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

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.

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Genetic Testing in Neurodevelopmental Disorders

Frontiers in Pediatrics ◽

10.3389/fped.2021.526779 ◽

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.

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Routine Chromosomal Microarray Analysis is Necessary in Korean Patients With Unexplained Developmental Delay/Mental Retardation/Autism Spectrum Disorder

Annals of Laboratory Medicine ◽

10.3343/alm.2015.35.5.510 ◽

2015 ◽

Vol 35 (5) ◽

pp. 510-518 ◽

Cited By ~ 11

Author(s):

Saeam Shin ◽

Nae Yu ◽

Jong Rak Choi ◽

Seri Jeong ◽

Kyung-A Lee

Keyword(s):

Autism Spectrum Disorder ◽

Mental Retardation ◽

Developmental Delay ◽

Microarray Analysis ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Korean Patients

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Mothers' appreciation of chromosomal microarray analysis for autism spectrum disorder

Journal for Specialists in Pediatric Nursing ◽

10.1111/jspn.12121 ◽

2015 ◽

Vol 20 (4) ◽

pp. 244-258 ◽

Cited By ~ 7

Author(s):

Ellen Giarelli ◽

Marian Reiff

Keyword(s):

Autism Spectrum Disorder ◽

Microarray Analysis ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis

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Autism spectrum disorder and comorbid neurodevelopmental disorders (ASD-NDDs): Clinical and genetic profile of a pediatric cohort

Clinica Chimica Acta ◽

10.1016/j.cca.2021.11.014 ◽

2021 ◽

Author(s):

Shimeng Chen ◽

Juan Xiong ◽

Baiyu Chen ◽

Ciliu Zhang ◽

Xiaolu Deng ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Neurodevelopmental Disorders ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Genetic Profile

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A Genetic Multimutation Model of Autism Spectrum Disorder Fits Disparate Twin Concordance Data from the USA and Canada

International Scholarly Research Notices ◽

10.1155/2015/519828 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10

Author(s):

Ivan Kramer ◽

Paul H. Lipkin ◽

Alison R. Marvin ◽

Paul A. Law

Keyword(s):

Autism Spectrum Disorder ◽

Age Of Onset ◽

Autism Spectrum ◽

Concordance Rate ◽

Spectrum Disorder ◽

Critical Test ◽

The Usa ◽

Males And Females ◽

Kennedy Krieger Institute ◽

Genetic Hypothesis

Whether autism spectrum disorder (ASD) is caused by genetics, environmental factors, or a combination of both is still being debated today. To help resolve this issue, a genetic multimutation model of ASD development was applied to a wide variety of age-of-onset data from the USA and Canada, and the model is shown to fit all the data. Included in this analysis is new, updated data from the Interactive Autism Network (IAN) of the Kennedy Krieger Institute in Baltimore, Maryland. We find that the age-of-onset distribution for males and females is identical, suggesting that ASD may be an autosomal disorder. The ASD monozygote concordance rate in twin data predicted by the genetic multimutation model is shown to be compatible with the observed rates. If ASD is caused entirely by genetics, then the ASD concordance rate of a cohort of monozygote twins should approach 100% as the youngest pair of twins in the cohort passes 10 years of age, a prediction that constitutes a critical test of the genetic hypothesis. Thus, by measuring the ASD concordance rate as a cohort of monozygote twins age, the hypothesis that this disorder is caused entirely by genetic mutations can be tested.

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Case Report: An Atypical Angelman Syndrome Case With Obesity and Fulfilled Autism Spectrum Disorder Identified by Microarray

Frontiers in Genetics ◽

10.3389/fgene.2021.755605 ◽

2021 ◽

Vol 12 ◽

Author(s):

Areerat Hnoonual ◽

Phawin Kor-anantakul ◽

Chariyawan Charalsawadi ◽

Juthamas Worachotekamjorn ◽

Pornprot Limprasert

Keyword(s):

Autism Spectrum Disorder ◽

Clinical Features ◽

Angelman Syndrome ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Chromosomal Microarray ◽

Unknown Etiology ◽

Methylation Specific Pcr ◽

Specific Pcr

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which are etiologically heterogeneous. Chromosomal microarray is now recommended as the first-tier clinical diagnostic test for ASD. We performed chromosomal microarray in 16 Thai patients with ASD using an Illumina HumanCytoSNP-12 v2.1 array and found one case with uniparental disomy (UPD) of chromosome 15. Methylation-specific PCR showed abnormal methylation of the maternal SNRPN allele. Haplotype analysis revealed that the patient had received both chromosomes 15 from his father. These results were consistent with Angelman syndrome. However, his clinical features had no clinical significance for classic Angelman syndrome. He had first presented at the pediatric clinic with no speech, poor social interaction skills and repetitive behaviors consistent with ASD based on the DSM-IV criteria at 2 years of age and later confirmed by ADOS at 5 years of age. He was strikingly overweight but had no dysmorphic facies, seizures nor ataxia and was diagnosed as non-syndromic ASD, a diagnosis which was believed until at 10 years of age, his DNA was included for analysis in this current cohort study. Our findings suggest that ASD patients with unknown etiology should be considered for methylation-specific PCR testing for Angelman syndrome where chromosomal microarray is not available. In the study, we also review the clinical features of Angelman syndrome caused by UPD and the frequency of ASD in individuals with Angelman syndrome.

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Etiological investigation of genetic cause in autism spectrum disorder

Scientia Medica ◽

10.15448/1980-6108.2021.1.39581 ◽

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.

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