Table 4. GRADE assessment of evidence linking Slo2 potassium channels to cognitive impairment in intellectual disability.
This table summarizes the key findings of studies on Slo2/KCNT1/KCNT2 channels in intellectual disability, with GRADE ratings and rationale highlighting limitations, sample size, model relevance, and translational applicability.
| Study | Outcome/findings | GRADE certainty | Rationale |
| Zhang et al. (2012) [6] | FMRP enhances Slack channel activity | Low | Single study, in vitro/animal data only, no behavioral assessment, indirect relevance to human cognition |
| Kim and Kaczmarek (2014) [9] | Slack channels linked to ID in epilepsy | Low-moderate | Review compiles evidence; mechanisms not experimentally tested, indirect focus on epilepsy rather than cognition |
| Bausch et al. (2015) [11] | Slack channels required for cognitive flexibility and anxiety regulation | Moderate | Animal behavioral data supports cognition role; mechanisms underlying bidirectional plasticity unclear; limited translation to humans |
| Quraishi et al. (2020) [12] | Kcnt1 deletion/mutation affects behavior, seizure susceptibility | Low-moderate | Adult animal models, different genetic backgrounds, seizure protocols non-standard, indirect relevance to infancy-onset human disease |
| Kessi et al. (2020) [13] | Potassium channelopathies contribute to ID; gain/loss mutations implicated | Low | Mechanistic understanding limited; lack of animal models; sparse therapeutic data; mostly descriptive |
| Gong et al. (2021) [14] | KCNT2 de novo variants cause DEE; quinidine potential therapy | Very low | Only two patients; small sample; genotype-phenotype correlation limited; long-term effects unknown |
| Wu et al. (2024) [15] | HCN-Slack complex regulates PFC excitability and working memory | Low-moderate | Mechanistic and behavioral evidence present, but preclinical, small sample, limited generalizability |
| Malone et al. (2025 [16] | Slack mutations affect FMRP-mediated translation, may contribute to ID | Low-moderate | Mechanistic insights strong, but in vitro models; off-target effects and measurement discrepancies reduce certainty |