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Background: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. Method: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was intellectual disability. The most frequently overrepresented GO biological process, cellular component and molecular function terms were regulation of membrane potential, ion channel complex, voltage-gated ion channel activity/voltage-gated channel activity, respectively. Conclusion: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Self-limited familial neonatal epilepsy is an autosomal dominant epileptic syndrome characterized by episodes of seizures occurring in the first days of life. Most patients have heterozygous mutations of KCNQ2 gene located on 20q13. A variety of clinical phenotypes have been associated with KCNQ2 mutations, making the prediction of this rare entity difficult. Herein, we report a rare KCNQ2 variant in two siblings with self-limited familial neonatal epilepsy. The siblings had tonic seizures accompanied by clonic jerks in the first few days after birth. Genetic analysis of the siblings revealed a heterozygous KCNQ2 variant: c.1589G > A; (p.Ser530Asn). The identical variant subsequently was identified in the mother. To our knowledge, this variant has not been previously reported in individuals with KCNQ2-related disease. This is the first report that reveals c.1589G > A variant of KCNQ2 gene as a pathogenic variant in two siblings.