Neurogenetic Disorder Research Articles

Neurobehavioral Dimensions of Prader Willi Syndrome: Relationships Between Sleep and Psychosis-Risk Symptoms.

BackgroundPrader Willi Syndrome (PWS) is a genetic disorder caused by the absence of expression of the paternal copies of maternally imprinted gene(s) located at 15q11–q13. While the physical and medical characteristics of PWS, including short stature, hyperphagia and endocrine dysfunction are well-characterized, systematic investigation of the long-recognized psychiatric manifestations has been recent.MethodsHere, we report on the first remote (web-based) assessment of neurobehavioral traits, including psychosis-risk symptoms (Prodromal Questionnaire-Brief Version; PQ-B) and sleep behaviors (Pittsburgh Sleep Quality Index), in a cohort of 128 participants with PWS, of whom 48% had a paternal deletion, 36% uniparental disomy, 2.4% an imprinting mutation and 13% unknown mutation (mean age 19.3 years ± 8.4; 53.9% female). We aimed to identify the most informative variables that contribute to psychosis-risk symptoms. Multiple domains of cognition (accuracy and speed) were also assessed in a subset of PWS participants (n = 39) using the Penn Computerized Neurocognitive Battery (Penn-CNB).ResultsIndividuals with PWS reported a range of psychosis-risk symptoms, with over half reporting cognitive disorganization (63.1%) and about one third reporting unusual beliefs (38.6%) and/or suspiciousness (33.3%). Subjectively-reported sleep quality, nap frequency, sleep duration, sleep disturbance, and daytime dysfunction were significant predictors of psychosis-risk symptom frequency and severity (all p's < 0.029). Sleep disturbance ratings were the strongest predictors of psychosis-risk symptoms. Regarding cognition, individuals with PWS showed the most prominent deficits in accuracy on measures of social cognition involving faces, namely Face Memory, Age Differentiation and Emotion Recognition, and greatest slowing on measures of Attention and Emotion Recognition. However, there were no significant differences in psychosis-risk symptoms or cognitive performance as a function of PWS genetic subtype.ConclusionsPWS is associated with a high prevalence of distressing psychosis-risk symptoms, which are associated with sleep disturbance. Findings indicate that self/parent-reported neurobehavioral symptoms and cognition can be assessed remotely in individuals with PWS, which has implications for future large-scale investigations of rare neurogenetic disorders.

Variegation of autism related traits across seven neurogenetic disorders

Gene dosage disorders (GDDs) constitute a major class of genetic risks for psychopathology, but there is considerable debate regarding the extent to which different GDDs induce different psychopathology profiles. The current research speaks to this debate by compiling and analyzing dimensional measures of several autism-related traits (ARTs) across seven diverse GDDs. The sample included 350 individuals with one of 7 GDDs, as well as reference idiopathic autism spectrum disorder (ASD; n = 74) and typically developing control (TD; n = 171) groups. The GDDs were: Down, Williams–Beuren, and Smith–Magenis (DS, WS, SMS) syndromes, and varying sex chromosome aneuploidies (“plusX”, “plusXX”, “plusY”, “plusXY”). The Social Responsiveness Scale (SRS-2) was used to measure ARTs at different levels of granularity—item, subscale, and total. General linear models were used to examine ART profiles in GDDs, and machine learning was used to predict genotype from SRS-2 subscales and items. These analyses were completed with and without covariation for cognitive impairment. Twelve of all possible 21 pairwise GDD group contrasts showed significantly different ART profiles (7/21 when co-varying for IQ, all Bonferroni-corrected). Prominent GDD–ART associations in post hoc analyses included relatively preserved social motivation in WS and relatively low levels of repetitive behaviors in plusX. Machine learning revealed that GDD group could be predicted with plausible accuracy (~60–80%) even after controlling for IQ. GDD effects on ARTs are influenced by GDD subtype and ART dimension. This observation has consequences for mechanistic, clinical, and translational aspects of psychiatric neurogenetics.

Song Imitation in Congenital Amusia

Congenital amusia is a neurogenetic disorder of pitch perception that may also compromise pitch production. Despite amusics’ long documented difficulties with pitch, previous evidence suggests that familiar music may have an implicit facilitative effect on their performance. It remains, however, unknown whether vocal imitation of song in amusia is influenced by melody familiarity and the presence of lyrics. To address this issue, thirteen Mandarin speaking amusics and 13 matched controls imitated novel song segments with lyrics and on the syllable /la/. Eleven out of these participants in each group also imitated segments of a familiar song. Subsequent acoustic analysis was conducted to measure pitch and timing matching accuracy based on eight acoustic measures. While amusics showed worse imitation performance than controls across seven out of the eight pitch and timing measures, melody familiarity was found to have a favorable effect on their performance on three pitch-related acoustic measures. The presence of lyrics did not affect either group’s performance substantially. Correlations were observed between amusics’ performance on the Montreal Battery of Evaluation of Amusia and imitation of the novel song. We discuss implications in terms of music familiarity, memory demands, the relevance of lexical information, and the link between perception and production.

The Road to Personalized Therapies: Lessons Learned From Angelman Syndrome.

Angelman syndrome (AS) is a neurogenetic disorder characterized by delays including a severe expressive language delay, motor concerns, ataxia, epilepsy, sleep disturbances, gastrointestinal problems, and characteristic behaviors, including a happy demeanor, hyperactivity, and excitability. The syndrome is one of the first neurodevelopmental disorders with a clear trajectory towards meaningful treatment with approximately 20 companies actively developing targeted therapeutics for AS. Herein, we highlight the historical context of the road to therapeutics and some of the challenges in the field with the potential to impact the success of clinical trials for Angelman syndrome and also have relevance of other neurogenetic developmental disabilities.

Advancing the diagnosis of repeat expansion disorders

Genomic technologies are transforming health care, with next-generation sequencing providing an important tool that underpins diagnostics, gene discovery, and the mechanistic understanding of disease. 1 Rehm HL Evolving health care through personal genomics. Nat Rev Genet. 2017; 18: 259-267 Google Scholar However, next-generation sequencing has had limited success in bringing the power of genomic medicine to neurological disorders caused by pathogenic repeat expansions. 2 Ashley EA Towards precision medicine. Nat Rev Genet. 2016; 17: 507-522 Google Scholar The development of research tools to identify repeat expansions in next-generation sequencing data has begun to address this deficit. 3 Bahlo M Bennett MF Degorski P Tankard RM Delatycki MB Lockhart PJ Recent advances in the detection of repeat expansions with short-read next-generation sequencing. F1000Res. 2018; 7: 736 Google Scholar In The Lancet Neurology, Kristina Ibañez and colleagues 4 Ibañez K Polke J Hagelstrom RT et al. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol. 2022; 21: 232-243 Google Scholar present compelling evidence of translation to clinical use, showing the utility of genome sequencing to diagnose neurogenetic repeat expansion disorders. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation studyIn our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder. Full-Text PDF Open Access

Circular RNA_0061587 is associated with the tumorigenesis of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a kind of common neurogenetic disorder associated with various developmental deficits. Circular RNAs (circRNAs) have been frequently verified to be crucial modulators in human diseases. However, the functions of circRNAs on the occurrence of NF1 remain largely obscure. In our study, RT-qPCR was applied to analyze circ_0061,587 expression and we noticed that circ_0061,587 expression was overtly elevated in human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cell lines. Meanwhile, the results of loss-of-function assays revealed that silencing of circ_0061,587 hampered the proliferation, migration, and invasion but stimulated the apoptosis of human NF1-associated MPNST cells. In addition, mechanism assays were implemented to unveil the possible regulatory mechanism behind circ_0061,587. As a result, circ_0061,587 sequestered microRNA-485–5p (miR-485–5p) to modulate the expression of RUNX family transcription factor 1 (RUNX1) and annexin A11 (ANXA11). Finally, rescue experiments confirmed that circ_0061,587 boosted the malignant behaviors of human NF1-associated MPNST cells through up-regulating RUNX1 and ANXA11. In conclusion, circ_0061,587 functioned as an oncogene in NF1-associated MPNST cells and this study might provide novel insights for the diagnosis and treatment of NF1.

A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BackgroundAngelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence‐based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon.MethodsWe compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed.ResultsAreas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence‐based care guidelines.ConclusionStandards of care in the management of AS are keys to ensure optimal care at a critical time when new disease‐modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Personalized medicine for rare neurogenetic disorders: can we make it happen?

Rare neurogenetic disorders are collectively common, affecting 3% of the population, and often manifest with complex multiorgan comorbidity. With advances in genetic, -omics, and computational analysis, more children can be diagnosed and at an earlier age. Innovations in translational research facilitate the identification of treatment targets and development of disease-modifying drugs such as gene therapy, nutraceuticals, and drug repurposing. This increasingly allows targeted therapy to prevent the often devastating manifestations of rare neurogenetic disorders. In this perspective, successes in diagnosis, prevention, and treatment are discussed with a focus on inherited disorders of metabolism. Barriers for the identification, development, and implementation of rare disease-specific therapies are discussed. New methodologies, care networks, and collaborative frameworks are proposed to optimize the potential of personalized genomic medicine to decrease morbidity and improve lives of these vulnerable patients.

Neurogenetic disorders across the lifespan: from aberrant development to degeneration.

Intellectual disability and autism spectrum disorder (ASD) are common, and genetic testing is increasingly performed in individuals with these diagnoses to inform prognosis, refine management and provide information about recurrence risk in the family. For neurogenetic conditions associated with intellectual disability and ASD, data on natural history in adults are scarce; however, as older adults with these disorders are identified, it is becoming clear that some conditions are associated with both neurodevelopmental problems and neurodegeneration. Moreover, emerging evidence indicates that some neurogenetic conditions associated primarily with neurodegeneration also affect neurodevelopment. In this Perspective, we discuss examples of diseases that have developmental and degenerative overlap. We propose that neurogenetic disorders should be studied continually across the lifespan to understand the roles of the affected genes in brain development and maintenance, and to inform strategies for treatment.

Abstract- Poster

BACKGROUND:Sanfilippo syndrome, one of mucopolysaccharidoses is neuro developmental disorder characterised by severe degeneration of the central nervous system, resulting in mental retardation and hyperactivity, typically commencing during childhood. Visual changes, difficulty in breathing and swallowing, respiratory infections, heart disease, enlarged liver and spleen, hernias are also present along with musculoskeletal abnormalities of spine, hip and knee limiting the overall life expectancy to late teens or early twenties. Multi system involvement in neurodevelopmental disorders like Sanfilippo syndrome demands a multi modal approach.CASE REPORT:A 7-year-old, girl, studying kindergarten, coming from a middle socio-economic status, living in a nuclear family set-up was diagnosed with Sanfillipo syndrome with co-morbid ADHD and moderate intellectual disability. Born to third degree consanguineous parents her ante-natal, natal and immediate post-natal period was uneventful. In 2019 she presented to us referred from our Paediatric orthopaedic department with incidental finding for mucopolysaccharidoses. She presented to us with complaints of hyperactivity and poor scholastic performance. She was initially seen in our Child health Clinic and later was evaluated and diagnosed as Sanfilippo syndrome is one of mucopolysaccharidoses in Pediatric neurology and Medical genetics clinic. After assessment of for the concerns of referral under ACTeRS she was diagnosed with co-morbid ADHD. She was treated with low dose anti-psychotic and had no response. Hence as a multi-modal treatment approach for her co-morbid ADHD with Sanfillipo syndrome - she was started on T.Atomoxetine and had 3 months training program for NDD in our Nambikkai Nilayam (NN) with surgical corrections for skeletal deformities in our Pediatric ortho department prior to her admission in NN. With these multi -modality measures she improved in her symptoms overall.CONCLUSION:With increasing awareness and health care facility there has been an outburst in incidence of neuro developmental and genetic disorders. Though a number of genetic and biochemical diagnostic methods have been developed to confirm the diagnosis, there is no effective therapy available for neuro developmental and genetic disorders – in this patient it was MPS III. Multi system involvement demanding multi-disciplinary approach – involving multiple specialities is needed to improve the quality of life in these children and to reduce the care giver burden.

AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

Tauopathies comprise a spectrum of genetic and sporadic neurodegenerative diseases mainly characterized by the presence of hyperphosphorylated TAU protein aggregations in neurons or glia. Gene therapy, in particular adeno-associated virus (AAV)-based, is an effective medical approach for difficult-to-treat genetic diseases for which there are no convincing traditional therapies, such as tauopathies. Employing AAV-based gene therapy to treat, in particular, genetic tauopathies has many potential therapeutic benefits, but also drawbacks which need to be addressed in order to successfully and efficiently adapt this still unconventional therapy for the various types of tauopathies. In this Viewpoint, we briefly introduce some potentially treatable tauopathies, classify them according to their etiology, and discuss the potential advantages and possible problems of AAV-based gene therapy. Finally, we outline a future vision for the application of this promising therapeutic approach for genetic and sporadic tauopathies.

Water-soluble optical sensors: keys to detect aluminium in biological environment.

Metal ion plays a critical role from enzyme catalysis to cellular health and functions. The concentration of metal ions in a living system is highly regulated. Among the biologically relevant metal ions, the role and toxicity of aluminium in specific biological functions have been getting significant attention in recent years. The interaction of aluminium and the living system is unavoidable due to its high earth crust abundance, and the long-term exposure to aluminium can be fatal for life. The adverse Al3+ toxicity effects in humans result in various diseases ranging from cancers to neurogenetic disorders. Several Al3+ ions sensors have been developed over the past decades using the optical responses of synthesized molecules. However, only limited numbers of water-soluble optical sensors have been reported so far. In this review, we have confined our discussion to water-soluble Al3+ ions detection using optical methods and their utility for live-cell imaging and real-life application.

Heterogeneity in biomarkers, mitogenome and genetic disorders of the Arab population with special emphasis on large-scale whole-exome sequencing.

More than 25 million DNA variations have been discovered as novel including major alleles from the Arab population. Exome studies on the Saudi genome discovered > 3000 novel nucleotide variants associated with > 1200 rare genetic disorders. Reclassification of many pathogenic variants in the Human Gene Mutation Database and ClinVar Database as benign through the Arab database facilitates building a detailed and comprehensive map of the human morbid genome. Intellectual disability comes first with the combined and observed carrier frequency of 0.06779 among Saudi Arabians; retinal dystrophy is the next highest. Genome studies have discovered interesting novel candidate disease marker variations in many genes from consanguineous families. More than 7 pathogenic variants in the C12orf57 gene are prominently associated with the etiology of developmental delay/intellectual impairment in Arab ancestries. Advances in large-scale genome studies open a new outlook on Mendelian genes and disorders. In the past half-dozen years, candidate genes of intellectual disability, neurogenetic disorders, blood and bleeding disorders and rare genetic diseases have been well documented through genomic medicine studies in combination with advanced computational biology applications. The Arab mitogenome exposed hundreds of variations in the mtDNA genome and ancestral sharing with Africa, the Near East and East Asia and its association with obesity. These recent discoveries in disease markers and molecular genetics of the Arab population will have a positive impact towards supporting genetic counsellors on reaching consanguineous families to manage stress linked to genetics and precision medicine. This narrative review summarizes the advances in molecular medical genetics and recent discoveries on pathogenic variants. Despite the fact that these initiatives are targeting the genetics and genomics of disorders prevalent in Arab populations, a lack of complete cooperation across the projects needed to be revisited to uncover the Arab population's prominent disease markers. This shows that further study is needed in genomics to fully comprehend the molecular abnormalities and associated pathogenesis that cause inherited disorders in Arab ancestries.

Stimulant intolerance in children with Angelman syndrome with hyperactivity: a case series.

Angelman syndrome is a neurogenetic disorder resulting from the loss of expression of the ubiquitin-protein ligase E3A gene on chromosome 15. Problematic behaviors including attention-deficit/hyperactivity disorder (ADHD) symptoms of hyperactivity, impulsivity and inattention are highly prevalent in Angelman syndrome. The efficacy, safety and tolerability of stimulant medications in children with Angelman syndrome for the treatment of ADHD symptoms have not been previously reported. We describe three boys with Angelman syndrome who were treated with open-label stimulant medications for ADHD symptoms. Stimulant medications were highly intolerable, and treatment had to be discontinued after limited dosing in all three cases due to marked increases in hyperactivity and impulsivity along with worsened distractibility. The findings of this study suggest that stimulant medications may be ineffective and poorly tolerated in children with Angelman syndrome.

A perspective on human cell models for POLG-spectrum disorders: advantages and disadvantages of CRISPR-Cas-based vs. patient-derived iPSC models.

Neurogenetic diseases represent a broad group of diseases with variable genetic causes and clinical manifestations. Among these, polymerase-gamma (POLG)-spectrum disorders are relatively frequent with an estimated disease frequency of ∼1:10.000. Also, mutations in the POLG gene are by far the most important cause for mitochondriopathy. POLG-spectrum disorders usually result in progressive loss of brain function and may involve severe and deadly encephalopathy, seizures, and neuromuscular disease, as well as cardiac and hepatic failure in some cases. Onset of disease may range from birth to late adulthood, and disease duration ranges from weeks in severe cases to decades. There is no curative treatment; current animal models do not faithfully recapitulate human disease, complicating preclinical therapeutic studies. Human-based preclinical model systems must be developed to understand the human disease mechanisms and develop therapeutic approaches. In this review, we provide an overview of the current approaches to model neurogenetic disorders in a human cellular and neuronal environment with a focus on POLG-spectrum disorders. We discuss the necessity of using neuronal cells and the advantages and pitfalls of currently available cell model approaches, namely (i) CRISPR-based (i. e., genetically engineered) and induced pluripotent stem cell (iPSC) (i. e., stem cell like)-derived neuronal models and (ii) the reprogramming of patient-derived cells into iPSCs and derived neurons. Despite the fact that cell models are by definition in vitro systems incapable of recapitulating all aspects of human disease, they are still the reasonable point of start to discover disease mechanisms and develop therapeutic approaches to treat neurogenetic diseases.

Advances in gene therapy for neurogenetic diseases: a brief review.

Neurogenetic diseases are neurological conditions with a genetic cause (s). There are thousands of neurogenetic diseases, and most of them are incurable. The development of bioinformatics and elucidation of the mechanism of pathogenesis have allowed the development of gene therapy approaches, which show great potential in treating neurogenetic diseases. Viral vectors delivery, antisense oligonucleotides, gene editing, RNA interference, and burgeoning viroid delivery technique are promising gene therapy strategies, and commendable therapeutic effects in the treatment of neurogenetic diseases have been achieved (Fig.1). This review highlights a sampling of advances in gene therapies for neurogenetic disorders. Fig. 1 Examples of gene therapy strategies used in the treatment of neurogenetic diseases. The schematic diagram shows different gene therapy approaches used for treating a sampling of neurogenetic disorders, such as ASO therapy, gene editing, gene augmentation, and RNA interference.

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview.

Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

Gene Therapy for Huntington's Disease: The Final Strategy for a Cure?

Huntington’s disease (HD) has become a target of the first clinical trials for gene therapy among movement disorders with a genetic origin. More than 100 clinical trials regarding HD have been tried, but all failed, although there were some improvements limited to symptomatic support. Compared to other neurogenetic disorders, HD is known to have a single genetic target. Thus, this is an advantage and its cure is more feasible than any other movement disorder with heterogeneous genetic causes. In this review paper, the authors attempt to cover the characteristics of HD itself while providing an overview of the gene transfer methods currently being researched, and will introduce an experimental trial with a preclinical model of HD followed by an update on the ongoing clinical trials for patients with HD.

Validation of the Distress Thermometer Questionnaire for Parents of Children with Down syndrome

Abstract Background Down syndrome is the most common neuro-genetic disorder in the world. In Tunisia, the number of births of children with Down's syndrome is estimated at 200 each year. However, few studies have assessed the quality of life of these families and their specific needs. The most used tool to assess the distress of parents of a chronically ill child is the DT-P. Aim The aim of this study was to validate the DT-P in Arabic language and evaluate the degree of distress of parents having a child with a Down syndrome in Arabic-speaking members of the Tunisian union for assistance to intellectual disability in the city of Sousse and those consulting in the department of hereditary and congenital disorders at the University Hospital Charles Nicolle of Tunis during the period between June, 1st 2020 and July, 31st 2020. Results The translation was process according to the translation -back translation method. Two aspects of validity were tested: Content validity via pretest and judgment experts. The construct validity was tested in its external component via the convergent validity, by determining the correlations of the DT-P results with the results of the Hospital Anxiety and Depression Scale (HADS). Overall, the correlations were moderate to strong. Precision was tested using the Cronbach index and was globally satisfactory with indices greater than 0.8. The distress thermometer average was 5.19 ± 2.9. The majority of parents reported distress (75.3%). The emotional problems were the most reported and 67.7% of parents asked to be referred to a professional for psychological support. Conclusions The DT-P appeared to be a valid and reliable short screening-tool for identifying parental distress. Therefore, it would be easier to provide them with professional support. Key messages The quality of life of families with child with Down Syndrom is usually neglected. The DT-P can be used as a reliable short screening-tool for identifying parental distress and providing them with professional support.

New genes involved in Angelman syndrome-like: Expanding the genetic spectrum.

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10–15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis.