Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome. METHODS: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features. RESULTS: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers. CONCLUSIONS: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account.

Social behavioral impairments in SYNGAP1-related intellectual disability.

Introduction: Developmental synaptopathies are neurodevelopmental disorders caused by genetic mutations disrupting the development and function of neuronal synapses. Methods: We administered the validated Social Responsiveness Scale, Second Edition (SRS-2) to investigate the phenotypic presentation of social-behavioral impairments for the developmental synaptopathy-SYNGAP1-related Intellectual Disability (SYNGAP1-ID) (n = 32) compared with a phenotypically similar disorder Phelan-McDermid syndrome (PMD) (n = 27) and healthy controls (n = 43). A short form SRS-2 analysis (n = 85) was also conducted. Results: Both SYNGAP1-ID and PMD had significantly elevated total and subcategory T-scores, with no significant score differences between SYNGAP1-ID and PMD, consistent between the full and short form. Mild to severe deficiencies in reciprocal social behavior were found in 100% of PMD individuals and 87.1% of SYNGAP1-ID individuals. Surprisingly, a positive correlation between age and total score was discovered for SYNGAP1-ID participants and not found in individuals with PMD or healthy controls. Discussion: The short form demonstrated greater utility for SYNGAP1-ID participants due to lower item-omission rates. In conclusion, significant impairment in reciprocal social behaviors is highly prevalent in SYNGAP1-ID.

Updated consensus guidelines on the management of Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

COVID-19 Induced Environments, Health-Related Quality of Life Outcomes and Problematic Behaviors: Evidence from Children with Syndromic Autism Spectrum Disorders.

Between July 2020 and January 2021, 230 principal caregivers completed a questionnaire to measure proxy-assessed health-related quality of life outcomes (HRQoL), behavioral outcomes in children with syndromic autism spectrum disorders and COVID-19 induced changes to lifestyle and environments. HRQoL and behavioral outcomes reported earlier during the pandemic were generally worse compared to those reported later. COVID-19 induced reduction to a caregiver's mental health appointments, and hours spent watching TV were associated with decreases in HRQoL and increased the likelihood of problematic behaviors. Increasing time outdoors and time away from digital devices were positively associated with HRQoL and behaviors and might protect children from COVID-19 induced restrictions.

Health-Related Quality of Life in Pediatric Patients with Syndromic Autism and their Caregivers.

Children with autism have a significantly lower quality of life compared with their neurotypical peers. While multiple studies have quantified the impact of autism on health-related quality of life (HRQoL) through standardized surveys such as the PedsQL, none have specifically investigated the impact of syndromic autism. Here we evaluate HRQoL in children diagnosed with three genetic disorders that strongly predispose to syndromic autism: Phelan-McDermid syndrome (PMD), Rett syndrome (RTT), and SYNGAP1-related intellectual disability (SYNGAP1-ID). We find the most severely impacted dimension is physical functioning. Strikingly, syndromic autism results in worse quality of life than other chronic disorders including idiopathic autism. This study demonstrates the utility of caregiver surveys in prioritizing phenotypes, which may be targeted as clinical endpoints for genetically defined ASDs.

Sleep Abnormalities in the Synaptopathies-SYNGAP1-Related Intellectual Disability and Phelan-McDermid Syndrome.

Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Children's Sleep Habits Questionnaire (CSHQ) to examine the nature of sleep abnormalities occurring in individuals with two synaptopathies-Phelan-McDermid syndrome (PMD) (N = 47, male = 23, female = 24, age 1-46 years) and SYNGAP1-related intellectual disability (SYNGAP1-ID) (N = 64, male = 31, female = 33, age 1-64 years), when compared with unaffected siblings (N = 61, male = 25, female = 36, age 1-17 years). We found that both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. In addition, sleep disturbances were more severe for PMD in individuals 11 years and older compared with those less than 11 years old. Individuals with either disorder were more likely to use sleep aids than unaffected siblings. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders.

Genetics in Epilepsy.

The presence of unprovoked, recurrent seizures, particularly when drug resistant and associated with cognitive and behavioral deficits, warrants investigation for an underlying genetic cause. This article provides an overview of the major classes of genes associated with epilepsy phenotypes divided into functional categories along with the recommended work-up and therapeutic considerations. Gene discovery in epilepsy supports counseling and anticipatory guidance but also opens the door for precision medicine guiding therapy with a focus on those with disease-modifying effects.

SYNGAP1 Controls the Maturation of Dendrites, Synaptic Function, and Network Activity in Developing Human Neurons.

SYNGAP1 is a major genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. De novo loss-of-function variants in this gene cause a neurodevelopmental disorder defined by cognitive impairment, social-communication disorder, and early-onset seizures. Cell biological studies in mouse and rat neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, with loss-of-function variants driving formation of larger dendritic spines and stronger glutamatergic transmission. However, studies to date have been limited to mouse and rat neurons. Therefore, it remains unknown how SYNGAP1 loss of function impacts the development and function of human neurons. To address this, we used CRISPR/Cas9 technology to ablate SYNGAP1 protein expression in neurons derived from a commercially available induced pluripotent stem cell line (hiPSC) obtained from a human female donor. Reducing SynGAP protein expression in developing hiPSC-derived neurons enhanced dendritic morphogenesis, leading to larger neurons compared with those derived from isogenic controls. Consistent with larger dendritic fields, we also observed a greater number of morphologically defined excitatory synapses in cultures containing these neurons. Moreover, neurons with reduced SynGAP protein had stronger excitatory synapses and expressed synaptic activity earlier in development. Finally, distributed network spiking activity appeared earlier, was substantially elevated, and exhibited greater bursting behavior in SYNGAP1 null neurons. We conclude that SYNGAP1 regulates the postmitotic maturation of human neurons made from hiPSCs, which influences how activity develops within nascent neural networks. Alterations to this fundamental neurodevelopmental process may contribute to the etiology of SYNGAP1-related disorders.SIGNIFICANCE STATEMENTSYNGAP1 is a major genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. While this gene is well studied in rodent neurons, its function in human neurons remains unknown. We used CRISPR/Cas9 technology to disrupt SYNGAP1 protein expression in neurons derived from an induced pluripotent stem cell line. We found that induced neurons lacking SynGAP expression exhibited accelerated dendritic morphogenesis, increased accumulation of postsynaptic markers, early expression of synapse activity, enhanced excitatory synaptic strength, and early onset of neural network activity. We conclude that SYNGAP1 regulates the postmitotic differentiation rate of developing human neurons and disrupting this process impacts the function of nascent neural networks. These altered developmental processes may contribute to the etiology of SYNGAP1 disorders.

Unwind and Relax: DDX3X RNA Helicase as a Critical Mediator of Cortical Neurogenesis.

In this issue of Neuron, Lennox et al. (2020) report the largest cohort of patients to date with DDX3X syndrome, discovering unique genotype-phenotype relationships that inform molecular pathogenesis. They then uncover unique roles of DDX3X in cortical neuron development and ribonucleoprotein granule formation.

A kinome-wide RNAi screen identifies ERK2 as a druggable regulator of Shank3 stability.

Neurons are sensitive to changes in the dosage of many genes, especially those regulating synaptic functions. Haploinsufficiency of SHANK3 causes Phelan-McDermid syndrome and autism, whereas duplication of the same gene leads to SHANK3 duplication syndrome, a disorder characterized by neuropsychiatric phenotypes including hyperactivity and bipolar disorder as well as epilepsy. We recently demonstrated the functional modularity of Shank3, which suggests that normalizing levels of Shank3 itself might be more fruitful than correcting pathways that function downstream of it for treatment of disorders caused by alterations in SHANK3 dosage. To identify upstream regulators of Shank3 abundance, we performed a kinome-wide siRNA screen and identified multiple kinases that potentially regulate Shank3 protein stability. Interestingly, we discovered that several kinases in the MEK/ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo. Mechanistically, we show that ERK2 binds Shank3 and phosphorylates it at three residues to promote its poly-ubiquitination-dependent degradation. Altogether, our findings uncover a druggable pathway as a potential therapeutic target for disorders with reduced SHANK3 dosage, provide a rich resource for studying Shank3 regulation, and demonstrate the feasibility of this approach for identifying regulators of dosage-sensitive genes.

An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function.

Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued. However, some missense variants can be informative for developing a more profound understanding of disease pathogenesis and ultimately targeted therapies. Here we present an example of this by studying a missense variant in a well-known autism spectrum disorder (ASD) causing gene SHANK3. We analyzed Shank3's in vivo phosphorylation profile and identified S685 as one phosphorylation site where one ASD-linked variant has been reported. Detailed analysis of this variant revealed a novel function of Shank3 in recruiting Abelson interactor 1 (ABI1) and the WAVE complex to the post-synaptic density (PSD), which is critical for synapse and dendritic spine development. This function was found to be independent of Shank3's other functions such as binding to GKAP and Homer. Introduction of this human ASD mutation into mice resulted in a small subset of phenotypes seen previously in constitutive Shank3 knockout mice, including increased allogrooming, increased social dominance, and reduced pup USV. Together, these findings demonstrate the modularity of Shank3 function in vivo. This modularity further indicates that there is more than one independent pathogenic pathway downstream of Shank3 and correcting a single downstream pathway is unlikely to be sufficient for clear clinical improvement. In addition, this study illustrates the value of deep biological analysis of select missense mutations in elucidating the pathogenesis of neuropsychiatric phenotypes.

Phenotypic characterization of individuals with SYNGAP1 pathogenic variants reveals a potential correlation between posterior dominant rhythm and developmental progression.

BACKGROUND: The SYNGAP1 gene encodes for a small GTPase-regulating protein critical to dendritic spine maturation and synaptic plasticity. Mutations have recently been identified to cause a breadth of neurodevelopmental disorders including autism, intellectual disability, and epilepsy. The purpose of this work is to define the phenotypic spectrum of SYNGAP1 gene mutations and identify potential biomarkers of clinical severity and developmental progression. METHODS: A retrospective clinical data analysis of individuals with SYNGAP1 mutations was conducted. Data included genetic diagnosis, clinical history and examinations, neurophysiologic data, neuroimaging, and serial neurodevelopmental/behavioral assessments. All patients were seen longitudinally within a 6-year period; data analysis was completed on June 30, 2018. Records for all individuals diagnosed with deleterious SYNGAP1 variants (by clinical sequencing or exome sequencing panels) were reviewed. RESULTS: Fifteen individuals (53% male) with seventeen unique SYNGAP1 mutations are reported. Mean age at genetic diagnosis was 65.9 months (28-174 months). All individuals had epilepsy, with atypical absence seizures being the most common semiology (60%). EEG abnormalities included intermittent rhythmic delta activity (60%), slow or absent posterior dominant rhythm (87%), and epileptiform activity (93%), with generalized discharges being more common than focal. Neuroimaging revealed nonspecific abnormalities (53%). Neurodevelopmental evaluation revealed impairment in all individuals, with gross motor function being the least affected. Autism spectrum disorder was diagnosed in 73% and aggression in 60% of cases. Analysis of biomarkers revealed a trend toward a moderate positive correlation between visual-perceptual/fine motor/adaptive skills and language development, with posterior dominant rhythm on electroencephalogram (EEG), independent of age. No other neurophysiology-development associations or correlations were identified. CONCLUSIONS: A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1. An abnormal posterior dominant rhythm on EEG correlated with abnormal developmental progression, providing a possible prognostic biomarker.

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits.

In addition to cognitive impairments, neurodevelopmental disorders often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with neurodevelopmental disorders are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina somatosensory cortex neurons. These results were unexpected, given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients.

Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations.

Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods: We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results: SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions: Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3.

A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability.

SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.

The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations.

OBJECTIVE: The coincidence of autism with epilepsy is 27% in those individuals with intellectual disability.1 Individuals with loss-of-function mutations in SHANK3 have intellectual disability, autism, and variably, epilepsy.2-5 The spectrum of seizure semiologies and electroencephalography (EEG) abnormalities has never been investigated in detail. With the recent report that SHANK3 mutations are present in approximately 2% of individuals with moderate to severe intellectual disabilities and 1% of individuals with autism, determining the spectrum of seizure semiologies and electrographic abnormalities will be critical for medical practitioners to appropriately counsel the families of patients with SHANK3 mutations. METHODS: A retrospective chart review was performed of all individuals treated at the Blue Bird Circle Clinic for Child Neurology who have been identified as having either a chromosome 22q13 microdeletion encompassing SHANK3 or a loss-of-function mutation in SHANK3 identified through whole-exome sequencing. For each subject, the presence or absence of seizures, seizure semiology, frequency, age of onset, and efficacy of therapy were determined. Electroencephalography studies were reviewed by a board certified neurophysiologist. Neuroimaging was reviewed by both a board certified pediatric neuroradiologist and child neurologist. RESULTS: There is a wide spectrum of seizure semiologies, frequencies, and severity in individuals with SHANK3 mutations. There are no specific EEG abnormalities found in our cohort, and EEG abnormalities were present in individuals diagnosed with epilepsy and those without history of a clinical seizure. SIGNIFICANCE: All individuals with a mutation in SHANK3 should be evaluated for epilepsy due to the high prevalence of seizures in this population. The most common semiology is atypical absence seizure, which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings, or EEG findings were present in the majority of individuals with SHANK3 mutations.

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.

OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.