Table 2.
Genes causally linked to CAS and other neurodevelopmental phenotypes between 2001 and 2023.
| Gene | Disease name, OMIM | Loci | Mode of inheritance | Year, method of discovery | Molecular pathway & function | Associated features | Independent cases linked to CAS | Strength of evidence |
|---|---|---|---|---|---|---|---|---|
| FOXP2 | FOXP2-Related Speech & Language Disorder, 605317 | 7q31.1 | AD, de novo | 2001, Linkage/Sanger sequencing | Transcriptional regulation. Encodes putative forkhead box P2 transcription factor with forkhead DNA binding domain and polyglutamine tract [12]. Expressed in foetal and adult brain in regions important for speech and language development. Regulates at least 34 target genes in developing human brain including neurodevelopmental genes CNTNAP2, FOXP1, TBR1 [41]. | Cognition ranges from average to mild ID, feeding difficulties in infancy, fine & gross motor impairment, ASD, language impairment, anxiety, depression, sleep disturbance. | Morison et al., 2023 [29] | High |
| CHD3 | Snijders Blok-Campeau syndrome, 618205 | 17p13.1 | AD, de novo | 2019, WGS | Chromatin-remodeller/reader. Member of CHD family of ATP-dependent chromatin remodelling proteins that modulate gene expression. Encodes chromodomain DNA helicase ATPase highly expressed during early brain development. Remodels chromatin through deacetylation of histone proteins to modulate downstream transcription factors important for specification of cortical layering [42]. | ID/DD, macrocephaly, prominent forehead, hypertelorism, hypotonia, joint laxity, severity of neurologic deficits & presence of non-neurologic features are variable. Autistic features are commonly reported. | Snijders Blok et al., 2018 [43] | Medium |
| KAT6A | KAT6A syndrome, 601408 | 8p11 | AD, de novo | 2019, WGS | Chromatin writer/reader. Encodes for member of MYST family of histone methyltransferases, with wide range of core cellular functions, e.g., chromatin remodelling, transcriptional regulation, protein translation, metabolism, cellular replication. Forms complex with KAT6B, BRPF1, and two non-catalytic subunits with role in development of neural and hematopoietic stem cells [44]. | ID, vision impairment, GI dysfunction, sleep disturbance, ASD, majority minimally verbal & rely on alternate communication. Rates of epilepsy, ADHD, CP higher than typical population. | St John et al., 2022 [45] | High |
| MKL2/MRTFB^ | MRTFB-related disorder, 609463 | 16p13.12 | De novo | 2019, WGS | Transcriptional regulation. This transcriptional regulator binds with its cofactor, serum response factor (SRF) to regulate over 300 genes, including those that regulate the actin cytoskeleton of cells critical for development (ACTB, ACTG1, GSN) and synaptic activity (CDK5R1, CDK5, RYR1, RYR3, CLTC, DLG4, ARC) [46]. | ID, GDD, CAS, mild dysmorphic features, impulse control issues. | Andrews et al., 2023 [46] | High |
| SETBP1 | SETBP1 haplo-insufficiency disorder, 616078 | 18q12.3 | AD, de novo | 2019, WES | Transcriptional activity and expression. SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of HCF1/KMT2A/PHF8 epigenetic complex. Perturbed binding of SETBP1 to gDNA impairs target gene upregulation. SETBP1 target genes are key controllers of brain morphogenesis as shown by in utero brain electroporation of mutated SETBP1 which impairs mouse neurogenesis leading to profound delay in neuronal migration [47]. | ID, mild motor disorder, hypotonia, ASD, ADHD, vision impairment (refractive errors & strabismus). | Morgan et al., 2021 [30] | High |
| SETD1A | SETD1A neuro-developmental disorder, 619056 | 16p11.2 | AD, de novo | 2019, WGS | Transcriptional regulation/ epigenetic writer (histone methylation). SETD1A-mediated H3K4me3 is important for regulating cell cycle (e.g., activates β-catenin expression, required for proliferation of neuronal progenitor cells) and neuronal processes underlying normal cognitive functioning [48]. | ID/DD, epilepsy, facial dysmorphism subtle, increased risk of ASD and schizophrenia. | Kummeling et al., 202 [48] | Medium |
| TNRC6B | TNRC6B-related syndrome, 610740 | 22q13.1 | AD, de novo | 2019, WGS | Transcriptional regulation and RNA binding. Encodes for one of three paralogue proteins, involved in translational inhibition. TNRC6A, TNRC6B, and TNRC6C associate with Argonaute family of proteins to coordinate posttranscriptional gene silencing [49]. | ID/DD, fine & gross motor delay, ASD, ADHD, musculoskeletal findings. Rate of epilepsy higher than in the general population. | N/A | Low |
| WDR5 | WDR5 neuro-developmental disorder, 609012 | 9q34.2 | AD, de novo | 2019, WGS | Transcriptional regulation/chromatin scaffolding. Encodes a member of the WD repeat protein family. Members of this family are involved in variety of cellular processes and chromatin scaffolding functions including cell cycle progression, signal transduction, apoptosis, and transcriptional regulation [50]. | ID, speech & language impairments, epilepsy, ASD, ADHD. | Snijders Blok et al., 2023 [51] | Medium |
| ZFHX4 | ZFHX4-associated syndrome, 606940 | 8q21.11 | AD, de novo | 2019, WGS | Transcriptional regulation. Encodes for transcription factor important in embryonic processes, including regulating neural and mesenchymal cell differentiation. ZFHX4 binds to and modulates function in nucleosome remodelling and deacetylation [52]. | ID, hypotonia, sleep issues, over-friendly, anxiety, ASD, ADHD, imbalance, seizures/epilepsy. | N/A | Low |
| CDK13 | CDK13-related disorder, 603309 | 7p14 | AD, de novo | 2020, WGS |
Transcriptional regulation/expression. Encodes a member of ATP-dependent serine/threonine protein kinase family important in cell cycle control, transcription regulation, mRNA processing and hematopoiesis via phosphorylation [53]. |
ID/DD, recognizable facial features, behavioral findings, feeding difficulties in infancy, structural cardiac defects, seizures, ASD, ADHD. Reports of CP. | Morison et al., 2023 [54] | High |
| DDX3X | DDX3X syndrome, 300160 | Xp11.3–11.23 | X-Linked | 2020, WGS | Transcriptional regulation. Encodes for member of conserved DEAD-box protein family. This family has ATP-dependent RNA helicase activity, and is important for transcription regulation, gene splicing, RNA transport in the nucleus, translation, cell signalling and viral replication in the cytoplasm. DDX3X has important roles in cell cycle control, apoptosis, and tumorigenesis [55]. | ID/DD, hypotonia, feeding difficulty in infancy, ASD, ADHD, self-injurious behaviour, poor impulse control, aggression, many affected females remain nonverbal after age 5 years. Reports of epilepsy, CP. | N/A | Medium* |
| EBF3 | EBF3 neuro-developmental disorder, 607407 | 10q26.3 | AD, de novo | 2020, WES | Transcriptional regulator of neurogenesis, differentiation. Encodes for member of family of highly homologous transcription factors. Roles in B-cell differentiation, bone development, neurogenesis, laminar formation of cerebral cortex. EBF3 is a downstream transcriptional target of ARX and thought to be repressed by ARX [56]. | ID/DD, speech delay, gait or truncal ataxia/CP, hypotonia, behavioural problems, facial dysmorphism, significant variability between individuals. Rates of ASD/ADHD higher than in typical population. | Chao et al., 2017 [57] | High |
| GNAO1 | GNAO1 encephalopathy, 139311 | 16q13 | AD, de novo | 2020, WES | Synaptic protein/signal transduction. Encodes a guanine nucleotide-binding protein alpha subunit; part of family of signal-transducing molecules. Most abundant membrane protein in mammalian central nervous system, constituting 1% of total brain membrane protein [58]. | ID/DD, early infantile seizures, involuntary movements, CP. Rates of ASD/ADHD higher than in typical population. | Wirth et al., 2020 [59] | Unclear |
| GNB1 | GNB1 encephalopathy, 139380 | 1p36.33 | AD, de novo | 2020, WGS |
Synaptic protein/signal transduction. Encodes a guanine nucleotide-binding protein beta subunit, which is part of a large family of signal-transducing molecules [60]. |
ID/DD, structural brain anomalies, infantile hypotonia, CP, seizures. Rates of ASD/ADHD higher than in typical population. | N/A | Low |
| MEIS2 | MEIS2-related condition, 601740 | 15q14 | AD, de novo | 2020, WGS | Transcriptional regulation. Encodes for MEIS2 homeobox protein, which belongs to TALE homeodomain transcription factor family (alongside MEIS2 and MEIS3). Roles in cell migration, apoptosis, and metabolism [61]. | ID, facial dysmorphology, ASD, cleft palate, cardiac septal anomalies. | Douglas et al., 2018 [62] | High |
| POGZ | White-Sutton syndrome (POGZ-related disorder), 614787 | 1q21.3 | AD, de novo | 2020, WGS | Transcriptional regulation/chromatin-related. Encodes for a zinc-finger protein found in the cell nucleus. POGZ influences chromatin remodelling by binding to chromatin, and impacting gene transcription [63]. | ID/DD (wide spectrum of cognitive dysfunction), hypotonia, epilepsy, ASD, ADHD, behavioral issues. Schizophrenia reported. | Nagy et al., 2022 [64] | Unclear |
| UPF2 | UPF2-related disorder, 605529 | 10p14 | AD, de novo | 2020, WES | Transcriptional regulation. Encodes a core factor of the nonsense-mediated mRNA decay (NMD) complex alongside UPF3B and UPF1 that regulates transcription [65]. | ID, ASD, speech disorder. | N/A | Low |
| ZNF142 | ZNF142-related neuro-developmental disorder, 604083 | 2q35 | AR | 2020, WES | Transcriptional regulation. Encode member of Kruppel family of C2H2-type zinc finger proteins, involved in transcriptional regulation, signal transduction, meiotic recombination, DNA repair, cell proliferation and differentiation [66]. | ID, variable manifestation of seizures, tremor, dystonia. | Khan et al., 2019 [67]; Christensen et al., 2022 [68] | Medium |
| ARHGEF9 | ARHGEF9-related disorder & encephalopathy, 300429 | Xq11.1 | X-linked | 2022, WGS | Synaptic protein/signal transduction. Encodes Rho guanine nucleotide exchange factor that connects microtubule and actin cytoskeleton dynamics and is required for mitotic spindle formation and orientation that is critical for synaptic function [69]. | ID, epilepsy, ASD, dysmorphology. | N/A | Low |
| BRPF1 | BRPF1-related disorder, 602410 | 3p25 | AD, de novo | 2022, WGS | Chromatin reader/writer. Forms complex with KAT6A to activate histone acetylation. Role in transcriptional regulation, chromatin binding and remodelling [70]. | ID, facial dysmorphology, ptosis, variable expressivity speech & language disorder. Rates of ASD/ADHD higher than in typical population. | Yan et al., 2017 [71] | Medium |
| DIP2C | DIP2C-related disorder, 611380 | 10p15.3 | AD, de novo | 2022, WGS | Transcriptional regulation. Encodes member of disco-interacting protein homolog 2 family, with important roles in cell growth, cell cycle regulation, and migration related to DNA methylation and gene expression changes [72]. | ID, ASD, speech & language disorder. Reports of epilepsy, schizophrenia, CP. | N/A | Low |
| ERF | ERF-related craniosynostosis, 611888 | 19q13 | AD, de novo | 2022, WGS | Transcriptional regulation. Encodes for member of ETS family of transcription factors, which regulates cell proliferation and differentiation. | ID, ASD, ADHD, craniosynostosis (often postnatal), visual impairment, facial dysmorphism, speech delay, poor gross & fine motor control, hyperactivity, poor concentration. | N/A | Low |
| HNRNPK | HNRNPK-related condition, 600712 | 9q21.32 | AD, de novo | 2022, WGS | Transcriptional regulation. Encodes for conserved RNA-binding protein, involved in gene expression (chromatin remodelling and gene transcription), mRNA splicing, translation, and stability [73]. | ID/DD, motor delay, speech delay, structural brain abnormalities, epilepsy, ASD, ADHD, dysmorphic features, hypotonia, skeletal abnormalities, hand/feet abnormalities, cardiac abnormalities, genitourinary issues. | N/A | Low |
| KDM5C | KDM5C neurodevelopmental disorder, 314690 | Xp11.22 | X-linked, de novo | 2022, WGS | Chromatin eraser/reader. Encodes a histone demethylase protein that functions as a transcriptional repressor through the REST complex [74]. | ID, short stature, facial dysmorphology, epilepsy, ADHD, behavioural disorders, spasticity/CP. | Jensen et al., 2005 [75]; Tzschach et al., 2006 [76]; Leonardi et al., 2023 [77] | Unclear |
| PHF21A | PHF21A-related condition, 608325 | 11p11.2 | AD, de novo | 2022, WGS |
Transcriptional regulation/chromatin reader. Encodes for a protein that binds to demethylated histones to repress gene expression [78]. |
ID, hypotonia, dysmorphic features, speech & language delay, ASD, ADHD, epilepsy. | N/A | Low |
| PURA | PURA syndrome, 600473 | 5q31 | AD, de novo | 2022, WGS | Transcriptional regulation. Encodes for a highly conserved Pur-alpha protein, involved in DNA and RNA binding, contributing to transcription regulation, DNA replication, RNA transport and mRNA translation. Important for neurogenesis, synapse formation, and myelin maturation [79]. | ID, severely delayed walking & motor skills (may not walk), hypotonia, dysphagia, epilepsy, heart abnormalities, urogenital, respiratory, GI & skeletal anomalies, hormone disorders, minimally verbal or no speech. | N/A | Low |
| RBFOX3 | RBFOX3-related disorder, 616999 | 17q25.3 | AD, de novo | 2022, WGS | Transcriptional regulation. Encodes for member of RNA-binding Fox protein family that regulates RNA splicing. RBFOX3 is exclusively expressed in neurons and critical in brain development via regulation of neuronal differentiation, hippocampal neurogenesis, synaptogenesis [80]. | ID, epilepsy, ASD, speech & language impairment. Schizophrenia reported. | Lal et al., 2013 [81] | High |
| SETD1B | SETD1B-related neurodevelopmental disorder, 611055 | 12q24.31 | AD, de novo | 2022, WGS | Transcriptional regulation/chromatin-related epigenetic writer (histone methylation). Encodes lysine-specific catalytic SET domain protein of histone methyltransferase complex. Plays important role in epigenetic regulation of gene transcription. Member of COMPASS complex including KMT2A-D and KMT2F [82]. | ID/DD (precedes seizure onset), ASD, ADHD, variable epilepsy phenotypes, behavioural issues; males over-represented. | N/A | Low |
| SHANK3 | SHANK3-related condition, 606230 | 22q13 | AD, de novo | 2022, WGS | Synaptic protein. Encodes for scaffolding protein enriched in postsynaptic densities of excitatory synapses required for formation and maturation of dendritic spines [83]. | ID/DD, ASD, ADHD, epilepsy, absent to severely delayed speech. Schizophrenia reported. | Brignell et al., 2021 [84] | High# |
| SPAST | Spastic paraplegia type 4, 604277 | 2p22.3 | AD, de novo | 2022, WGS | Encodes for protein, spastin, which is a microtubule-severing ATPase and member of AAA protein family. Role in regulating microtubule cytoskeleton length, structure; important in organelle transport, cell division, neuronal morphogenesis [85]. | ID/DD, motor & speech delay, ASD, progressive ascending spasticity/CP, dystonia, neurogenic bladder dysfunction, GI dysmotility, epilepsy. | N/A | Low |
| TAOK2 | TAOK2 neurodevelopmental disorder, 613199 | 16p11.2 | AD, de novo | 2022, WGS | Signal transduction. Encodes for serine/threonine protein kinase involved in cell signalling, microtubule organization, stability, and apoptosis. | ASD, speech & language impairments. At risk for schizophrenia. | N/A | Low‡ |
| TRIP12 | TRIP12-related condition, 604506 | 2q36.3 | AD, de novo | 2022, WGS | Transcriptional regulation. Encodes for a chromatin remodelling E3 ubiquitin-protein ligase, important in cell cycle progression and maintenance of genome integrity. Important in DNA replication, mitotic progression, chromosome stability [86]. | ID/DD, ASD, epilepsy, speech & language disorder. Rate of ADHD higher than typical population. | N/A | Low |
| ZBTB18 | ZBTB18-related condition, 608433 | 1q44 | AD, de novo | 2022, WGS | Transcriptional regulation. Encodes a transcriptional repressor of key pro-neurogenic genes. Involved in chromatin assembly [87]. | ID, hypotonia, microcephaly, corpus callosal anomalies, epilepsy, ADHD, growth problems, variable facial dysmorphologies, speech & language impairments. | N/A | Low |
Table 2 key: ^MKL2 now known as MRTFB, AD autosomal dominant, AR autosomal recessive, ID intellectual disability, DD developmental delay, ASD autism spectrum disorder, ADHD attention deficit hyperactivity disorder, CP cerebral palsy, GI gastrointestinal.
Strength of evidence: Low = single case in one CAS cohort; Medium = >1 case, <20% verbal cases in an independent reverse phenotyping study; High = >20% of verbal cases in an independent phenotyping study.
Unclear = independent study reporting severe speech disorder but no assessment of CAS.
*Independent cases found in Hildebrand et al. (2020) and Kaspi et al. (2022) cohorts.
#2/3 with CAS in a cohort of individuals with Phelan-McDermid/22q13 deletion syndrome, caused by heterozygous loss of function of SHANK3.
‡34/44 (77%) individuals with CAS in a cohort of individuals with 16p11.2 deletion syndrome, of which TAOK2 is a core gene (Mei et al., 2018).