scholarly journals Genetic Testing in Neurodevelopmental Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Juliann M. Savatt ◽  
Scott M. Myers
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Genetic Testing ◽  
Neurodevelopmental Disorders ◽  
Diagnostic Yield ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Cgg Repeat

Neurodevelopmental disorders are the most prevalent chronic medical conditions encountered in pediatric primary care. In addition to identifying appropriate descriptive diagnoses and guiding families to evidence-based treatments and supports, comprehensive care for individuals with neurodevelopmental disorders includes a search for an underlying etiologic diagnosis, primarily through a genetic evaluation. Identification of an underlying genetic etiology can inform prognosis, clarify recurrence risk, shape clinical management, and direct patients and families to condition-specific resources and supports. Here we review the utility of genetic testing in patients with neurodevelopmental disorders and describe the three major testing modalities and their yields – chromosomal microarray, exome sequencing (with/without copy number variant calling), and FMR1 CGG repeat analysis for fragile X syndrome. Given the diagnostic yield of genetic testing and the potential for clinical and personal utility, there is consensus that genetic testing should be offered to all patients with global developmental delay, intellectual disability, and/or autism spectrum disorder. Despite this recommendation, data suggest that a minority of children with autism spectrum disorder and intellectual disability have undergone genetic testing. To address this gap in care, we describe a structured but flexible approach to facilitate integration of genetic testing into clinical practice across pediatric specialties and discuss future considerations for genetic testing in neurodevelopmental disorders to prepare pediatric providers to care for patients with such diagnoses today and tomorrow.

Clinical and Genetic Profile of Autism Spectrum Disorder–Epilepsy (ASD-E) Phenotype: Two Sides of the Same Coin!

2020 ◽  
Vol 51 (6) ◽  
pp. 390-398 ◽  
Author(s):  
Sudhakar Karunakaran ◽  
Ramshekhar N. Menon ◽  
Sruthi S. Nair ◽  
S. Santhakumar ◽  
Muralidharan Nair ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Age Of Onset ◽  
Focal Epilepsy ◽  
Diagnostic Yield ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Chromosomal Microarray ◽  
Seizure Type ◽  
Epilepsy Syndrome ◽  
Genetic Profile

The clinical phenotype of autism spectrum disorder and epilepsy (ASD-E) is a common neurological presentation in various genetic disorders, irrespective of the underlying pathophysiological mechanisms. Here we describe the demographic and clinical profiles, coexistent neurological conditions, type of seizures, epilepsy syndrome, and EEG findings in 11 patients with ASD-E phenotype with proven genetic etiology. The commonest genetic abnormality noted was CDKL5 mutation (3), MECP2 mutation (2), and 1p36 deletion (2). The median age of onset of clinical seizures was 6 months (range, 10 days to 11 years). The most common seizure type was focal onset seizures with impaired awareness, observed in 7 (63.6%) patients followed by epileptic spasms in 4 (30.8%), generalized tonic-clonic and atonic seizures in 3 (27.3%) patients each and tonic seizures in 2 (18.2%) patients and myoclonic seizures in 1 (9.1%) patient. Focal and multifocal interictal epileptiform abnormalities were seen in 6 (54.6%) and 5 (45.5%) patients, respectively. Epileptic encephalopathy and focal epilepsy were seen in 7 (63.6%) and 4 (36.4%) patients, respectively. The diagnostic yield of genetic testing was 44% (11 of 25 patients) and when variants of unknown significance and metabolic defects were included, the yield increased to 60% (15 of 25 patients). We conclude that in patients with ASD-E phenotype with an underlying genetic basis, the clinical seizure type, epilepsy syndrome, and EEG patterns are variable. Next-generation exome sequencing and chromosomal microarray need to be considered in clinical practice as part of evaluation of children with ASD-E phenotype.

scholarly journals Etiological investigation of genetic cause in autism spectrum disorder

2021 ◽  
Vol 31 (1) ◽  
pp. e39581
Author(s):  
Carla Andreia Esteves Fernandes ◽  
Ana Francisca Henriques Cardoso ◽  
Caroline Reis Lopes ◽  
Margarida Maria Videira Henriques ◽  
Ester Preciosa Maio Nunes Pereira
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Family History ◽  
Diagnostic Yield ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Development ◽  
Significance Level ◽  
Development Delay ◽  
Relevant Family History

AIMS: The aims of this study were to characterize the etiological investigation of genetic cause in the autism spectrum disorder and to determine the factors related to its identification.METHODS: A retrospective descriptive study, with an analytical component, included children and adolescents with autism spectrum disorder followed in consultation at a level 2 hospital, between November 2017 and October 2019. The following variables were analyzed: age, sex, age at the first consultation, family history, objective examination, cognitive assessment, etiological investigation of genetic cause and etiological diagnosis of genetic cause. Statistical analysis was performed using the SPSS®v23 program (significance level 0.05).RESULTS: We identified 153 children with autism spectrum disorder, of which 48 underwent a genetic cause investigation: 45 performed microarray analysis (15.6% pathogenic); 42 carried out a molecular study of the Fragile X syndrome (one altered); two performed sequencing of the methyl CpG binding protein 2 (MECP2) gene (one altered). The diagnosis of genetic cause was made in 18.8% of the sample. The identification of the etiology of a genetic cause was related to global development delay/ intellectual disability (p = 0.04) and the presence of relevant family history (p = 0.005).CONCLUSIONS: The diagnostic yield of the genetic study was higher in patients with a global development delay /intellectual disability and in patients with relevant family history.

Stress in mothers of children with neurodevelopmental disorders

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Ghorban Hemati Alamdarloo ◽  
Farzad Majidi
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Learning Disorder ◽  
Content Type ◽  
Specific Learning Disorder ◽  
Specific Learning

Purpose Most parents experience stress when their children are diagnosed with some kind of disability. This paper aims to compare the level of stress among mothers of children with neurodevelopmental disorders. Design/methodology/approach Research sample consisted of 150 mothers of children with neurodevelopmental disorders (50 mothers of children with autism spectrum disorder, 50 mothers of children with intellectual disability and 50 mothers of children with specific learning disorder selected by convenience sampling). The Stress Response Inventory was used for measuring stress. One-way analysis of variance, multivariate analysis of variance and Scheffe post hoc tests were used for data analysis. Findings The results showed that the stress of mothers of children with autism spectrum disorder was significantly higher than to the other groups of mothers. It was also observed that the stress of mothers of children with intellectual disability was significantly higher than the mothers of children with the specific learning disorder. Originality/value Therefore, designing and implementing preventive and interventional programs to decrease the stress of mothers of children with neurodevelopmental disorders, especially mothers of children with autism spectrum disorder is necessary.

scholarly journals Assessment of autism zebrafish mutant models using a high-throughput larval phenotyping platform

2020 ◽  
Author(s):  
Alexandra Colón-Rodríguez ◽  
José M. Uribe-Salazar ◽  
KaeChandra B. Weyenberg ◽  
Aditya Sriram ◽  
Alejandra Quezada ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Candidate Genes ◽  
High Throughput ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Null Alleles ◽  
Time Points ◽  
Zebrafish Larvae

ABSTRACTIn recent years zebrafish have become commonly used as a model for studying human traits and disorders. Their small size, high fecundity, and rapid development allow for more high-throughput experiments compared to other vertebrate models. Given that zebrafish share >70% gene homologs with humans and their genomes can be readily edited using highly efficient CRISPR methods, we are now able to rapidly generate mutations impacting practically any gene of interest. Unfortunately, our ability to phenotype mutant larvae has not kept pace. To address this challenge, we have developed a protocol that obtains multiple phenotypic measurements from individual zebrafish larvae in an automated and parallel fashion, including morphological features (i.e., body length, eye area, and head size) and movement/behavior. By assaying wild-type zebrafish in a variety of conditions, we determined optimal parameters that avoid significant developmental defects or physical damage; these include morphological imaging of larvae at two time points (3 days post fertilization (dpf) and 5 dpf) coupled with motion tracking of behavior at 5 dpf. As a proof-of-principle, we tested our approach on two novel CRISPR-generated mutant zebrafish lines carrying predicted null-alleles of syngap1b and slc7a5, orthologs to two human genes implicated in autism-spectrum disorder, intellectual disability, and epilepsy. Using our optimized high-throughput phenotyping protocol, we recapitulated previously published results from mouse and zebrafish models of these candidate genes. In summary, we describe a rapid parallel pipeline to characterize morphological and behavioral features of individual larvae in a robust and consistent fashion, thereby improving our ability to better identify genes important in human traits and disorders.AUTHOR SUMMARYZebrafish (Danio rerio) are a well-established model organism for the study of neurodevelopmental disorders. Due to their small size, fast reproduction, and genetic homology with humans, zebrafish have been widely used for characterizing and screening candidate genes for many disorders, including autism-spectrum disorder, intellectual disability, and epilepsy. Although several studies have described the use of high-throughput morphological and behavioral assays, few combine multiple assays in a single zebrafish larva. Here, we optimized a platform to characterize morphometric features at two developmental time points in addition to behavioral traits of zebrafish larvae. We then used this approach to characterize two autism candidate genes (SYNGAP1 and SLC7A5) in two CRISPR-generated zebrafish null mutant models we developed in house. These data recapitulate previously published results related to enhanced seizure activity, while identifying additional defects not previously reported. We propose that our phenotyping platform represents a feasible method for maximizing the use of single zebrafish larvae in the characterization of additional mutants relevant to neurodevelopmental disorders.

A Comparative Study of Sociability in Angelman, Cornelia de Lange, Fragile X, Down and Rubinstein Taybi Syndromes and Autism Spectrum Disorder

2016 ◽  
Vol 121 (6) ◽  
pp. 465-486 ◽  
Author(s):  
Joanna Moss ◽  
Lisa Nelson ◽  
Laurie Powis ◽  
Jane Waite ◽  
Caroline Richards ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Down Syndrome ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Selective Mutism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Cornelia De Lange

Abstract Few comparative studies have evaluated the heterogeneity of sociability across a range of neurodevelopmental disorders. The Sociability Questionnaire for People with Intellectual Disability (SQID) was completed by caregivers of individuals with Cornelia de Lange (n = 98), Angelman (n = 66), Fragile X (n = 142), Down (n = 117) and Rubinstein Taybi (n = 88) syndromes and autism spectrum disorder (ASD; n = 107). Between groups and age-band (<12yrs; 12–18yrs; >18yrs) comparisons of SQID scores were conducted. Rates of behaviors indicative of selective mutism were also examined. Fragile X syndrome achieved the lowest SQID scores. Cornelia de Lange, ASD, and Fragile X groups scored significantly lower than Angelman, Down and Rubinstein Taybi groups. Selective mutism characteristics were highest in Cornelia de Lange (40%) followed by Fragile X (17.8%) and ASD (18.2%). Age-band differences were identified in Cornelia de Lange and Down syndrome.

scholarly journals Prenatal Neuropathologies in Autism Spectrum Disorder and Intellectual Disability: The Gestation of a Comprehensive Zebrafish Model

2018 ◽  
Vol 6 (4) ◽  
pp. 29 ◽  
Author(s):  
Robert Kozol
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Critical Periods ◽  
Zebrafish Model ◽  
Behavioral Deficits ◽  
Embryonic Exposure ◽  
Circuit Development

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with overlapping diagnostic behaviors and risk factors. These include embryonic exposure to teratogens and mutations in genes that have important functions prenatally. Animal models, including rodents and zebrafish, have been essential in delineating mechanisms of neuropathology and identifying developmental critical periods, when those mechanisms are most sensitive to disruption. This review focuses on how the developmentally accessible zebrafish is contributing to our understanding of prenatal pathologies that set the stage for later ASD-ID behavioral deficits. We discuss the known factors that contribute prenatally to ASD-ID and the recent use of zebrafish to model deficits in brain morphogenesis and circuit development. We conclude by suggesting that a future challenge in zebrafish ASD-ID modeling will be to bridge prenatal anatomical and physiological pathologies to behavioral deficits later in life.

Access, utilization, and awareness for clinical genetic testing in autism spectrum disorder in Sweden: A survey study

Autism ◽  
2021 ◽  
pp. 136236132110661
Author(s):  
Anna Hellquist ◽  
Kristiina Tammimies
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Genetic Testing ◽  
Language Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Autistic Children ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Autism Spectrum Disorder Diagnosis

Clinical genetic testing is recommended for individuals diagnosed with autism spectrum disorder. There are only a few reports of how these recommendations are followed and especially missing for European countries. We aimed to analyze the rate of access, utilization, and awareness of clinical genetic testing among autistic individuals in Sweden through online surveys targeting parents with at least one autistic child and autistic adolescents (from 15 years) and adults. In total, 868 parents of autistic children and 213 autistic adolescents or adults completed the survey. Only 9.1% ( n = 79) of parents and 2.8% ( n = 6) of autistic adolescents/adults reported having received a referral for clinical genetic testing after autism spectrum disorder diagnosis. The autistic children offered a referral were younger at diagnosis ( p < 0.001) and more likely to have an additional neurodevelopmental diagnosis ( p < 0.01), including intellectual disability ( p < 0.001) or a language disorder ( p < 0.001). Genetic counseling was provided to less than half of the families that were referred for clinical genetic testing. Finally, we report that both respondent groups preferred to be informed by written text and an expert in genetics about clinical genetic testing. This study highlights a lack of awareness and access to clinical genetic testing after autism spectrum disorder diagnosis in Sweden and demonstrates the need for additional studies on how clinical guidelines for genetic testing are followed in different countries. Lay abstract Several medical professional societies recommend clinical genetic testing for autistic individuals as many genetic conditions are linked to autism. However, it is unclear to what extent autistic individuals and parents of autistic children are offered clinical genetic testing. We conducted a community-based survey to estimate the access, utilization, and awareness for clinical genetic testing in Sweden. In total, 868 parents of autistic children and 213 autistic adolescents or adults participated as respondents. The referral rate for clinical genetic testing after autism spectrum disorder diagnosis was low, with only 9.1% for the autistic children as reported by their parents and 2.8% for autistic adolescents/adults. The autistic children who got referrals were more likely to have intellectual disability and language disorder. We also report that awareness of the clinical genetic testing possibility was low in both respondent groups. We also highlight preferred communication means and needs for information before clinical genetic testing. Our results show that utilization and access are low in Sweden, and more studies should be conducted to report these rates in different countries to analyze the effects of clinical genetic testing on healthcare for autistic individuals. Our results highlight the most important information for the families and how the information should be communicated prior to clinical genetic testing.

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