scholarly journals Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 560
Author(s):  
Ana Arteche-López ◽  
Maria José Gómez Rodríguez ◽  
Maria Teresa Sánchez Calvin ◽  
Juan Francisco Quesada-Espinosa ◽  
Jose Miguel Lezana Rosales ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Genetic Diagnosis ◽  
Diagnostic Algorithm ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
De Novo Mutations ◽  
Whole Exome

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44; 75%) compared to CMA (9/44; 20.4%) or FMR1 testing (2/44; 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome.

scholarly journals Identification of a β-Arrestin 2 Mutation Related to Autism by Whole-Exome Sequencing

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yunfei Tang ◽  
Yamei Liu ◽  
Lei Tong ◽  
Shini Feng ◽  
Dongshu Du ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Developmental Stages ◽  
De Novo ◽  
Repetitive Behavior ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Potential Contribution ◽  
De Novo Mutations ◽  
Whole Exome

Autism spectrum disorder (ASD) is a complex neurological disease characterized by impaired social communication and interaction skills, rigid behavior, decreased interest, and repetitive activities. The disease has a high degree of genetic heterogeneity, and the genetic cause of ASD in many autistic individuals is currently unclear. In this study, we report a patient with ASD whose clinical features included social interaction disorder, communication disorder, and repetitive behavior. We examined the patient’s genetic variation using whole-exome sequencing technology and found new de novo mutations. After analysis and evaluation, ARRB2 was identified as a candidate gene. To study the potential contribution of the ARRB2 gene to the human brain development and function, we first evaluated the expression profile of this gene in different brain regions and developmental stages. Then, we used weighted gene coexpression network analysis to analyze the associations between ARRB2 and ASD risk genes. Additionally, the spatial conformation and stability of the ARRB2 wild type and mutant proteins were examined by simulations. Then, we further established a mouse model of ASD. The results showed abnormal ARRB2 expression in the mouse ASD model. Our study showed that ARRB2 may be a risk gene for ASD, but the contribution of de novo ARRB2 mutations to ASD is unclear. This information will provide references for the etiology of ASD and aid in the mechanism-based drug development and treatment.

scholarly journals Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment

2021 ◽  
Vol 12 ◽  
Author(s):  
Bingbo Zhou ◽  
Chuan Zhang ◽  
Lei Zheng ◽  
Zhiqiang Wang ◽  
Xue Chen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Language Impairment ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Behavioral Abnormalities ◽  
Whole Exome ◽  
Chinese Case

Introduction: Neurodevelopmental disorders with language impairment and behavioral abnormalities (NEDLIB) are a disease caused by heterozygous variants in the glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) gene, which manifest as impaired mental development or developmental delay, behavioral abnormalities including autistic characteristics, and language disorders. Currently, only a few mutations in the GRIA2 gene have been discovered.Methods: A GRIA2 variation was detected in a patient by whole-exome sequencing, and the site was validated by Sanger sequencing from the family.Results: We report a Chinese case of NEDLIB in a girl with language impairment and developmental delay through whole-exome sequencing (WES). Genetic analysis showed that there was a de novo missense mutation, c.1934T > G (p.Leu645Arg), in the GRIA2 gene (NM_001083619.1), which has never been reported before.Conclusion: Our case shows the potential diagnostic role of WES in NEDLIB, expands the GRIA2 gene mutation spectrum, and further deepens the understanding of NEDLIB. Deepening the study of the genetic and clinical heterogeneity, treatment, and prognosis of the disease is still our future challenge and focus.

scholarly journals Case report : a novel ASXL3 gene variant in a Sudanese boy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ke Wu ◽  
Yan Cong
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Psychomotor Development ◽  
Gene Variant ◽  
Feeding Difficulties ◽  
Severe Intellectual Disability ◽  
Whole Exome

Abstract Background Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, moderate to severe intellectual disability, poor or absent speech, feeding difficulties, growth failure, dysmorphic craniofacial features and minor skeletal features. The aim of this study was to investigate the genetic etiology of a Sudanese boy with severe developmental delay, intellectual disability, and craniofacial phenotype using trio-based whole-exome sequencing. To our knowledge, no patients with ASXL3 gene variant c.3043C>T have been reported detailedly in literature. Case presentation The patient (male, 3 years 6 months) was the first born of a healthy non-consanguineous couple originating from Sudan, treated for “psychomotor retardation” for more than 8 months in Yiwu. The patient exhibited severely delayed milestones in physiological and intellectual developmental stages, language impairment, poor eye-contact, lack of subtle motions of fingers, fear of claustrophobic space, hypotonia, clinodactyly, autistic features. Peripheral blood samples were collected from the patient and his parents. Trio-based whole-exome sequencing(Trio-WES) identified a de novo heterozygous ASXL3 gene variant c.3043C>T;p.Q1015X. Sanger sequencing verified variants of this family. Conclusion Trio-WES analysis identified a de novo nonsense variant (c.3043C>T) of ASXL3 gene in a Sudanese boy. To our knowledge, the patient with this variant has not been reported previously in literature. This study presents a new case for ASXL3 gene variants, which expanded the mutational and phenotypic spectrum.

25. Identification of De novo, Deleterious Mutations through Exome Sequencing of Sporadic Autism Spectrum Disorder Trios

2018 ◽  
Author(s):  
Shalandra Wood
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations ◽  
Genetic Etiology ◽  
Affected Child ◽  
Biological Relevance

  Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder that has a strong genetic component consisting of many genes contributing to its cause. To help understand this complex genetic etiology, we are looking for novel genes that may be involved in the reason individuals develop ASD. We are doing this by using 5 sporadic ASD cases to determine de novo mutations (mutations new to the affected child that are not previously found in the family). These sporadic cases ensure that the disorder is not likely to arise through any inherited mutations, but through a new mutation found solely in the affected child. We use a trio analysis in which the genes of the affected child are compared to those of their mother and father, so pure de novo single nucleotide polymorphisms (SNPs) can be determined. These SNPs are then filtered based on predicted deleterious effect, quality and biological relevance. Using whole-exome sequencing on these 5 sporadic trios numerous deleterious, de novo mutations have been determined. These are being reviewed for biological relevance, and will be validated using Sanger Sequencing. Of these proposed SNPs being validated a few, such as SHANK3 and DVL1, have previously been linked to ASD. Whereas others, such as C11orf31, are novel candidate genes for the disorder. Through this experiment our understanding of the genetic etiology of ASD continues to grow and evolve, leading to greater insight into this disorder and new directions for possible treatments

scholarly journals A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

2018 ◽  
Vol 08 (01) ◽  
pp. 010-014 ◽  
Author(s):  
Wafa Alazaizeh ◽  
Asem Alkhateeb
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Frameshift Mutation ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Magnetic Resonance Imaging ◽  
Comparative Genomic ◽  
Feeding Difficulties ◽  
Whole Exome

AbstractIntellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

scholarly journals De novo mutations revealed by whole-exome sequencing are strongly associated with autism

Nature ◽  
2012 ◽  
Vol 485 (7397) ◽  
pp. 237-241 ◽  
Author(s):  
Stephan J. Sanders ◽  
Michael T. Murtha ◽  
Abha R. Gupta ◽  
John D. Murdoch ◽  
Melanie J. Raubeson ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
De Novo Mutations ◽  
Whole Exome
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