Table 1.
Mouse and human stem cell models for NDD + E
| Gene | Disease | Genotype | Phenotype | ||||
|---|---|---|---|---|---|---|---|
| Patients | Mouse models | Human stem cell models | Patients | Mouse models | Human stem cell models | ||
| MECP2 | Rett Syndrome | X‐linked, LoF mutations (Amir et al., 1999) | Exon 3–4 deletion (Guy et al., 2001), Exon 3 deletion (Chen, Akbarian, Tudor, & Jaenisch, 2001), R168X (Lawson‐Yuen et al., 2007), R255X, T158A (Goffin et al., 2011), T158M, Y120D (Gandaglia et al., 2019), R306C (Lyst et al., 2013) | R306C, 1155del32, Q244X and T158M (Marchetto et al., 2010), exon 3–4 deletion (Cheung et al., 2011), R294X, T158M, V247X and R306C (Ananiev, Williams, Li, & Chang, 2011) (Williams et al., 2014) | Developmental arrest or regression (>1y), deterioration in communication, social and fine motor skills (Singer & Naidu, 2001). Epilepsy in 50%–90% of patients, heterogeneous seizure phenotype with generalized or focal onset (Tarquinio et al., 2017) | Motor and sensory impairments, behavioural dysfunction, myoclonic jerks, spontaneous or handling‐induced seizures (Katz et al., 2012) | Reduced soma size, neurite outgrowth and glutamatergic synapses. Decreased frequency of spontaneous post‐synaptic currents. Adverse effect of RTT astrocytes on WT neurons. (Marchetto et al., 2010; Cunningham Williams et al., 2014) |
| FMR1 | Fragile X | X‐linked, >200 CGG expansion, FMR1 methylation and transcriptional silencing, LoF (Richter et al., 2015) | PTC in exon 5 (Bakker et al., 1994), exon 1 deletion (Mientjes et al., 2006); CGG(98) (Bontekoe et al., 2001), CGG‐CCG (120) (Entezam et al., 2007) | 450 CGG repeats (Urbach et al., 2010), 94 CGG repeats (Liu et al., 2012) | ASD, ID and epilepsy in around 20% of cases (Musumeci et al., 1999) | Audiogenic seizures, network hyperactivity, behavioural abnormalities, cognitive deficits. No spontaneous seizures. (Dahlhaus, 2018) | Decreased neurite outgrowth and synapse formation. Increased amplitude and frequency of calcium transients. (Liu et al., 2012) |
| UBE3A | Angelman Syndrome | LoF of maternal allele (Sell & Margolis, 2015) | Maternal exon 5 deletion (Jiang et al., 1998), PTC in exon 5 (Wang, van Woerden, Elgersma, & Borst, 2017) | 5bp deletion in exon 6 (Sun et al., 2019) | Microcephaly, ataxia, hypotonia and motor delay. Seizures in 90% of cases, no distinctive seizure phenotype (Buiting et al., 2016). | Mild cognitive impairment, motor and behavioural dysfunction, audiogenic and flurothyl‐induced seizures, abnormal EEG. No spontaneous seizures. (Rotaru et al., 2020) | Altered excitability, increased fAHP, augmented BK channel expression and synchronous, epileptiform activity (Sun et al., 2019). |
| TSC1 | Tuberous sclerosis complex | Germline LoF mutations, second‐hit somatic mutation (Curatolo et al., 2008) | Tsc1+/‐ exon 6–8 deletion (Goorden et al., 2007) | Patient‐derived iPSCs: W750X (Nadadhur et al., 2019) | ASD, ID and intractable epilepsy. Tumours: subependymal nodules and subependymal giant cell astrocytomas. Cortical tubers. Less severe than TSC2 mutation. | Cognitive deficits and impairments in social behaviour. No cerebral lesions, no seizures (Goorden et al., 2007) | Increased network activity, hypertrophy, increased OL proliferation and decreased maturation (Nadadhur et al., 2019) |
| TSC2 | Tuberous sclerosis complex | Germline LoF mutations, second‐hit somatic mutation (Curatolo et al., 2008) | Tsc2+/− exon 2 deletion (Ehninger et al., 2008) | Patient‐derived iPSCs: c.1444 − 2A> C (Li et al., 2017), H522T (Nadadhur et al., 2019), N1515 del1573 and Q794X (Zucco et al., 2018) Genetically engineered hESCs: exon 11 deletion (Costa et al., 2016) | ASD, ID and intractable epilepsy. Tumours: subependymal nodules and subependymal giant cell astrocytomas. Cortical tubers. More severe than TSC1 mutation. | Cognitive deficits. No cerebral lesions, no seizures (Ehninger et al., 2008) | Altered synaptic transmission and differentiation in heterozygotes (Costa et al., 2016) |
| SCN1A | FS, GEFS+, Dravet syndrome | LoF mutations, happloinsufficiency (Catterall et al., 2010) | Exon 1 deletion (Miller et al., 2014), Exon 26 deletion (Yu et al., 2006), R1407X (Ogiwara et al., 2007), R1648H ((Escayg et al., 2000), E1099X (Tsai et al., 2015) and A1783V (Ricobaraza et al., 2019) | S1328P (Sun et al., 2016), R1645X (Higurashi et al., 2013), G1410W and I1183CfsX21 (Kim et al., 2018) | Phenotypic severity correlated with genotype, from FS to DS. DS characterized by prolonged febrile and afebrile, generalized clonic or hemiclonic seizures in the first year of life. Cognitive, behavioural and motor impairments in the second year of life. (Catterall et al., 2010) | Ataxia, spontaneous and thermal seizures, premature death, cognitive impairment, behavioural disturbances. Phenotype largely dependent on background strain. (Mistry et al., 2014; Ricobaraza et al., 2019; Yu et al., 2006) | Decreased sodium current densities and action potential firing in inhibitory neurons but not excitatory neurons (Sun et al., 2016). |
| SCN2A | SCN2A encephalopathy | GoF and LoF mutations (Brunklaus et al., 2020) | Scn2aQ54 (Kearney et al., 2001); exon 1 deletion (Planells‐Cases et al., 2001) | SCN2A GoF: neonatal and early onset epilepsy. SCN2A LoF: later‐onset epilepsy, ASD, ID. Both: Variable seizure phenotype but no absence seizures. (Wolff et al., 2017) | Scn2a GoF: focal and absence‐like seizures, stereotyped repetitive behaviour. (Kearney et al., 2001) Scn2a LoF: hyperactivity, anxiety, social and communication impairments, cognitive deficits, absence‐like seizures. (Lena & Mantegazza, 2019) | ||
| SCN8A | SCN8A encephalopathy | GoF and LoF mutations (Brunklaus et al., 2020) | N1768D (Veeramah et al., 2012), R1872W (Bunton‐Stasyshyn et al., 2019) | SCN8A GoF: neonatal and early onset epilepsy. SCN8A LoF: ID and myoclonus without epilepsy (Wagnon et al., 2018) Both: variable seizure phenotype, ataxia, dystonia, hypotonia (Larsen et al., 2015) | Scn8a GoF: Spontaneous seizures, premature death. (Veeramah et al., 2012; Stasyshyn et al., 2019) | ||
| KCNQ2/KCNQ3 | Benign familial neonatal epilepsy | LoF mutations (Shellhaas et al., 2017) | Kcnq2 exon 3–5 deletion (Watanabe et al., 2000), Kcnq2 A306T and Kcnq3 G311V (Singh et al., 2008) | Early onset epilepsy, developmental delay, hypotonia, dystonia (McTague et al., 2016) | Increased sensitivity to PTZ and electrically induced seizures, early onset spontaneous generalized seizures in homozygous but not heterozygous mice. (Singh et al., 2008) | ||
| KCNT1 | Epilepsy of infancy with migrating focal seizures | GoF mutations (McTague et al., 2013) | P924L (Burbano et al., 2018) | Early onset epilepsy, nocturnal or migrating focal seizures, hypotonia, microcephaly (McTague et al., 2013) | Increased sensitivity to thermal and chemically induced seizures in heterozygotes. Spontaneous seizures, behavioural deficits and decreased lifespan in homozygotes. (Burbano et al., 2018) | ||
| KCNC1 | KCNC1 encephalopathy | LoF and dominant‐negative mutations (Cameron et al., 2019; Park et al., 2019) | Epilepsy with myoclonic seizures, developmental delay (Park et al., 2019; Cameron et al., 2019) | ||||
| STXBP1 | STXBP1 encephalopathy | LoF mutations, happloinsufficiency (Stamberger et al., 2016) | Exon 3 deletion (Miyamoto et al., 2017), exon 2–6 deletion (Kovacevic et al., 2018) | ID and epilepsy in 95% of cases (Stamberger et al., 2016) | Normal motor function and diurnal behaviour. Myoclonic jerks, spike‐wave discharges, cognitive deficits, hyperactivity, anxiety and altered social behaviour. (Kovacevic et al., 2018) | ||
| SYN1/SYN2 | ASD, X‐linked focal epilepsy | LoF mutations (Fassio et al., 2011; Corradi et al., 2014) | SynI exon 1 deletion (Chin, Li, Ferreira, Kosik, & Greengard, 1995), SynII exon 9–10 deletion (Rosahl et al., 1995) | ASD and partial epilepsy (Fassio et al., 2011; Corradi et al., 2014) | Spontaneous seizures in homozygous but not heterozygous mice. Autistic‐like social and behavioural alterations in homozygous mice. (Greco et al., 2013; Michetti, Castroflorio, et al., 2017) | ||
| PRRT2 | Benign familial neonatal epilepsy, Paroxysmal kinesigenic dyskinesia | LoF mutations (Ebrahimi‐Fakhari et al., 2015) | Exon 1–2 deletion (Michetti, Castroflorio, et al., 2017) |
c.649dupC (Fruscione et al., 2018) |
Early onset epilepsy, dyskinesia, ID and ASD (Ebrahimi‐Fakhari et al., 2015) | Abnormal motor behaviours and motor paroxysms. No cognitive defects, no spontaneous seizures. (Michetti, Castroflorio, et al., 2017) | Increased Na + currents, increased AIS length and augmented spontaneous and evoked activity (Fruscione et al., 2018). |
| DNM1 | DNM1 encephalopathy | Dominant‐negative mutations (Spiczak et al., 2017) | A408T (Boumil et al., 2010) | Refractory epilepsy, ID and hypotonia (Spiczak et al., 2017) | Handling and electrically induced seizures in heterozygotes. Spontaneous seizures, ataxia, vision and hearing impairments in homozygotes. (Boumil et al., 2010) | ||
| GABRG2 | GEFS+, Dravet syndrome | LoF and dominant‐negative mutations (Kananura et al., 2002) | Q390X (Kang et al., 2015) | DS‐like early onset refractory epilepsy, developmental delay (Kananura et al., 2002) | Spontaneous and thermal seizures, premature death. (Kang et al., 2015) | ||
| GABRA1 | Dravet syndrome, Juvenile myoclonic epilepsy | LoF mutations (Cossette et al., 2002) | Exon 9 deletion (Arain et al., 2012) | Variable seizure type: myoclonus, absence, generalized and focal (Steel et al., 2017) | Absence‐like seizures, premature death. (Arain et al., 2012) | ||
| GRIA2 | NDD with or without epilepsy, Idiopathic focal epilepsy | LoF mutations (Lemke et al., 2013; Salpietro et al., 2019) | ASD and ID with or without epilepsy. If epilepsy, usually tonic‐clonic, focal or focal with rolandic spikes (Lemke et al., 2013; Salpietro et al., 2019) | ||||
| GRIN1 | GRIN1 encephalopathy | LoF mutations (Lemke et al., 2016) | Nr1‐neo in intron 20 (Mohn, Gainetdinov, Caron, & Koller, 1999), exon 5 deletion (Liu et al., 2019) | Epilepsy, ID and movement disorders (Lemke et al., 2016) | Defects in sensorimotor gating and cognitive deficits in hypomorph mice. Increased susceptibility to chemically induced seizures in homozygous mice but no spontaneous seizures. (Barkus et al., 2012; Liu et al., 2019) | ||
| GRIN2A | Epilepsy and ID, Epilepsy‐aphasia spectrum | GoF or LoF mutations (Myers et al., 2019) | Grin2a KO (Salmi et al., 2018) | Epilepsy, ID, ASD, aphasia, hypotonia, dystonia (Myers et al., 2019) | Epileptiform discharges, no spontaneous seizures. (Salmi et al., 2018) | ||
| GRIN2B | NDD with or without epilepsy | GoF or LoF mutations (Fedele et al., 2018) | Epilepsy, ID, ASD (Myers et al., 2019) | ||||
| SYNGAP1 | MRD5 | LoF mutations, happloinsufficiency (Deciphering Developmental Disorders Study, 2017) | Exon 7–8 deletion (Kim, Lee, Takamiya, & Huganir, 2003), exon 4–9 deletion (Vazquez, Chen, Sokolova, Knuesel, & Kennedy, 2004), stop codon at exon 4 (Komiyama et al., 2002). | Epilepsy and ID (Deciphering Developmental Disorders Study, 2017) | Cognitive deficits, spontaneous interictal activity and increased sensitivity to fluorothyl‐induced seizures in heterozygous mice. No spontaneous seizures. (Kilinc et al., 2018) | ||
| CDKL5 | CDKL5 deficiency disorder | X‐linked, LoF mutations (Olson et al., 2019) | Exon 2 deletion (Okuda et al., 2017), conditional exon 4 deletion (Amendola et al., 2014), exon 7 deletion (Wang et al., 2012) | Patient‐derived iPSCs: R59X and L220P (Ricciardi et al., 2012), G347X and T288I (Livide et al., 2015) | Epilepsy, ID, developmental delay, hypotonia, visual impairment. Primarily affects females (Olson et al., 2019). | Hyperexcitability, autistic‐like phenotype, impaired vision, motor control and memory. Reduced dendritic arborization of cortical neurons. Abnormal EEG and increased susceptibility to NMDA‐induced seizures but no spontaneous seizures. (Amendola et al., 2014; Wang et al., 2012; Okuda et al., 2017) | Decreased synapse formation and abnormal spine morphology. (Ricciardi et al., 2012) |
ASD, autism spectrum disorder; FS, febrile seizure; GEFS, generalized epilepsy with febrile seizures plus; ID, intellectual disability; PRRT2, proline‐rich transmembrane protein 2.