Non-syndromic intellectual disability (NS-ID) is a genetically heterogeneous disorder, with more than 200 candidate genes identified to date. Despite the increasing number of novel mutations detected, less than 20 genes (≤ 10%) are clinically screened to determine the genetic contribution of intellectual disability. Furthermore, there is no consistency in terms of the number of reportable genes across medical institutions, leaving affected families without appropriate genetic counselling.
The aetiology of NS-ID remains unknown and is recognised to be under-researched. Through a systematic search of PubMed and Medline, we curated 245 NS-ID candidate genes harbouring non-synonymous variants, insertions or deletions from case reports or from linkage or pedigree analyses were identified. Gene networks and protein-protein interactions were analysed using GeneGO MetaCoreTM and DAPPLE databases, respectively.
From the list of 245 NS-ID candidate genes, we identified common pathways of axon guidance, synaptogenesis, cell adhesion and neurotransmission, all of which are key neurodevelopmental processes for the establishment of mature neuronal circuitry in the brain. These genes are evolutionarily constrained, consistent with expectations for a disorder such as NS-ID that is associated with reduced fecundity. In addition, we report enrichment of dopaminergic and glutamatergic pathways for those candidate NS-ID genes which are common to syndromic intellectual disability (S-ID) and/or disorders that exhibit intellectual disability.
This study suggests modulation of neurotransmission, particularly dopaminergic and glutamatergic systems as key contributors to synaptic dysfunction in NS-ID. Collectively, the candidate genes and molecular pathways reported in this study provide reference information for future genetic studies of NS-ID.