis for the clinical diagnosis of KS.