SYNGAP1-Related Neurodevelopmental Disorder

SYNGAP1-related developmental and epileptic encephalopathy; autosomal dominant intellectual disability 5 (MRD5)

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

SYNGAP1-related disorder is among the most frequent monogenic causes of intellectual disability and childhood-onset developmental and epileptic encephalopathy. Facial features or malformations rarely identify it clinically; its distinguishing feature is a temporal pattern. An infant with hypotonia and global delay develops generalised seizures with eyelid myoclonia, falls and absences between the second and fourth years, often triggered by chewing, while autistic features, very limited expressive language, relative pain insensitivity and severe sleep and behavioural abnormalities become established. SYNGAP1-ID, used by GeneReviews, emphasises intellectual disability; SYNGAP1-DEE, used by Orphanet and epileptology, emphasises developmental and epileptic encephalopathy (DEE). Both describe the same spectrum, termed SYNGAP1-related disorder (SRD) here [1, 2, 7, 9].

The condition’s history begins with synaptic neurobiology. In 1998, two groups independently described a Ras GTPase-activating protein highly abundant in excitatory neuronal postsynaptic densities, associated with PSD-95 and regulated by calcium/calmodulin-dependent protein kinase II (CaMKII): Mary Kennedy’s group called it p135 SynGAP and Richard Huganir’s group SynGAP [15, 16]. Eleven years later, Fadi Hamdan, Jacques Michaud and colleagues sequenced the gene in 94 people with non-syndromic intellectual disability, identifying three de novo truncating variants (K138X, R579X and L813RfsX22). They found no de novo or truncating variants in 142 people with autism spectrum disorder, 143 with schizophrenia and 190 controls. They concluded that SYNGAP1 disruption causes autosomal dominant non-syndromic intellectual disability, at a time when, as they noted, autosomal forms accounted for most non-syndromic intellectual disability but the genes involved remained largely unknown [17].

Subsequent years showed that the phenotype was not strictly “non-syndromic”. In 2010, a University of São Paulo group described a de novo microdeletion encompassing the gene in a person with intellectual disability, among the first 6p21.3 deletion reports [18]. In 2011, a balanced translocation disrupting SYNGAP1 was associated with epilepsy with myoclonic absences [19]. In 2013, Berryer and colleagues described the first pathogenic missense variants, demonstrated loss of function in the ERK pathway and reported transmission from a mosaic father; targeted screening of 500 people with epileptic encephalopathy found de novo variants in approximately 1% [20, 21]. In 2015, the British Deciphering Developmental Disorders (DDD) study identified SYNGAP1 among genes with excess de novo variants in developmental disorders, and Parker and colleagues delineated a syndromic pattern with broad-based gait, constipation, strabismus, hip dysplasia and myopathic facial appearance [22, 23]. Mignot’s French and European series (2016) and Vlaskamp’s international cohort of 57 patients (2019) characterised the epilepsy as a generalised DEE with a distinctive profile; von Stülpnagel described chewing-induced reflex seizures [9, 24, 25].

Between 2023 and 2026, research moved from description towards clinical-trial preparation: adult studies, natural history registries based on medical records and insurance data, caregiver-developed conceptual disease models, EEG and sleep biomarkers, and genetic treatment programmes including antisense oligonucleotides, adeno-associated viral (AAV) gene therapy and CRISPR transcriptional activation [3, 7, 14, 26, 27]. GeneReviews, created in 2019 and revised in August 2025 only in its investigational therapy section, remains the reference synthesis for diagnosis and counselling. However, its clinical figures derive mainly from just over 50 patients published through 2017; later cohorts provide updated estimates here, with population and method identified for each [1].

2. Molecular Genetics and Pathophysiology

2.1. Gene, protein and synaptic function

SYNGAP1 lies at 6p21.32. The longest transcript, now MANE Select NM_006772.3, has 19 exons and encodes a 1343-amino-acid protein with a pleckstrin homology (PH) domain, C2 domain, catalytic RasGAP domain, SH3-binding motifs and a coiled-coil region. An isoform with a different carboxy-terminal end (NM_001130066.1, 1292 amino acids) contains the QTRV motif required for interaction with postsynaptic scaffold proteins; further isoforms arise through alternative promoters and splicing [1, 5]. SynGAP is among the most abundant excitatory postsynaptic density proteins and forms part of the NMDA receptor signalling complex. Receptor activation permits calcium entry and activates CaMKII, which phosphorylates SynGAP. SynGAP accelerates GTP hydrolysis by Ras and Rap, restraining the Ras–ERK pathway and AMPA receptor insertion into the postsynaptic membrane [15, 16, 28].

The protein’s function extends beyond enzymatic activity. SynGAP forms trimers binding multiple PSD-95 copies and inducing phase separation, organising the postsynaptic density as a liquid condensate and regulating SynGAP dispersal during activity-dependent plasticity [29]. In heterozygous mice, loss of one allele accelerates dendritic spine maturation early in postnatal life, increases developing hippocampal excitability and produces behavioural abnormalities. Inducing the mutation after critical windows have closed has little effect, and correcting it in adulthood does not reverse behaviour [30]. Mouse studies in 2025 separated these roles: reduced cortical neuronal intrinsic excitability depends on GAP activity, while susceptibility to pentylenetetrazol-induced seizures relates to the structural role [31]. These animal observations alone do not establish an age limit for effective human intervention.

2.2. Haploinsufficiency and loss-of-function intolerance

SRD results from haploinsufficiency: pathogenic variants abolish expression of one allele or produce a truncated or misfolded non-functional protein [1]. The ClinGen Dosage Sensitivity Working Group assigned score 3 (sufficient haploinsufficiency evidence) on 9 November 2021, without triplosensitivity evidence. The epilepsy expert panel classified the gene’s relationship with “SYNGAP1-related complex neurodevelopmental disorder” (MONDO:0100038) as definitive on 2 April 2019. MANE-transcript gnomAD v4 metrics show pLI 1 and LOEUF 0.13, consistent with strong selection against loss-of-function variants [4]. In organotypic cultures, Berryer and colleagues demonstrated that wild-type SynGAP reduces activity-dependent phosphorylated ERK, an effect absent with p.Trp362Arg, p.Pro562Leu and p.Arg579* [20].

Haploinsufficiency has a direct therapeutic implication: the normal allele remains present in all neurons and could, in principle, be stimulated. Predominantly neuronal polypyrimidine tract-binding protein 2 (PTBP2) binds SYNGAP1 messenger RNA and promotes alternative splicing producing transcripts degraded by nonsense-mediated decay (NMD). Oligonucleotides blocking this interaction redirected splicing and partly increased protein in induced pluripotent stem cell-derived neurons from two patients [32]. The same rationale supports oligonucleotides acting on regulatory RNAs at the locus, full-gene AAV therapy and CRISPR transcriptional activation, described in section 7 [3, 14].

2.3. Variant spectrum and nomenclature

Most pathogenic variants cause loss of function: nonsense, frameshift, splice alterations, exon deletions and 6p21.3 microdeletions that include the gene; pathogenic missense variants are less frequent and tend to cluster in functional domains [1, 9]. In Vlaskamp’s cohort, the 57 patients had 34 truncating variants, 8 splice variants, 11 missense or in-frame insertion/deletion variants and 4 microdeletions; in the Citizen Health aggregated registries cited by SynGAP Research Fund, approximately 80% of diagnosed patients’ variants caused haploinsufficiency and approximately 12% were missense or small in-frame insertions/deletions [9, 14]. The true distribution may differ: López-Rivera’s mutational model predicted more missense than truncating variants, and SynGAP Research Fund interprets the discrepancy as underdiagnosis of patients with missense variants currently classified as of uncertain significance, a hypothesis that has not been demonstrated [14, 33].

Different numbering systems appear in the literature. The founding article used abbreviated protein notation; post-2013 articles often use NM_006772.2, and GeneReviews recommends coverage of all 19 exons of that reference [1, 17]. The current version is NM_006772.3; RefSeq marks NM_006772.2 as superseded, and version .3 corresponds to MANE Select ENST00000646630 [5, 6]. Table 1 gives examples checked in ClinVar and VariantValidator, without manually calculated conversions.

Table 1. SYNGAP1 variants cited in this article, normalised to NM_006772.3

2.4. Genotype–phenotype correlations and allelic disorders

GeneReviews concludes that no definitive correlation exists between variant type (missense, truncating or intragenic deletion) and cognitive ability or comorbidities. It considers penetrance 100% for developmental delay, cognitive dysfunction, intellectual disability and/or epilepsy in pathogenic germline variant carriers [1]. Nevertheless, recurring positional signals do not converge into a predictive rule. Mignot found greater seizure medication responsiveness with exon 4–5 than exon 8–15 variants. Combining its cohort with the literature, Vlaskamp found milder phenotypes in 6 of 12 people with exon 1–4 variants versus 6 of 85 with exon 5–19 variants (p = 0.001). A 246-published-case meta-analysis associated exon 1–6 variants with milder intellectual disability and lower autism risk but more refractory epilepsy. A 99-child Chinese series associated the PH domain with myoclonic seizures, C2 with epilepsy in 92.3%, and SH3 with a lower proportion of drug-resistant epilepsy. A 44-case Spanish cohort associated PH-domain variants with milder phenotypes and rare variants in related network genes with greater overall severity [9, 24, 37–39]. Alternative-promoter isoforms partially escaping loss of function have been proposed to explain proximal variant effects, but this remains unproven [9]. Identical recurrent variants produced different phenotypes in unrelated patients, while monozygotic twins had concordant phenotypes, suggesting additional genetic and environmental influences [9].

In families with inherited variants described in 2025, two early-exon variants were associated with attenuated maternal phenotypes, but a third family, also with a proximal variant, had typical presentations in both mother and child. The study concluded that familial transmission is not confined to mild phenotypes [8]. Gene-containing 6p21.3 microdeletions involving other genes (4–13 genes in Vlaskamp’s cohort) were associated with earlier seizure onset (20 months), without a difference in intellectual disability severity [9]. GeneReviews recognises no allelic disorders: no distinct germline phenotypes are associated with the gene. Associations between common variants and psychiatric disorders in the general population have no individual clinical application and cannot be transferred to SRD [1].

3. Clinical Spectrum and Manifestations by System

3.1. Data origins and comparison limitations

SRD figures come from series with very different recruitment methods; comparing percentages requires knowing what each measures. Vlaskamp recruited through researchers in Australia, Italy, the Netherlands and China (39) and a social-media family group (27). The authors acknowledge that this route may have favoured children with epilepsy and underestimated mild phenotypes [9]. McKee combined reconstructed medical records (158 people, from Citizen Health and the Children’s Hospital of Philadelphia) with US insurance data identified through F78.A1 (246 people). Epilepsy was coded in 65.4% of insurance data and 82.9% of medical records, reflecting both increasing access to genetic testing for children without seizures and administrative coding limitations [7]. Table 2 summarises the principal sources; none is population-based.

Table 2. Principal clinical series used in this article

3.2. Development, cognition and language

Developmental delay is the first manifestation. Vlaskamp identified it shortly after birth in 55 of 56 patients (96%), always preceding seizure onset. Development plateaued or regressed with epilepsy onset in 56 patients. Intellectual disability affected 55 of 57, moderate to severe in 50 and mild in 5; 12 patients aged 2–33 had no verbal language [9]. GeneReviews reports a mean walking age of 26 months (range 10.5 months–5 years), one third of those aged 5 or older remaining non-verbal, and speech ranging from single words to four- or five-word sentences [1]. All domains were impaired in the Texas series, with gross motor skills least affected [40]. McKee’s real-world analysis showed prominent verbal skill acquisition deficits and a more than fivefold risk of emerging autistic behaviour between 27 and 30 months, coinciding with the age when absent language becomes apparent [7]. Citizen registry developmental data documented delay and loss of previously acquired words [42].

3.3. Epilepsy: seizure types, triggers and evolution

Epilepsy is generalised in almost all cases and starts later than in other monogenic DEEs. GeneReviews gives onset between 6 months and 7 years, averaging 3.5 years in one series. Vlaskamp found median onset at 2 years (4 months–7 years); McKee found a median of 2.8 years (interquartile range 2.0–3.8), with 6 onsets in the first year, 26 in the second, 40 in the third and 59 after the third year [1, 7, 9]. This timing distinguishes SRD from neonatal or first-six-month DEEs such as STXBP1-, SCN2A- or SCN8A-related disorders [7].

Table 3. Seizure types and triggers in three cohorts

Sources: [7, 9, 38].

The most characteristic seizures are eyelid myoclonia with or without absence. Vlaskamp described a new seizure type: in 13 of 36 patients with eyelid myoclonia, it evolved into a fall through a myoclonic-atonic (5) or atonic (8) component, particularly with clustered seizures and poorer control. Ictal EEG showed generalised spike-wave coinciding with eyelid myoclonia, followed by a spike-wave complex corresponding to the myoclonic and atonic components [9]. Reflex seizures occurred in clusters, triggered by eating (25%), sounds (7%) or touch (4%). Hunger was associated with seizures in 7%, and three patients self-induced seizures through hyperventilation [9]. Von Stülpnagel described eight children with reflex seizures induced by chewing or simple orofacial stimuli. In the index patient, EEG showed 1–5-second bursts of irregular spike-wave at approximately 3 Hz with temporo-occipital or bioccipital onset; eye closure preceded eating-induced eyelid myoclonia in 30 of 38 seizures [25]. Four Vlaskamp patients had febrile seizures before epilepsy, and the spectrum rarely includes infantile spasms [9].

Nosologically, SRD combines features of two International League Against Epilepsy (ILAE) syndromes: epilepsy with eyelid myoclonia (EEM, formerly Jeavons syndrome) and epilepsy with myoclonic-atonic seizures (EMAtS, formerly Doose syndrome). The 2022 ILAE classification lists SYNGAP1 among genes implicated in both and notes that some variant carriers have the syndrome without DEE [45]. For EMAtS, however, it defines moderate-to-severe developmental delay preceding seizures as a diagnostic alert and requires normal background activity at onset. For EEM, a markedly slow background should suggest an alternative diagnosis [45]. Since SRD delay precedes seizures and background is often slow, Vlaskamp considers it a distinct generalised DEE; formal EMAtS/EEM overlap was identified in 35% of patients [9]. In an Italian EMAtS series using uniform criteria, global delay at onset was associated with drug resistance and intellectual disability, consistent with poorer prognosis in genetic forms with prior delay [46]. In an Italian multicentre cohort of 160 monogenic epilepsies with EEG-documented absences, SYNGAP1 was among the five most frequent genes alongside SLC2A1, SLC6A1, CHD2 and SCN1A [47].

Epilepsy often accompanies developmental plateauing or regression. In eight Vlaskamp patients, regression preceded seizure recognition by 2 months to more than 3 years; in a 9-year-old boy, parents interpreted blinking as seizures only after molecular diagnosis [9]. Ten of 56 patients (18%) were seizure-free at a median age of 7, while drug resistance persists in approximately 71% of adults [9, 26].

3.4. Electroencephalography and neuroimaging

EEG typically shows generalised epileptiform discharges, often posteriorly predominant, photosensitivity and fixation-off or eye-closure sensitivity [1, 3]. In the Texas series, the posterior dominant rhythm was slow or absent in 87%, intermittent rhythmic delta activity occurred in 60% and epileptiform activity in 93%. Posterior dominant rhythm correlated moderately with visuoperceptual, fine motor, adaptive and language progress, suggesting a potential prognostic biomarker [40]. The Spanish series of 63 video-EEGs showed that synchronous and asynchronous bilateral posterior discharges accounted for at least 50% of abnormalities at all ages; background disorganisation and anterior-amplitude generalised discharges became more common with age, and diffuse fast activity predominated from age 6 [41]. Spectral analysis identified loss of gamma-power modulation during behavioural state transitions, resembling heterozygous mice. The 2026 humanised model reproduced patient-like epileptiform activity and generalised slowing; these findings are being explored as trial biomarkers [48, 49]. MRI was normal in 37 of 53 patients (70%). Others had non-specific findings such as a thin corpus callosum, ventricular or subarachnoid space enlargement and white matter hyperintensities; one had subcortical nodular heterotopia [9]. GeneReviews rarely reports atrophy or delayed myelination [1].

3.5. Behaviour, autism and sensory processing

Behavioural abnormalities are the principal determinant of caregiver burden. Vlaskamp found behavioural problems in 41 of 56 (73%), including opposition, aggression, self-injury and tantrums, autism spectrum disorder (ASD) in 30 (54%), and a high pain threshold in 72%, delaying diagnosis of injuries and inflammation [9]. ASD was diagnosed in 73% of the Texas series, where aggression affected 60%, and 60.6% of the Chinese series; the 246-case meta-analysis estimated 57.3% [37, 38, 40]. Compared with other epilepsies and Angelman and Rett syndromes, insurance data showed odds ratios of 12.35 for behavioural abnormalities and 12.23 for autism [7]. On the Social Responsiveness Scale (SRS-2), 87.1% of people with SRD had social reciprocity deficits, without a significant difference from Phelan-McDermid syndrome, and scores increased with age [50]. In a Scottish study, the highest SRS scores involved restrictive and repetitive behaviours and the lowest social awareness. ADHD features were frequent, with relatively few oppositional or conduct disorder symptoms [51]. GeneReviews also lists inattention, impulsivity, hyperacusis and stereotypies such as hand flapping [1]. In the conceptual disease model, caregivers described poor danger awareness, heat and cold intolerance, and absent satiety, symptoms missing from clinical notes. Caregivers and clinicians identified seizures, intellectual disability, emotional regulation and communication as the most relevant trial outcomes [27].

3.6. Sleep, feeding and gastrointestinal system

Sleep problems affected 62% of Vlaskamp’s cohort and 73% of the Spanish cohort [9, 41]. In São Paulo, 81.8% of 11 children had poor sleep habits on the CSHQ questionnaire (bedtime resistance, anxiety, awakenings, parasomnias and daytime sleepiness). A second sample of 23 people showed more bedtime resistance, longer sleep duration and more awakenings than controls, requiring parental presence to fall asleep, with poorer caregiver sleep [43, 44]. Actigraphy in five SRD children compared with 42 controls found no difference in total sleep time, but sleep episodes were distributed across day and night, with more wakefulness after sleep onset, higher fragmentation and early waking [52]. Feeding difficulties, including oral aversion, affected 68% in Vlaskamp’s cohort, with poor intake or, conversely, compulsive eating in more than half [9]. Constipation is frequent and may need medical treatment; dysphagia is rare but may require nasogastric feeding or gastrostomy [1, 23]. Adult constipation affected 71% [26].

3.7. Motor function, musculoskeletal system, eyes and physical appearance

Hypotonia (67%) and ataxia or unstable gait (51%) are frequent; tremor affects 9% [9]. Neuropathology in a 33-year-old woman with a nonsense variant who died of aspiration pneumonia showed cerebellar Purkinje cell loss with astrocytosis and low brain weight, supporting a cerebellar contribution to gait impairment [9]. Orthopaedic abnormalities (28%) include flat, pronated or cavus feet, scoliosis, and congenital hip dislocation and dysplasia. GeneReviews additionally lists kyphoscoliosis and hip rotation abnormalities [1, 9]. Strabismus is the most frequently reported eye finding, and limb and lumbar hypertrichosis are occasionally described [1, 23]. Acquired microcephaly occurs in a minority (1 of 54 in Vlaskamp’s cohort), and growth was normal in the Citizen registry [9, 42]. Some authors describe almond-shaped palpebral fissures, a myopathic face and open mouth, but GeneReviews considers these insufficiently distinctive to suggest diagnosis [1, 23].

3.8. Adult phenotype

Adult data are limited and derive from late-diagnosed patients. In a study of 14 adults with DEE (median age 21, range 18–65), 71% had persistent drug-resistant seizures on a median of two antiseizure medications, all had abnormal pain processing, and 86% had sleep disorders, social communication impairment and aggressive or self-injurious behaviours. Only half walked with little or no assistance, continence was normal in 29%, and none read or comprehended verbal material at sixth-grade level. Aggression and self-injury were the main sources of caregiver burden [26]. The oldest person, aged 65, no longer walked despite previously walking independently; an adult with partial exon 3 deletion had better daily living and social skills than others [26]. Prchalova’s case, described in section 10, documents slow loss of abilities and worsening gait and aggression during adolescence [28].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the disorder

GeneReviews suggests considering SRD in anyone with developmental delay or intellectual disability, with or without generalised epilepsy and/or ASD; no formal clinical criteria exist [1]. In practice, suspicion increases when Table 4 features occur together. Because diagnosis is molecular and overlaps many other disorders, these signs prioritise genetic investigation and interpretation of variants found through agnostic testing rather than replacing testing.

Table 4. Signs increasing the probability of SRD

4.2. Situations requiring prompt action

Some situations change urgency or management. A convulsive seizure lasting 5 minutes or more constitutes status epilepticus and should be treated according to the individual emergency plan or, without one, with a buccal or rectal benzodiazepine in the community and intravenous lorazepam in hospital [53]. Blinking or an eyelid “tic” may represent subtle seizures and warrants video and EEG documentation, because recognition changes treatment [9]. Recent regression or plateauing should prompt investigation for unrecognised seizures or non-convulsive status, although SRD regression may precede epilepsy diagnosis by months or years [9, 45]. Frequent atonic falls require head protection and injury assessment. A high pain threshold requires active investigation for fractures, otitis and dental or abdominal problems after behavioural change, because complaints may be absent [9]. Dysphagia, food refusal and recurrent respiratory infections warrant swallowing assessment, given documented death from aspiration pneumonia [1, 9]. Severe aggression, self-injury or destructive behaviour warrants child psychiatry referral [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Establishing the diagnosis

Diagnosis is established in a person with developmental delay or intellectual disability whose molecular testing identifies a heterozygous pathogenic or likely pathogenic SYNGAP1 variant or a 6p21.3 deletion including the gene. American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) rules give pathogenic and likely pathogenic variants the same significance for clinical decisions; a variant of uncertain significance (VUS) neither establishes nor excludes diagnosis [1, 54]. No confirmatory biochemical or functional test exists. EEG and semiology support suspicion and variant interpretation but never confirm diagnosis [1].

5.2. Test selection

Current recommendations converge on broad, early testing. ACMG strongly recommends considering exome or genome sequencing as a first- or second-line test in children with congenital anomalies, developmental delay or intellectual disability, because of higher yield and potentially greater cost-effectiveness when requested early [55]. The American Academy of Pediatrics’ (AAP) 2025 clinical report recommends phenotype-directed testing when a recognisable diagnosis exists and otherwise an agnostic approach based on diagnostic yield and test complexity [56]. For epilepsy, the UK National Institute for Health and Care Excellence (NICE) NG217 guideline, updated August 2026, recommends considering genome sequencing for unexplained epilepsy beginning before age 2 or accompanied by learning difficulty, ASD, structural abnormalities or cognitive decline. It also recommends consideration for onset at ages 2–3 with agreement from a specialist multidisciplinary team, after consent and genetic counselling [53]. The ILAE Genetics Commission recommends prioritising testing when an informative result is likely and arranging counselling before and after testing [57]. For childhood epilepsy, the Oxford Desk Reference recommends introducing panels, exome or genome early because of heterogeneity, and microarray for all children with non-isolated epilepsy. Figure 3.10 places SYNGAP1 among “other predominantly myoclonic epilepsies”, with onset before or after the first year [58, 59].

GeneReviews, structured before these recommendations, proposes starting with chromosomal microarray (CMA), then, if non-diagnostic, an intellectual disability multigene panel including deletion/duplication analysis or exome sequencing. Single-gene testing is rarely useful and not recommended [1]. In current practice, genome or exome with copy-number variation (CNV) analysis covers most alterations; CMA remains useful for sizing deletions and identifying included contiguous genes.

Table 5. Methods, detectable alterations and limitations in SRD

The 89% and 11% proportions describe published cases through 2017 by alteration type; they are neither each test’s clinical sensitivity nor independent additive estimates [1]. Two situations require attention. First, variants outside the canonical dinucleotide: c.1676+5G>A did not alter the donor GT, but blood RNA demonstrated activation of a cryptic donor 37 base pairs before exon 10’s end and frameshift transcripts [28]. Second, parental mosaicism: in Harrison’s family 3, deletion from the 5′ untranslated region through coding exon 3 was not detected by next-generation sequencing of a buccal sample from the clinically unaffected mother, but an exon-level array showed an intermediate median signal consistent with mosaicism [8]. Negative testing does not exclude a suggestive diagnosis if the method lacks intragenic CNV, intronic region or mosaicism coverage. Following inconclusive initial testing, the ILAE Genetics Commission recommends periodic sequencing reanalysis or more sensitive testing and, in selected cases, considering whether the appropriate tissue was studied [57].

5.3. Variant interpretation and reporting

Reports should specify the gene, versioned transcript (NM_006772.3), HGVS c. and p. nomenclature, genomic coordinate and build, zygosity, origin (de novo, inherited or undetermined), ACMG/AMP classification with applied criteria and method limitations, including CNV and intronic coverage [54]. For loss-of-function variants, ClinGen-established haploinsufficiency supports PVS1 use; according to ClinGen’s variant interpretation group, its strength depends on predicted NMD, variant position, affected exon and inclusion in biologically relevant transcripts [4, 60]. Missense variants require functional, domain and segregation evidence. Harrison described two families with inherited missense variants, c.250C>G (p.Arg84Gly) and c.2050G>A (p.Asp684Asn), both ACMG/AMP VUS. In the first, the carrier father had ASD, language impairment and IQ 89, the carrier grandmother had learning difficulties, and REVEL 0.139 was below the pathogenicity-evidence threshold [8]. Partial cosegregation with common neuropsychiatric features does not convert a VUS into a pathogenic variant. These cases illustrate caution rather than phenotype expansion [8]. Parental testing is recommended for all apparently de novo variants [1].

5.4. Practical algorithm

Table 6. Diagnostic sequence proposed from the sources

5.5. Initial assessment following diagnosis

If not already performed, GeneReviews recommends ophthalmological assessment (strabismus); reflux, constipation and feeding assessment with gastroenterology or feeding-therapy referral; musculoskeletal assessment (hips, kyphoscoliosis, flat feet); neurological assessment with EEG and MRI if seizures are suspected; neuropsychiatric screening from 12 months (sleep, ADHD, anxiety, ASD features); motor, language, cognitive and vocational developmental assessment; and genetic consultation [1].

6. Differential Diagnosis

The differential includes most autosomal dominant intellectual disability disorders and epileptic encephalopathies compatible with the gait phenotype [1]. Table 7 prioritises conditions sharing developmental delay, generalised epilepsy with myoclonia or falls, and autistic features.

Table 7. Differential diagnosis

The Oxford Desk Reference reiterates that children with seizures and developmental delay also require consideration of chromosomal causes, cortical malformations, metabolic and mitochondrial disorders. Progressive abnormalities and progressive microcephaly should suggest recessive causes with recurrence risks up to 25% [59]. Clinical overlap with other synaptopathies, documented through direct comparison with Angelman, Rett and Phelan-McDermid syndromes, explains the reliance on broad genetic rather than single-gene testing [7, 50].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

As of this article’s date, no therapy is specifically authorised for SRD, no disease-specific antiseizure medication selection guideline exists, and no randomised SRD trial has been published [1, 3]. Treatment is symptomatic and problem-based, drawing on three distinct evidence types: general epilepsy syndrome and intellectual disability recommendations extrapolated by phenotypic similarity; observational SRD cohort data; and case reports. Follow-up by a paediatric neurologist experienced in epilepsy is central. NICE recommends tertiary paediatric neurology discussion for children with EMAtS and children under 4 with myoclonic seizures [53]. ERN EpiCARE, for rare and complex epilepsies, and ERN-ITHACA, for rare intellectual disability, offer virtual case consultation between European centres [12, 13].

Caregiver and clinician priorities in the conceptual disease model are seizure control, cognition, emotional regulation and communication. Intervention assessment should include these domains rather than seizure frequency alone [27].

7.2. Epilepsy: antiseizure medication selection

GeneReviews states that approximately half respond to one antiseizure medication and the remainder are drug-resistant [1]. Twenty medications were used in Vlaskamp’s cohort. Valproate and lamotrigine were most often prescribed (45 and 22 patients) and most frequently retained (64% and 77%); 5 of 6 cannabidiol recipients continued it. Of 10 seizure-free patients, 3 received valproate alone, 1 levetiracetam and 1 corticosteroids (infantile spasms); others received combinations including levetiracetam/topiramate, valproate/lamotrigine, or cannabidiol with valproate and lamotrigine. The authors emphasise that historical data cannot assess efficacy [9]. McKee’s comparative effectiveness analysis of 94 patients with reconstructed prescriptions and seizure frequency associated valproate with reduced frequency (n = 43; odds ratio 1.33; 95% CI 1.05–1.67) and maintained seizure freedom (1.38; 1.06–1.77), lamotrigine with maintained seizure freedom (n = 35; 1.93; 1.53–2.42), and levetiracetam (0.36) and clobazam (0.67; 0.49–0.90) with lack of seizure freedom [7]. These observations cannot establish an efficacy ranking: clobazam, for example, is more often added in severe epilepsy, creating confounding by indication. In a Chinese six-child series, five improved with valproate, with recurrence after withdrawal, and two with drug-resistant epilepsy achieved control after adding clobazam [63]. In the 99-child Chinese series, 39.7% became seizure-free; eyelid myoclonia independently predicted poorer response [38].

By analogy with ILAE syndromes, NG217 helps structure choices. For absences with other seizure types, it recommends considering lamotrigine, levetiracetam or sodium valproate first-line, adding ethosuximide second-line. For myoclonic seizures, first-line choices are levetiracetam or valproate; second-line options are brivaracetam, clobazam, clonazepam, lamotrigine, phenobarbital, piracetam, topiramate or zonisamide, noting that lamotrigine occasionally worsens myoclonia. For EMAtS, levetiracetam or valproate are first-line, ketogenic diet second-line, and clobazam, ethosuximide, topiramate or zonisamide third-line [53]. It advises against carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine and vigabatrin in myoclonic seizures or EMAtS because of possible exacerbation; for absences it adds phenobarbital to this list [53]. None is authorised for SRD itself; use follows the relevant label’s seizure-type or syndrome indication or is off-label (Table 8). Prchalova’s case became seizure-free with topiramate after ineffective polytherapy, an individual observation rather than a preferred-choice basis [28].

In a prospective adjunctive-use study of three patients with drug-resistant SRD, purified cannabidiol reduced seizures by 90% and 80% in two after 9 months and by 80% in the third after a delayed response, with disappearance of falls and improved EEG. In a multicentre study of 266 patients with 77 monogenic epilepsies, effectiveness did not differ between approved and off-label indications [64, 65]. Cannabidiol use in SRD is off-label in the USA and EU. Perampanel, an AMPA receptor antagonist, restored gamma activity homeostasis in a mouse model. In a 25-month-old child receiving low-dose off-label treatment, it normalised gamma modulation and coincided with improved development and sleep, without reducing epileptiform discharges or seizures [48, 66].

7.3. Doses and formulations of commonly used medicines

Table 8 reproduces official label doses for authorised indications. In SRD, selection follows seizure type or symptom, with dosing and titration determined by the treating physician. Doses are not given for uses lacking dosing support in a cited label or study.

Table 8. Symptomatic medicines: indication, labelled dose and SRD status

Label sources: openFDA/DailyMed (effective versions specified in section 13) and European Medicines Agency (EMA) Summaries of Product Characteristics.

Valproate and lamotrigine are authorised in the EU through national procedures, without a centralised EMA SmPC; European doses must be checked against national SmPCs (INFARMED in Portugal). The European Commission’s 31 May 2018 decision contraindicates valproate in girls and women of childbearing potential unless pregnancy-prevention programme requirements are met, and during pregnancy for epilepsy unless no suitable alternative exists. In January 2024, the Pharmacovigilance Risk Assessment Committee (PRAC) recommended specialist initiation and supervision for male patients and discussion of contraception, based on a study in which approximately 5 in 100 children of fathers treated with valproate during the 3 months before conception had neurodevelopmental disorders, versus approximately 3 in 100 with lamotrigine or levetiracetam [68, 69]. NG217 incorporated these restrictions in January 2025 and notes that prolonged valproate treatment may reduce bone mineral density [53]. These rules are particularly relevant in SRD, where valproate has the strongest observational signals but many female patients will reach puberty while treated.

7.4. Comparative regulatory status

Table 9. Regulatory status of cited medicines (USA and European Union)

Marketing authorisation does not guarantee national availability, reimbursement or access. No specific INFARMED or ANVISA information on these medicines in SRD was identified in the sources consulted.

7.5. Emergency plan and injury prevention

Everyone with epilepsy should have an individual emergency plan accessible to caregivers and school. For convulsive seizures lasting 5 minutes or longer, NG217 recommends planned medication or, without a plan, buccal midazolam or rectal diazepam in the community and intravenous lorazepam when venous access and resuscitation facilities are available. For repeated or clustered seizures, benzodiazepine options include clobazam or midazolam [53]. Caregivers should learn SRD-specific seizure presentations, including subtle eyelid myoclonia, falls and mealtime seizures. GeneReviews refers families to educational resources such as the Epilepsy Foundation [1, 25]. Atonic seizures warrant head protection and feeding supervision because of aspiration risk and possible chewing-triggered reflex seizures [9].

7.6. Ketogenic diet and other non-pharmacological interventions

GeneReviews mentions anecdotal reports of better control with ketogenic diet [1]. NG217 recommends considering it under tertiary-centre supervision in EMAtS, Lennox–Gastaut and drug-resistant epilepsy after other options fail, placing it second-line in EMAtS. The same guideline acknowledges no clear trial benefit and long-term risks [53]. Reviews mention neuromodulation for drug-resistant SRD epilepsy, without disease-specific efficacy data [3].

7.7. Development, communication and behaviour

GeneReviews recommends early intervention at ages 0–3 with occupational therapy, physiotherapy, speech and feeding therapy; individualised educational programmes from age 3; and transition discussions from age 12 (financial, vocational and medical). Physiotherapy aims to maximise mobility and reduce contractures, scoliosis and hip dislocation, using aids where needed. Occupational therapy addresses fine motor skills, feeding and independence; augmentative and alternative communication should be assessed for expressive impairment. Applied behaviour analysis (ABA) and other ASD interventions may benefit these children. Severe aggression or destructive behaviour warrants child psychiatry referral [1]. GeneReviews describes US service organisation; Portugal and Brazil use their national early-intervention and inclusive education systems.

US insurance data showed more frequent risperidone (odds ratio 5.43), aripiprazole (3.52) and guanfacine (2.97) prescribing in SRD than other epilepsies [7]. Before medicating worsening behaviour, investigate pain, constipation, unrecognised seizures, sleep deprivation or antiseizure medication adverse effects, given the high pain threshold [9]. Sleep hygiene is first-line for insomnia; prolonged-release melatonin has a European indication for neurogenetic disorders with altered melatonin secretion or nocturnal awakenings, and the 2026 review includes melatonin in routine practice [3, 79]. Constipation, strabismus and orthopaedic abnormalities receive conventional specialist treatment; persistent feeding difficulties may require tube feeding or gastrostomy [1].

7.8. Clinical trials and therapies in development

According to SynGAP Research Fund, the SRD therapeutic pipeline developed from non-existent to diversified over five years [14]. Table 10 distinguishes each programme’s evidence level; most remain preclinical.

Table 10. Trials and research programmes (updated 6 October 2026)

These findings require interpretation by evidence level. Animal and cellular results do not demonstrate clinical benefit; mouse critical-window evidence suggests that treatment age may matter but does not define a human age threshold [30, 91]. Clearance to start a trial is not a clinical result, and no CMP-002-treated patients are yet reported in the consulted sources. Biomarkers (quantitative EEG, digital eye tracking, gait parameters, actigraphy) and population-validated scales remain under development. In Philadelphia’s natural history study, inter-rater agreement for gross motor function (GMFCS), manual ability (MACS/Mini-MACS) and communication (CFCS) scales in 101 SRD individuals yielded weighted kappa 0.66–0.81, but test–retest stability ranged from 0.38 to 0.78, lower than in STXBP1-related disorder, limiting their isolated use as outcomes [3, 52, 94].

7.9. Special populations and circumstances

Maintaining valproate in girls approaching puberty and women of childbearing potential requires the EU pregnancy-prevention programme and annual specialist reassessment. PRAC precautions have applied to boys and men since 2024 [68, 69]. Combined oestrogen–progestogen contraceptives reduce lamotrigine concentrations and require label-directed adjustment [70]. No pregnancy data for women with SRD were found in the sources consulted; reported carrier women had attenuated phenotypes or mosaicism [8, 20]. No disease-specific anaesthetic data were identified either. High pain thresholds and communication difficulties support observational pain assessment and individual perioperative planning [9].

8. Reproductive Options and Family Counselling

8.1. Inheritance and risk to relatives

SRD is autosomal dominant and overwhelmingly caused by de novo variants [1]. GeneReviews recommends parental testing for every apparently de novo proband variant. If absent from both parents’ leucocyte DNA, the event is considered likely de novo, without excluding parental germline mosaicism [1]. Sibling risk is low but exceeds population risk. For de novo epileptic encephalopathies with variants not detected in parents generally, the Oxford Desk Reference gives approximately 1.3% recurrence risk and notes that demonstrated parental mosaicism requires upward adjustment [1, 58]. No validated SRD-specific recurrence estimate exists in the sources consulted.

Familial transmission evidence changed in 2025. Previously reported cases included a mildly affected mosaic father transmitting c.283dup and, according to Harrison’s review, two siblings sharing a frameshift variant absent from clinically unaffected parents, attributed to gonadal mosaicism; Vlaskamp’s cohort also contained two affected siblings [8, 9, 20]. Harrison and colleagues identified three families with inherited truncating variants among 92 natural history probands, estimating inherited SRD at approximately 3% (95% CI 0.85–9.9%). In two families, the mother was heterozygous and affected (one with epilepsy from age 6 and intellectual disability, the other with mild intellectual disability, IQ 67 and no seizures); in the third, the clinically unaffected mother was mosaic for a deletion transmitted to three daughters [8]. These findings challenge the idea that people with SRD do not reproduce, still stated in GeneReviews. A heterozygous individual’s offspring risk is 50%, while a mosaic parent’s risk depends on the proportion of carrier germ cells [1, 8].

Table 11. Counselling scenarios

8.2. Reproductive options

Once the familial pathogenic variant is identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. The Oxford Desk Reference notes that non-invasive prenatal diagnosis may be appropriate for dominant de novo variants [58]. Discussion should ideally precede pregnancy and respect differing family and professional perspectives; choosing whether to use testing is personal [1]. Investigating parental mosaicism may require greater sensitivity or other tissues, because conventional buccal-sample sequencing missed the alteration in Harrison’s family 3 [8].

8.3. Communicating the diagnosis

Counselling should explain that diagnosis supports organised surveillance, symptomatic treatment and trial access, but cannot precisely predict each child’s language, independence or seizure control. Variability among people sharing a variant and concordance in monozygotic twins illustrate this uncertainty [9]. Referral to patient organisations, registries and natural history studies forms part of counselling (section 9.3) [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency: what each estimate measures

SRD frequency estimates concern different entities and denominators and should not be conflated (Table 12).

Table 12. Frequency estimates

The gap between modelled incidence and the Orphanet category indicates underdiagnosis, particularly of adults and people with missense variants currently classified as VUS, but its extent is unquantified [1, 14]. GeneReviews emphasises that many adults with disability have never had advanced genetic testing and are probably underrepresented [1].

9.2. Sex, ancestry and geographical distribution

Cohorts show no consistent sex differences: males accounted for 53% in Vlaskamp’s and the Texas cohorts, 55.9% in the Spanish cohort, and 140 versus 106 females in US insurance data. Citizen registry diagnosis age was similar between sexes [7, 9, 40–42]. The predominant de novo mechanism suggests worldwide distribution without a founder effect. No high-frequency allele was identified in Citizen, and recurrent variants occur in unrelated patients of different origins [9, 42]. No founder populations with increased frequency were identified in the sources consulted.

Published data come mainly from the USA (Texas, Philadelphia, New York and national insurance data), Europe (the Netherlands, Italy, France and other Mignot centres, the Czech Republic, Spain and the United Kingdom), Australia and China [7, 9, 23, 24, 27, 28, 38–41]. Race and ethnicity information is limited: McKee’s medical-record subgroup with this information included 11 White, 3 Asian and 1 multiracial individuals, 5 Hispanic and 11 non-Hispanic; insurance and Citizen registry data lacked it [7]. Brazil is represented by one of the first SYNGAP1-containing 6p21.3 microdeletion reports from the University of São Paulo and two sleep studies from Instituto do Sono and Universidade Federal de São Paulo, with 11 and 23 participants [18, 43, 44]. No Portuguese data were found in the sources consulted, which does not establish that patients or publications are absent. Latin American families have an organisation legally based in Colombia within SynGAP Research Fund [14].

9.3. European networks, registries and patient organisations

In Europe, SRD falls within ERN EpiCARE for rare and complex epilepsies and ERN-ITHACA for rare congenital malformations and intellectual disability, including its neurodevelopmental disorders working group [12, 13]. GeneReviews lists the SYNGAP1 Foundation and SYNGAP1 (MRD5) patient registry [1]. SynGAP Research Fund has independent organisations in the USA, United Kingdom, Europe (a Netherlands-based foundation), Australia and Latin America, and belongs to Syngap Global Network. National organisations include Germany’s SYNGAP Elternhilfe, France’s Overcôme, SYNGAP1 España, and organisations in Switzerland, Italy (Famiglie Syngap1) and Poland. They maintain quarterly patient censuses, promote awareness day on 21 June and support study recruitment [14]. Natural history registries (Citizen Health, Children’s Hospital of Philadelphia study, Brain Gene Registry) support trial preparation [42, 89, 96]. The first international SYNGAP1-related brain disorders conference, reported in 2018, brought together 150 family members, researchers, clinicians and regulators and prioritised a robust prospective natural history registry [97].

10. Illustrative Clinical Case

10.1. A 31-year-old woman with a splice variant outside the canonical dinucleotide (Prchalova and colleagues, 2017)

Prchalova and colleagues at Prague’s Motol University Hospital published this case, with follow-up from age 16 and earlier history reconstructed from records, photographs and parental interviews [28]. She was born at 42 weeks after an uncomplicated pregnancy to healthy, unrelated parents aged 26 and 29, weighing 3950 g (percentile 97) and measuring 52 cm (percentile 75). Sucking was weak. Around age three, food-refusal periods required glucose infusions, recurring at least three times before age eight. Later she ate almost everything but without chewing, becoming increasingly dependent on puréed food. Constipation was substantial from the first year, with unsuccessful anal sphincter surgery at age 14. Strabismus developed at 2 months and was corrected surgically at 13 months.

Delay became evident from 6 months: she sat unsupported at 18 months and walked at 3 years with an unstable gait and frequent falls. Language began at the usual age, with cooing at 3 months and syllables at 12 months, but plateaued at a one-year-old level. Seizures began at two years: behavioural arrest with blinking followed by head drop and falling. EEG showed irregular generalised spike-wave discharges, and MRI at 18 was normal. After several antiseizure medications, topiramate achieved seizure freedom. Self-injury began at 4 and aggression at preschool age, becoming uncontrollable from 15 and requiring several antidepressants and behaviour-sedating drugs. Autism was proposed at age 5, followed by pervasive developmental disorder not otherwise specified with severe intellectual disability. Autistic features peaked in preschool years then diminished, with persistent insistence on routine and hypersensitivity to some sounds. Difficulty falling asleep and short sleep persisted [28].

Growth was delayed, with puberty approximately four years late (menarche at 18), microcephaly and low weight at 16 (155 cm, 41 kg, head circumference 51.5 cm, all at or below percentile 3), subsequently normalising. At 28, she measured 167 cm (percentile 48), weighed 58 kg and had head circumference 53.1 cm (percentile 11). Facial features, subtle in childhood, became long and hypomimic, with almond-shaped palpebral fissures, open mouth, protruding incisors and an increasingly myopathic appearance after age 28; dysarthria and excessive salivation developed. During adolescence, gait became crouched with flexed knees and forward-flexed neck, dystonic hands and intention tremor. At 31, intellectual disability was severe to profound, with slow cognitive and language decline without abrupt regression [28]. Facial photographs from one month to age 31 appear in original Figure 1 (Figure 1, PMC); RNA analysis appears in Figure 2 (Figure 2, PMC). The figure legends and descriptive text were consulted for this article.

Karyotype and microarray were normal, and Angelman syndrome had previously been investigated. Trio exome identified the sole de novo variant NM_006772.2:c.1676+5G>A (GRCh37 chr6:33406701), corresponding to NM_006772.3:c.1676+5G>A and NC_000006.12:g.33438924G>A, now classified as pathogenic in ClinVar [6, 28, 36]. All prediction programmes indicated intron 10 donor loss. Blood RT-PCR showed activation of a cryptic donor 37 base pairs before exon 10’s end, producing frameshift transcripts with premature stop codons (p.Cys547Serfs*7 and p.Cys547Serfs*117), alongside an alternative transcript containing part of intron 10 also present in controls [28].

10.2. Lessons from the case

The case illustrates four points. First, GT/AG-dinucleotide-focused exome filtering may miss pathogenic variants in extended splice regions, and RNA studies may resolve classification [28]. Second, adult evolution includes worsening gait and aggression and slow cognitive decline despite controlled seizures, consistent with the 2023 adult series [26]. Third, initial confusion with Angelman syndrome and autism supports broad testing [28, 56]. Fourth, topiramate response is an individual observation; the reported management does not constitute routine guidance.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Intellectual disability is permanent, usually moderate to severe, and expressive language remains very limited in most individuals [1, 9]. Epilepsy is drug-resistant in approximately half to two thirds of children and 71% of adults in one series, but a substantial proportion achieves prolonged seizure-free periods; 39.7% became seizure-free in the Chinese study [1, 9, 26, 38]. In that series, delay severity correlated negatively with epilepsy onset age, and significant EEG abnormalities and ASD were associated with severe delay [38]. Posterior dominant EEG rhythm is a candidate prognostic biomarker [40]. Aggression, self-injury and dependence in daily activities dominate adulthood [26]. Life expectancy is unknown: adults up to 65 are described, with one death at 33 from aspiration pneumonia; no mortality studies exist [1, 9, 26]. As with any epilepsy involving uncontrolled tonic-clonic seizures, sudden unexpected death in epilepsy (SUDEP) risk exists and should be discussed with families from diagnosis [53].

11.2. Surveillance

GeneReviews sets no fixed intervals: monitor seizures as clinically indicated, assess anxiety, attention, aggression and self-injury when needed, and monitor developmental progress and educational needs [1]. Table 13 organises surveillance using these recommendations, NG217 and labels. Specified intervals come from the sources; others remain clinically determined.

Table 13. Surveillance and follow-up

11.3. Transition to adult care

ERN-ITHACA guidance for young people with genetically caused intellectual disability recommends discussing and planning adulthood from age 13 or 14, reviewing the transition plan at least annually, identifying a transition coordinator, ensuring that an adult-service professional meets the young person before transfer, and actively involving the family [98]. GeneReviews suggests financial, vocational and medical discussions from age 12 [1]. In SRD, transfer must maintain antiseizure treatment, the emergency plan, psychiatric care for aggression and gait and swallowing surveillance, as these deteriorate in some adults [26, 28].

12. Summary and Final Considerations

SYNGAP1-related disorder is a synaptopathy caused by haploinsufficiency of a Ras and Rap GTPase-activating protein that organises the excitatory postsynaptic density and restrains premature dendritic spine maturation. Described in 2009 in three people with non-syndromic intellectual disability, it is now recognised as a distinctive generalised DEE: delay from the first year, seizures from ages 2–3 with eyelid myoclonia, absences, myoclonic-atonic falls and eating-triggered reflex seizures, autism, aggressive behaviour, high pain threshold, ataxia and sleep disturbance [9, 17].

Diagnosis is molecular, through broad sequencing with CNV analysis or microarray. Variants should be described against NM_006772.3, with attention to splice variants outside canonical dinucleotides, parental mosaicism and cautious missense interpretation [1, 8, 28]. Counselling now includes transmission from heterozygous or mosaic parents, estimated at approximately 3% in a natural history cohort [8].

Treatment remains symptomatic. Valproate and lamotrigine have the most favourable observational signals, interpreted within general absence, myoclonic seizure and EMAtS recommendations and constrained by valproate restrictions in people with reproductive potential. Cannabidiol, ketogenic diet and behavioural medications are individualised, often off-label options [7, 53, 68]. In 2026, the first SYNGAP1-targeted antisense oligonucleotide received clearance to begin a phase 1/2 trial, without human data yet available. Several strategies increasing normal-allele expression remain preclinical, including one for which recent findings suggest a biological limitation [11, 90, 91]. Trial preparation depends on natural history studies, biomarkers and outcomes reflecting family priorities such as communication and emotional regulation [27, 94].

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