scholarly journals Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder

2021 ◽  
Author(s):  
Sophie Waldron ◽  
Rachel Pass ◽  
Simonas Griesius ◽  
Jack R. Mellor ◽  
Emma S. J. Robinson ◽  
...  
Keyword(s):  
Copy Number ◽  
Messenger Rna ◽  
Copy Number Variants ◽  
Sensorimotor Gating ◽  
Autism Spectrum ◽  
Locomotor Response ◽  
Single Chromosome ◽  
Gene And Protein Expression ◽  
Behavioural Phenotypes ◽  
Protein Reduction

AbstractGenetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, providing a contrast to the gross deficits in Dlg2 homozygous models (Winkler, et al., 2018; Yoo et al., 2020a) which do not so specifically model the single chromosome DLG2 deletion in carriers of risk-associated copy number variants.

The Role of Copy Number Variation in Psychiatric Disorders

2018 ◽  
pp. 84-95
Author(s):  
Elliott Rees ◽  
George Kirov
Keyword(s):  
Autism Spectrum Disorders ◽  
Copy Number ◽  
Selection Pressure ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
High Odds ◽  
Strong Selection ◽  
Increase Risk ◽  
Number Variation

Copy number variants (CNVs) are deletions, duplications, inversions, or translocations of large DNA segments. They can play a significant role in human disease. Thirteen CNVs have received strong statistical support for involvement in schizophrenia. They are all rare in cases (<1%), much rarer among controls, and have high odds ratios (ORs) for causing disease. The same CNVs also increase risk for autism spectrum disorders, developmental delay, and medical/physical comorbidities. The penetrance of these CNVs for any disorder is relatively high, ranging from 10% for 15q11.2 deletions to nearly 100% for deletions at 22q11.2. Strong selection pressure operates against carriers of these CNVs. Most of these are formed by non-allelic homologous recombination (NAHR), which leads to high mutation rates, thus maintaining the rates of these CNVs in the general population, despite the strong selection forces.

scholarly journals Copy Number Variants in Extended Autism Spectrum Disorder Families Reveal Candidates Potentially Involved in Autism Risk

PLoS ONE ◽  
2011 ◽  
Vol 6 (10) ◽  
pp. e26049 ◽  
Author(s):  
Daria Salyakina ◽  
Holly N. Cukier ◽  
Joycelyn M. Lee ◽  
Stephanie Sacharow ◽  
Laura D. Nations ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
L. D’Abate ◽  
S. Walker ◽  
R. K. C. Yuen ◽  
K. Tammimies ◽  
J. A. Buchanan ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Recurrence Prediction ◽  
Common Genetic Variants ◽  
Spectrum Disorders ◽  
Atypical Development ◽  
Research Consortium

AbstractIdentification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

A Study from Turkey: Identification of Copy Number Variants in Children and Adolescents with Autism Spectrum Disorder

2021 ◽  
Author(s):  
Ahmet Özaslan ◽  
Gülsüm Kayhan ◽  
Elvan İşeri ◽  
Mehmet Ali Ergün ◽  
Esra Güney ◽  
...  
Keyword(s):  
Copy Number ◽  
Diagnostic Yield ◽  
Venous Blood ◽  
Copy Number Variants ◽  
Clinical Importance ◽  
Turkish Population ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Turkish Children ◽  
Children With Asd

Abstract Recent studies suggest that copy number variations (CNVs) play a significant role in the aetiology of ASD. This study aims to investigate CNVs, which are thought to be an important factor in ASD etiology. In addition it was aimed to specify the clinical usefulness of chromosomal microarrays (CMA) in the examination of ASD patients in Turkish population. Of 47 children (60.34±25.60 months; 82.9% boys) with ASD were constructed the sample. The karyotype structure of all participants was found to be normal using conventional cytogenetic methods. DNA obtained from the venous blood samples of the participants was evaluated using SurePrint G3 ISCA V2 CGH 8x60K Array (Agilent Technologies Santa Clara, CA, USA). We have identified 8 CNVs, ranging in size from 55 kb to 6.5 Mb in 7 (5 boys) of 47 children with ASD of the 4 of 8 CNVs were classified as pathogenic, which were 9p24.3p24.2 deletion in 3 Mb size, 15q11-q13 duplication in 6.5 Mb size, 16p11.2 deletion in 598 kb size and 22q13.3 deletion in 55 kb size. According to results has been demonstrated that diagnostic yield of CMA in Turkish children with ASD was 8.5%. Our results indicate that CNVs contribute a part to the genetic aetiology of Turkish children with ASD. In accordance with the literature, these results emphasize the clinical importance of CMA to investigate the aetiology of ASD.

scholarly journals Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Karen S. Ho ◽  
Hope Twede ◽  
Rena Vanzo ◽  
Erin Harward ◽  
Charles H. Hensel ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Detection Rate ◽  
Clinical Performance ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Ultrahigh Resolution ◽  
Significant Difference

Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.

scholarly journals Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

2013 ◽  
Vol 22 (1) ◽  
pp. 71-78 ◽  
Author(s):  
Caroline Nava ◽  
Boris Keren ◽  
Cyril Mignot ◽  
Agnès Rastetter ◽  
Sandra Chantot-Bastaraud ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Diagnostic Analysis ◽  
Snp Microarrays ◽  
Spectrum Disorders

scholarly journals Copy-Number Variants in The Contactin-5 Gene Are a Potential Risk Factor for Autism Spectrum Disorder

2021 ◽  
Author(s):  
Zoe Schmilovich ◽  
Guillaume Huguet ◽  
Qin He ◽  
Amélie Musa-Johnson ◽  
Elise Douard ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
Statistical Power ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Autistic Traits ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Small Scale ◽  
Phenotypic Data

Abstract BackgroundContactin-5 (CNTN5) is a candidate risk gene for autism spectrum disorder (ASD), yet previous attempts to associate copy-number variants (CNVs) encompassing CNTN5 with ASD-susceptibility were limited by insufficient statistical power. Here, we aim to clarify the putative association between CNTN5 CNVs and ASD-risk using large samples. MethodsFirst, we calculated the prevalence and transmission of CNTN5 CNVs in ASD across three ASD cohorts (SSC, MSSNG, and SPARK), the cases reported in the Mercati et al. study, and the BBGRE database (n = 16,607). Second, we modelled their transmission in children with ASD compared to their unaffected siblings. Third, we assessed their frequency in cases with ASD compared to unselected population controls (n = 24,898) and replicated the findings in UK Biobank (UKBB), an independent general population cohort (n = 459,855). Finally, we evaluated the clinical impact of CNTN5 CNVs by assessing their enrichment in a broad neurodevelopmental disorder (NDD) cohort, and the clinical profile of CNTN5 CNV carriers in the DECIPHER database.ResultsThe prevalence of CNTN5 exonic deletions and duplications was stable across ASD and across unselected cohorts (0.042% and 0.020%, respectively). We found a significant enrichment of intronic CNTN5 deletions CNVs in ASD compared to unselected controls (0.175% and 0.004%, respectively). CNVs in most cases with ASD (29 out of 30, 96.7%) were inherited. Parents transmitted the variants to their affected and unaffected children with the same frequency. No differences in exonic CNTN5 CNVs enrichment between cases with ASD compared to individuals with NDDs was observed. LimitationsThe lack of phenotypic data available for unaffected family members of probands with ASD limits the potential to assess whether CNTN5 CNVs segregate with other neuropsychiatric or sub-threshold autistic traits. Different genotyping or sequencing technologies may affect the differences in CNTN5 CNV prevalence across cohorts.ConclusionCNTN5 CNVs are rare inherited ASD susceptibility variants. They may also confer risk for other neuropsychiatric disorders. We offer a powerful framework to investigate candidate susceptibility variants that may not be detected through small-scale approaches. This approach may reveal more intermediate effect-size variants that are implicated in the etiology of ASD.

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