Big potassium (BK) channels are large-conductance Ca²⁺-activated and voltage-activated potassium channels present in various tissues (Contet et al., 2016). They are termed also Maxi-K, or Slo1. When open, BK channels cause a substantial efflux of K⁺ ions, leading to hyperpolarization of the cellular membrane (Contet et al., 2016). They can detect simultaneously increased intracellular Ca²⁺ levels and membrane depolarization (Contet et al., 2016). This property is useful in excitable cells, as it allows control of their activity via negative feedback regulation of Ca²⁺ influx through voltage-activated Ca²⁺ channels (Contet et al., 2016). BK channels localize to the plasma membrane of neurons in the central nervous system (CNS), where they modulate the shape, frequency, and propagation of action potentials, as well as the release of neurotransmitter from presynaptic terminals (Contet et al., 2016; Griguoli et al., 2016). BK channels are also present in the neurons' nuclear envelope, thereby controlling gene transcription and neuronal morphology (Li et al., 2014). Finally, their presence in astrocytes or vascular smooth muscle cells enables the regulation of blood flow in the brain, which can influence cerebral activity (Contet et al., 2016). Mutation of fragile X mental retardation protein (FMRP) is the leading cause of ID and autism spectrum disorder (Reymundo et al., 2014). FMRP regulates neurotransmitter release and the transmission of synaptic information by modulating the duration of action potentials via BK channels in hippocampal and cortical pyramidal cells (Deng et al., 2013; Deng and Klyachko, 2016; Ferron, 2016). Enhanced BK channel activity and reduced presynaptic glutamate release were shown to cause ID in Crbn knock-out (KO) mice, whereas BK channel blockers restored normal cognitive behavior (Choi et al., 2018). A BKCa channel opener molecule rescued hippocampal glutamate homeostasis as well as and cognitive impairments in Fmr1 KO mice (Hebert et al., 2014). An increased BK channel activity has been shown to manifest as an amplified intrinsic excitability in individual neurons and consequent network synchronization; whereas BK channel blockers stabilized neuronal excitability in both human and mouse neurons and improved seizure susceptibility in an Angelman syndrome mouse model (Sun et al., 2019).

Small potassium (SK) channels are important for learning and memory as they are expressed in the postsynaptic membrane of glutamatergic synapses (Adelman et al., 2012). There, they control synaptic transmission and stimulate synaptic plasticity (Adelman et al., 2012). It has been shown that an increase in SK channels activity impairs learning (Vick et al., 2010; Adelman et al., 2012); whereas SK channel blockers ameliorate learning and memory in animal models (Hammond et al., 2006; Lin et al., 2008).

KCNJ6 (potassium inwardly rectifying channel subfamily J member 6) encodes the Kir3.2 GABAB receptor-coupled channel, a member of the G protein-coupled family of Kir channels (Hattori et al., 2000). This gene is located in the Down syndrome critical region, in the middle of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and Down syndrome critical region gene 4 (DSCR4) genes (Hattori et al., 2000). The Kir3.2 channel mediates the inhibitory effect of G protein-coupled receptors required by neuromodulators and neurotransmitters, and thus controls neuronal excitability (Yamada et al., 1998; Mark and Herlitze, 2000). It is highly expressed in most mammalian tissues, where it participates in several physiological processes through coupling with other channel proteins, resulting in homo or hetero-multimeric complexes (Uhlen et al., 2005, 2010). Masotti et al. (2015) reported three cases with Keppen–Lubinsky syndrome, which is characterized by severe ID and multiple congenital anomalies. Genetic testing revealed the following mutations: in-frame heterozygous deletion of three nucleotides causing the loss of one amino acid (T152del) for two cases, and heterozygous missense mutation introducing the G154S amino acid change (Masotti et al., 2015). Animal models for in-frame deletions is presently not available and the mechanism underlying the above missense mutation is unknown.

Nevertheless, it has been demonstrated that an increase in Kcnj6 gene dosage is essential for insufficiencies in behavior and synaptic plasticity of the dentate gyrus in the Ts65Dn murine model of Down syndrome (Kleschevnikov et al., 2017). The Kir3.2 channel blocker fluoxetine could rescue synaptic plasticity (Kleschevnikov et al., 2017), suggesting that gain-of-function property is likely the underlying mechanism; nevertheless, further studies are required to confirm that.

KCNJ10 (potassium channel inwardly rectifying subfamily J, member 10) encodes an ATP-sensitive inward rectifier potassium (Kir) channel comprising two putative transmembrane domains held together by an extracellular pore-forming region and flanked by amino and carboxy termini on the cytoplasmic side (Takumi et al., 1995). The KCNJ10 protein is present in glial cells of the CNS, predominantly in the cerebral cortex, cerebellar cortex, putamen, and caudate nucleus, as well as in renal epithelial cells and inner ear cells (Bockenhauer et al., 2009). Known also as Kir4.1, it is expressed in astrocytes and oligodendrocytes neighboring synapses and blood vessels, chiefly in the cortex, hippocampus, cerebellum, brainstem, spinal cord, thalamus, and olfactory bulb (Higashi et al., 2001; Hibino et al., 2004, 2010; Sicca et al., 2011).

Mutations in this gene have been demonstrated to reduce the channel's potassium current amplitude, surface expression, heteromer activity, and pH sensitivity (Bockenhauer et al., 2009; Hibino et al., 2010). These changes may alter the primary functions of astrocytes, including extracellular glutamate homeostasis, K⁺ siphoning, maintenance of resting membrane potential, and water volume regulation (Nwaobi et al., 2016). KCNJ10 has been linked with EAST/SeSAME syndrome, which is characterized by epilepsy, ataxia, tubulopathy, sensorineural hearing loss, and occasionally ID (Celmina et al., 2019). Loss-of-function mutations are associated with mild ID (Scholl et al., 2009); whereas gain-of-function mutations correlate with mild to severe ID, depending on the variant (Sicca et al., 2011). The majority of reported mutations are of the loss-of-function type (Supplementary Table 1).

Sibille et al. (2014) showed that astroglial potassium clearance played a role in creating short-term plasticity of the tripartite synapse. Consequently, glial conditional Kir4.1 KO mice demonstrated that astroglial potassium uptake decreased synaptic plasticity (Sibille et al., 2014). The authors concluded that astrocytes participated in synaptic activity through numerous channels and transporters and contributed to short-term plasticity partly through removal of K⁺ via Kir4.1 channels (Sibille et al., 2014). Likewise, conditional KO of hippocampus- Kir4.1 led to inhibition of potassium and glutamate uptake, glial membrane depolarization, and heightened short-term synaptic potentiation (Djukic et al., 2007). Conditional KO of oligodendrocytes-Kcnj10 resulted in late-onset axonal degeneration and mitochondrial damage associated with neuronal loss and neuro-axonal dysfunction (Schirmer et al., 2018). Mice deficient in oligodendrocyte Kir4.1 channels showed slow clearance of extracellular K⁺, delayed axonal recovery following repetitive stimulation in white matter, as well as low seizure threshold and motor deficits (Larson et al., 2018).

KCNJ11 (potassium voltage-gated channel subfamily J member 11) encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (KATP) channel (Nichols and Lopatin, 1997; Aguilar-Bryan and Bryan, 1999). This channel has two important subunits: the pore-forming Kir6.2 subunit and the sulfonylurea receptor 1 regulatory subunit (Clement et al., 1997). Its expression is elevated in beta cells and neurons (Nichols and Lopatin, 1997; Aguilar-Bryan and Bryan, 1999). An increased KATP current caused by channel opening results in membrane hyperpolarization in beta cells and consequent inhibition of insulin secretion (Bennett et al., 2010). Conversely, closure of this channel in reaction to augmented glucose triggers the release of insulin from beta cells into the bloodstream, thus helping to control blood sugar levels (Bennett et al., 2010). In neurons, an increased KATP current results in reduced electrical activity (Fendler et al., 2013).

KCNJ11 mutations are associated with two major phenotypes: neonatal diabetes with moderate developmental delay and/or muscle weakness but not epilepsy (I-DEND) and developmental delay, epilepsy, and neonatal diabetes (DEND) (Flanagan et al., 2006; Mohamadi et al., 2010; Shah et al., 2012; Fendler et al., 2013; Lin et al., 2013; Carmody et al., 2016). Several variants with gain-of-function properties have been associated with ID: V59M, Y330C, V59A, G53D, R201C, C166Y, V59G, and Q52R. Most cases carry the V59M variant Supplementary Table 1, which shows clear association with ID symptoms (Svalastoga et al., 2020). Notably, Lin et al. (2013) reported a case with gain-of-function derived from the S225T mutation and P226_P232del, suggesting that both gain- and loss-of-function mutations could lead to I-DEND. Sulfonylureas act as inhibitors of KATP channels and represent an optimum treatment for diabetes and they can ameliorate the related neurological disorders (Pearson et al., 2006). However, other studies have not detected any benefits of sulfonylureas on neurological symptoms (Sagen et al., 2004; Klupa et al., 2005; Svalastoga et al., 2020), suggesting that sulfonylureas can partially cross the blood–brain barrier, and that the improved neurological symptoms observed resulted from increased cerebellar perfusion (Fendler et al., 2013). Thus, ID could be initiated from gain-of-function or as a complication of neonatal diabetes or due to unknown mechanisms associated with KATP channel, which the partial effects of sulfonylureas on neurological symptoms cannot confirm. The pathways involved to fully restore KATP channel function in other tissues might differ from those in the CNS (Bowman et al., 2019). Animal studies will help to determine which of these is most likely.

KCNA2 encodes the Kv1.2 channel, which is expressed widely in both the central and peripheral nervous systems (Vacher et al., 2008; Trimmer, 2015). Kv1.1, encoded by KCNA1, and Kv1.2 are co-expressed in big axons and are usually found in the same tetramers (Vacher et al., 2008; Trimmer, 2015). They contribute to the low-voltage-activated potassium current I Kv1. Kv1.2 channels are distributed in the distal axon initial segment and juxtaparanodes bordering the nodes of Ranvier (Trimmer, 2015). They mediate the D-type (delay) current (Storm, 1990; Grissmer et al., 1994; Brew et al., 2003), which is a critical controller of neuronal excitability as it actuates at subthreshold membrane potentials, rapidly deferring action potential commencement and averting repetitive firing (Storm, 1988, 1990). In addition, these channels work as delayed rectifiers, since blockage of Kv1.2 and D-type currents halts the surge in duration of action potentials (Kole et al., 2007; Shu et al., 2007), which is followed by increased calcium inflow in the presynaptic terminals and release of glutamate.

KCNA2 mutations are related to various phenotypes including mild to severe ID/GDD and epilepsy (Syrbe et al., 2015; Hundallah et al., 2016), encephalopathy (Masnada et al., 2017), hereditary spastic paraplegias, mild ID, and ataxia (Helbig et al., 2016). Both gain- and loss-of-function mutations have been reported. Gain-of-function mutations such as L298F and R294H are linked to severe ID (Syrbe et al., 2015; Helbig et al., 2016). In contrast, loss-of-function mutations are associated with mild to moderate ID (Syrbe et al., 2015; Helbig et al., 2016). Kcna2 KO mice revealed an important role of this channel in brain function, as gene deletion increased seizure susceptibility, reduced lifespan, and augmented the chance of premature death starting from the second week after birth (Brew et al., 2007). In a separate study, Kcna2 KO mice demonstrated less non-rapid eye movement sleep and fewer seizures originating during such period (Douglas et al., 2007). Further studies will determine how both gain- and loss-of-function mutations lead to GDD/ID.

KCNA4 encodes the Kv1.4 channel, also known as the Shaker-type potassium channel of the Kv channel family. The Kv1.4 channel is highly expressed in the striatal neurons, cerebral cortex, hippocampus, globus pallidus, cerebral peduncle, dorsal cochlear nuclei, and substantia nigra (Chung et al., 2000; Lujan et al., 2003), as well as in the retina (Holtje et al., 2007; Kaya et al., 2016). The Kv1.4 channel contributes to the generation of A-type K⁺ current channels in mature cortical pyramidal neurons (Carrasquillo et al., 2012) and the fast repolarizing phase of action potentials. A-type K⁺ currents play a central role in long-term plasticity, which is an essential mechanism for learning and memory (Chen et al., 2006).

Bauer et al. (2018) reported three cases that presented with facial dysmorphism, hypertrichosis, epilepsy, ID, and gingival overgrowth. Genetic testing revealed them to carry one of the following de novo mutations A172E, A244P, and A172E (Bauer et al., 2018). All three cases presented with severe ID and electrophysiological studies indicated gain-of-function as the underlying mechanism for this disorder (Bauer et al., 2018). Kaya et al. (2016) reported four cases from consanguineous family members, who presented with a novel disorder characterized by borderline ID, attention deficit hyperactivity disorder, striatal thinning, and congenital cataract. They all carried the R89Q variant (Kaya et al., 2016). Electrophysiological studies revealed loss-of-function as the mechanism responsible for this disorder (Kaya et al., 2016). Nevertheless, it remains unclear how KCNA4 loss-of-function may lead to ID, thus further studies are warranted.

KCND3 (potassium voltage-gated channel, Shal-related subfamily, member 3) encodes the Kv4.3 channel, an alpha subunit of the Shal family of Kv channels (Serodio et al., 1996; Isbrandt et al., 2000). It is found in the brain and heart, and is important for membrane repolarization (Serodio et al., 1996; Isbrandt et al., 2000). Smets et al. (2015) reported a case with mild ID, epilepsy, attention deficit hyperactivity disorder, early onset cerebellar ataxia, strabismus, and oral apraxia. A de novo mutation (A293F295dup) was identified and the mechanism of disease was found to be haploinsufficiency (Smets et al., 2015). Kurihara et al. (2018) reported another case, this one carrying a de novo missense mutation (G384S). The clinical presentation consisted of mild ID, early onset cerebellar ataxia, myoclonus, and dystonia; however, no follow-up electrophysiological study was performed (Kurihara et al., 2018). What remains to be determined is how KCND3 loss-of-function mutations may lead to ID.

KCNH1 (potassium voltage-gated channel, subfamily H (eag related), member 1) encodes the voltage-gated Kv10.1 potassium channel, also called ether-a-go-go-related gene 1 (Gutman et al., 2005). The Kv10.1 channel is expressed in the cerebral cortex, hippocampus, cerebellum, and olfactory bulb (Ludwig et al., 1994, 2000; Gomez-Varela et al., 2010). Its presence in dopaminergic cells and the dentate gyrus of hippocampal neurons maintains electrophysiological activity patterns (Ferreira et al., 2012). It has an N-terminal Per-Arnt-Sim (PAS) domain and a C-terminal cyclic nucleotide-binding domain that control gating (James and Zagotta, 2018). Activation of this channel depends on the extracellular concentration of Mg²⁺ and on membrane potential (James and Zagotta, 2018).

Mutations in KCNH1 are linked to Temple–Baraitser Syndrome, whose phenotype includes ID, epilepsy, and hypoplasia/aplasia of the nails of the thumb and great toe (Simons et al., 2015; Megarbane et al., 2016) and Zimmermann–Laband syndrome, which is characterized by ID, hypoplasia of nails and terminal phalanges, facial dysmorphism, gingival enlargement, and hypertrichosis (Kortum et al., 2015). In both conditions, cases present with severe to profound ID (Kortum et al., 2015; Simons et al., 2015; Megarbane et al., 2016). Reported variants include, G348R, G503R, L489F, I494V, K217N, I467V, S325Y, V356L, G469R, and L352V; all of them have gain-of-function channel properties (Kortum et al., 2015; Simons et al., 2015).

Zebrafish knockdown of kcnh1 demonstrated severe neuronal developmental impairment, manifested as delayed hindbrain formation, growth retardation, and embryonic lethality (Stengel et al., 2012). Surprisingly, Kv10.1 null mice display normal memory, learning, social behavior, and sensorimotor functioning with mild hyperactivity (Ufartes et al., 2013). Bronk et al. (2018) showed that increased activity of the Kv10.1 channel in Drosophila resulted in lower presynaptic activity but higher postsynaptic activity through homeostatic plasticity. While the experiment attempted to explain the occurrence of epilepsy, it remains unclear how increased activity of the Kv10.1 channel and subsequent surge in postsynaptic activity could lead to severe forms of ID. Mortensen et al. (2015) reported that the Kv10.1 channel was more abundant in the presynaptic terminals and did not contribute to somatic action potentials; instead, it controlled Ca²⁺ influx and neurotransmitter discharge throughout repetitive high-frequency activity. Future studies using different Kv10.1 variant knock-in mice will help identify the mechanism by which Kv10.1 gain-of-function mutations lead to severe ID and epilepsy.

KCNQ2 encodes the Kv7.2 subfamily Q member 2 Kv channel. Kv7.2 channels are widely expressed in the brain, especially in the axon's initial segment and nodes of Ranvier (Greene and Hoshi, 2017). They trigger the M current, a voltage-gated non-inactivating potassium current. They control the firing of pyramidal neurons in one of the following ways: (1) help set the initial segment membrane potential; (2) contribute to the generation of medium afterhyperpolarization for refractory period; (3) regulate firing frequency, theta resonance, and transient neuronal hyperexcitability (Greene and Hoshi, 2017). The activation and possibility of opening this channel depend on phosphatidylinositol 4, 5-bisphosphate (PIP2) (Li et al., 2005; Kim et al., 2016). Although mutations of this gene are associated with early infantile epileptic encephalopathy, West syndrome, and Ohtahara syndrome, all of which are often accompanied by severe ID (Weckhuysen et al., 2012, 2013; Kato et al., 2013; Zhang Y. et al., 2015; Dimassi et al., 2016; Zhang et al., 2017), cases with ID related to childhood onset of seizures have also been reported (Borgatti et al., 2004; Hewson et al., 2017). Hewson et al. (2017) reported a three-generation pedigree (n = 6), with ID ranging from borderline to moderate caused by R210C loss-of-function mutation (Soldovieri et al., 2019). Borgatti et al. (2004) reported two cases with moderate to profound ID accompanied by benign familial neonatal convulsion focal seizures, which were ascribed to the K554N loss-of-function mutation. Most of those who present with early infantile epileptic encephalopathy have loss-of-function mutations (Orhan et al., 2014; Zhang et al., 2017); nevertheless, some cases with gain-of-function mutations have been reported, too. Miceli et al. (2015a) proved that R201C, R144Q, and R201H mutations identified in patients with epileptic encephalopathies and/or ID possessed gain-of-function characteristics. Millichap et al. (2017) reported a case presenting with infantile spasms and severe ID, without previous neonatal seizures, carrying the R198Q gain-of-function variant. Gain-of-function R201C and R201H variants were found in 10 cases with severe neonatal encephalopathy but devoid of neonatal seizures (Mulkey et al., 2017). The M-current blocker XE991 has been reported to improve learning and memory in healthy mice (Fontan-Lozano et al., 2011). Thus, gain-of-function mutations might explain ID. For epileptic encephalopathy cases, it remains unclear whether the severe to profound ID is a consequence of epileptic activity per se, because seizure frequency and electroencephalography abnormalities do not match the degree of ID and behavioral disturbances in patients with SCN1A mutations (Nabbout et al., 2013). Nevertheless, this link has not been studied in KCNQ2 epileptic disorders. Retigabine, a Kv7.2/Kv7.3-channel opener, diminishes KA-induced seizure activities in knock-in mice (Kcnq2Y284C/⁺ and Kcnq2A306T/⁺), was approved by the Food and Drug Administration as an anticonvulsant (Ihara et al., 2016), however, it was removed due to its side effects (Abou-Khalil, 2019). Thus, more studies are required to explore how gain-of-function mutations result in epileptic encephalopathies, as well as how loss-of-function mutations lead to ID.

KCNQ3 (potassium voltage-gated channel subfamily Q member 3) encodes the Kv7.3 voltage-gated ion channel subunit. This, together with Kv7.2, facilitates the M-current (IKM), which is vital for putting off neuronal excitability (Wang et al., 1998). Kv7.3 channels are common in the brain especially in the axon's initial segment and nodes of Ranvier (Greene and Hoshi, 2017). They control the firing of pyramidal neurons either by initiating the axon initial segment membrane potential, restricting the depolarization that follows an action potential or defining their input resistance during relaxation and as neurons come near the action potential threshold (Greene and Hoshi, 2017). The activation and possibility of opening this channel depend on PIP2 (Li et al., 2005; Kim et al., 2016).

Gain-of-function mutations R230C and R227Q have been reported in cases presenting with moderate to severe ID (Sands et al., 2019); however, the same phenotype has been associated also with the loss-of-function mutation R330L (Miceli et al., 2015b). Hence, it remains to be determined how both types of mutations in KCNQ3 can lead to mild to severe ID. The M-current blocker XE991 has been demonstrated to improve learning and memory in healthy mice (Fontan-Lozano et al., 2011).

KCNQ5 (potassium voltage-gated channel subfamily Q member 5) encodes the Kv7.5 channel (Schroeder et al., 2000). This channel plays a key role in regulating M-type current and afterhyperpolarization conductance, resulting in neuronal excitability. It is highly expressed in the brain, especially in presynaptic terminals of pyramidal neurons and hippocampal interneurons, which enables the regulation of inhibitory inputs within the hippocampal network (Fidzinski et al., 2015). Lehman et al. (2017) reported three cases with mild to severe ID accompanied with epilepsy and characterized by both loss-of-function mutations, such as S448I, V145G, L341I, as well as the gain-of-function mutation P369R in one case that presented with severe to profound ID. Rosti et al. (2019) reported a case presenting with mild ID and epilepsy, for whom genetic tests revealed V133^*. The molecular mechanism underlying this condition was haploinsufficiency. A dominant-negative Kcnq5 mutation in mice showed alteration of synaptic inhibition and excitability in the hippocampus; however, no seizures were detected (Tzingounis et al., 2010; Fidzinski et al., 2015). Because the M-current blocker XE991 enhances learning and memory in healthy mice (Fontan-Lozano et al., 2011), it is unclear how both gain- and loss-of-function mutations in KCNQ5 can lead to ID.

KCNAB1 (potassium voltage-gated channel subfamily A member regulatory beta subunit 1) encodes the Kvbeta1 Shaker-related channel (Butler et al., 1998). Kvbeta1 channels are particularly abundant in the cerebral cortex, hippocampus, cerebellum, dorsal striatum, and colliculus (Butler et al., 1998). They control action potentials through their effect on pore-forming alpha subunits and facilitate closing of delayed rectifier potassium channels by using their N-terminal domain to block the pore (Accili et al., 1998). This ultimately makes it easier for other members of the same channel family to close as fast as possible (Accili et al., 1998). Zhang Y. et al. (2015) reported a case with early onset epileptic encephalopathy with severe ID. Genetic testing revealed de novo mutations in KCNAB1 (L355Hfs^*5), but were not complemented by electrophysiological studies. Murphy et al. (2004) demonstrated improved learning, neuronal excitability, and synaptic plasticity in Kvbeta1.1 KO mice. The Kvbeta1.1-deficient mice exhibited usual synaptic plasticity but displayed impaired learning of a water maze test and in the social transmission of food preference task, signifying that the Kvbeta1.1 subunit contributes to certain kinds of learning and memory (Giese et al., 1998). Thus, it remains unclear how KCNAB1 mutations lead to ID, and hence further investigations are warranted.

KCNC1 (potassium voltage-gated channel subfamily C member 1) encodes the Kv3.1 channel, a subunit of the Kv3 subfamily of channels. They are abundant in the CNS, particularly in GABAergic interneurons (Gan and Kaczmarek, 1998). These channels are critical constituents of the circuitry of neurons as they can fire action potentials at high frequency (Wang et al., 2007) and are among the channels regulated by FMRP (Strumbos et al., 2010).

Loss of Kv3 function interrupts the firing of fast-spiking neurons and disturbs the release of neurotransmitter (Sabatini and Regehr, 1997; Erisir et al., 1999; Issa et al., 2011). Poirier et al. (2017) reported three cases with moderate to severe ID carrying the loss-of-function mutation R339^* while a similar case, T399M, was reported recently by Park et al. (2019) and six cases were reported by Cameron et al. (2019), including mutations A421V, R317H, and Q492X.

Thus, it seems that both ID and epilepsy can occur due to loss-of-function mutations, although the exact mechanism underlying this process will require further studies. Mice lacking Kv3.1 channels demonstrated altered synaptic transmission and motor dysfunction, suggesting a role for this channel in cognition (Matsukawa et al., 2003). However, other studies showed that Kv3.1- deficient mice had no obvious learning or memory deficit, only motor dysfunction (Espinosa et al., 2001; Zhang and Kaczmarek, 2016). Kv3.1 channel modulator (AUT000206) could rescue cognitive deficits in a schizophrenia phencyclidine model (Reynolds and Neill, 2016).

KCNC3 (potassium voltage-gated channel subfamily C member 3) encodes the Kv channel Kv3.3 subunit (Gutman et al., 2005). Its major purpose is to initiate the repolarization phase of action potentials (Rudy and McBain, 2001). These channels are abundant in the brain stem and cerebellum (Rudy and McBain, 2001; Chang et al., 2007; Puente et al., 2010). Duarri et al. (2015) reported three cases, of which one presented with severe ID and two with mild ID accompanied with cerebellar ataxia. They had the following mutations: sporadic D129N (gain-of-function) for the case with severe ID, sporadic R423H (loss-of-function) and sporadic and familial V535M (gain-of-function) for the mild ID cases. How gain-of-function mutations can result in both severe and mild ID needs to be explored further. Mice lacking Kv3.3 channels demonstrated altered synaptic transmission and motor dysfunction, suggesting a role in cognition (Matsukawa et al., 2003). However, another study showed that Kv3.3-deficient mice had no obvious learning or memory deficit but displayed motor dysfunction (Espinosa et al., 2001; Zhang and Kaczmarek, 2016).

KCNB1 (potassium voltage-gated channel subfamily B member 1) encodes the Kv2.1 channel potentials (Guan et al., 2013; Liu and Bean, 2014). Kv2.1 channels produce delayed-rectifier potassium currents in hippocampal and cortical pyramidal neurons, and are essential for afterhyperpolarization by their action potentials (Guan et al., 2013; Liu and Bean, 2014). They are abundant in the proximal axon initial segment (Trimmer, 2015) and can result in either excitatory or inhibitory neuronal activity depending on the extent of the stimulus (Liu and Bean, 2014). Torkamani et al. (2014) reported three cases with severe ID accompanied by epileptic encephalopathy. All had mutations with loss of function effect, such as de novo missense mutations S347R, G379R, and T374I. Srivastava et al. (2018) reported two cases with severe ID diagnosed as atypical Rett syndrome. Genetic studies revealed their mutations to be G379R and T374I (loss of function effect). In addition, Krey et al. (2019) recently reported a case diagnosed with both severe ID and West syndrome, which was revealed to originate from the de novo heterozygous deletion mutation W370^*. Additional variants with loss-of-function properties detected in cases with severe GDD/ID include R583^*, K502fs, G401R, V378A, and R306C (Saitsu et al., 2015; Thiffault et al., 2015; de Kovel et al., 2017). Thus, it seems like loss-of-function mutations of KCNB1 may lead to ID.

Mutant Kv2.1(⁻/⁻) mice deficient for the Kv2.1 channel demonstrated decreased long-term potentiation at the Schaffer collateral-CA1 synapse, impaired spatial learning, failure to perform better in a Morris water maze, and hyperactivity (Speca et al., 2014). Besides, these mice were not prone to spontaneous seizures but rather exhibited enhanced seizure advancement. Kv2.1 is transferred to membrane-bound clusters, which are detected in rodent dopamine neurons both in vivo and in vitro (Lebowitz et al., 2019). This finding suggests that an altered functional interaction between the dopamine transporter and Kv2.1 impacts dopamine neuron activity (Lebowitz et al., 2019).

KCTD3 (potassium channel tetramerization domain containing 3) encodes a protein found to bind to the hyperpolarization-activated cyclic nucleotide-gated channel HCN3 (Cao-Ehlker et al., 2013). There are few studies regarding the function of this gene. Kctd3 and Hcn3 co-localize in the cerebellum, hypothalamus, and midbrain and Kctd3 upregulates the expression of Hcn3 (Cao-Ehlker et al., 2013). HCN3 modulates synaptic strength and cellular excitability (Biel et al., 2009; Huang et al., 2011). Faqeih et al. (2018) reported seven cases with severe GDD, epilepsy, and cerebellar hypoplasia, of which five were carrying P346Tfs^*4 and the other two were carrying R56^* mutations. Electrophysiological studies revealed loss-of-function as a mechanism underlying the disease (Faqeih et al., 2018). Similarly, Alazami et al. (2015) and Trujillano et al. (2017) reported two cases with severe GDD, epilepsy, and cerebellar hypoplasia, who carried the P346Tfs^*4 variant. Thus, it seems KCTD3 loss-of-function is the underlying mechanism for GDD/ID. However, more animal model studies are needed to confirm this hypothesis.