scholarly journals A large data resource of genomic copy number variation across neurodevelopmental disorders

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Mehdi Zarrei ◽  
Christie L. Burton ◽  
Worrawat Engchuan ◽  
Edwin J. Young ◽  
Edward J. Higginbotham ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Population Control ◽  
Large Data ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Genomic Disorder ◽  
Rare Cnvs ◽  
Data Resource ◽  
Compulsive Disorder

Abstract Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

scholarly journals Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders

2017 ◽  
Author(s):  
Sofia Stamouli ◽  
Britt-Marie Anderlid ◽  
Charlotte Willfors ◽  
Bhooma Thiruvahindrapuram ◽  
John Wei ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Single Cells ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Rare Cnvs ◽  
Number Variation ◽  
Discordant Twins ◽  
Mz Twins

AbstractHundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. Here, we sought to investigate the contribution of CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on MZ pairs discordant for autism spectrum disorder (ASD) using the PsychChip array. In our collection, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. When analyzing the burden of rare CNVs among pairs concordant and discordant for ASD/NDD in comparison with typically developed (TD) pairs, no differences were found. However, we did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p=0.02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood and, in the majority of MZ twins, do not explain the discordance of NDDs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.

scholarly journals Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders

2018 ◽  
Vol 21 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Sofia Stamouli ◽  
Britt-Marie Anderlid ◽  
Charlotte Willfors ◽  
Bhooma Thiruvahindrapuram ◽  
John Wei ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Single Cells ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Typically Developing ◽  
Rare Cnvs ◽  
Number Variation ◽  
Discordant Twins

Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. We sought to investigate the contribution of rare CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on postzygotic CNVs in MZ pairs discordant for autism spectrum disorder (ASD) using the Illumina Infinium PsychArray. In our sample, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. We did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system, such as a rare deletion affecting HNRNPU, in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p = .02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood, and suggests that the discordance of NDDs in our sample of twins is not explained by discordant CNVs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.

scholarly journals Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Olafur O. Gudmundsson ◽  
G. Bragi Walters ◽  
Andres Ingason ◽  
Stefan Johansson ◽  
Tetyana Zayats ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variant ◽  
Pleiotropic Effect ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Hyperactivity Disorder

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5–BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10−21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.

scholarly journals Role of Copy Number Variations in ADHD

2020 ◽  
Author(s):  
Danijela Krgović
Keyword(s):  
Autism Spectrum Disorder ◽  
Attention Deficit ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Spectrum Disorder ◽  
Genetic Diagnostics ◽  
Healthy Controls

Copy number variations (CNV) have an important role in etiology of neurodevelopmental disorders (NDD). Among them, individuals with attention-deficit and hyperactivity disorders (ADHD) have 1.33 times higher overall rate of CNVs larger than 100 kb compared to healthy controls. These CNVs are often shared with other NDDs and neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD), although duplications of 15q13.3 and 16p13.11 have been found enriched in ADHD cohorts. CNVs provide new opportunities for studying and management of psychiatric disorders including ADHD. Therefore this chapter provides a brief overview of the literature on this topic and presents the benefits of CNV genetic diagnostics in ADHD patients.

scholarly journals Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders

2010 ◽  
Vol 12 (11) ◽  
pp. 694-702 ◽  
Author(s):  
Jill A Rosenfeld ◽  
Blake C Ballif ◽  
Beth S Torchia ◽  
Trilochan Sahoo ◽  
J Britt Ravnan ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Spectrum Disorders

scholarly journals Detection of Clinically Relevant Copy Number Variations and Genes in a Bangladeshi Cohort of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
Hosneara Akter ◽  
Muhammad Mizanur Rahman ◽  
Shaoli Sarker ◽  
Mohammed Basiruzzaman ◽  
Mazharul Islam ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Critical Role ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosomal Microarray Analysis ◽  
Potential Candidate ◽  
Female Ratio ◽  
Pathogenic Cnvs

Abstract Background: Copy number variations (CNVs) play a critical role into the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh. Methods: We have conducted genome-wide chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare chromosomal abnormalities (deletion /duplication/ rearrangements). To identify candidate genes within the rare CNVs, multiple gene constraint metrics (i.e. “Critical-Exon Genes (CEGs)”) were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using R package. Results: In our cohort, the head circumference of males are significantly greater than females (p=0.0002). Of all samples assayed, 12.26% (26/212) and 47.17% (100/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. 2.83% (6/212) pathogenic CNVs are located at the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs in comparison to males (OR=4.2; p=0.0007). ADOS-2 subset show severe social communication deficit (p=0.014) and overall ASD symptoms severity (p=0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs and identified PSMC3 gene as a potential candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability. Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis therapeutics and management of NDD patients.

scholarly journals Reciprocal differentiation via GABAergic components and ASD-related phenotypes in hES with 1q21.1 CNV

2021 ◽  
Author(s):  
Yoshiko Nomura ◽  
Jun Nomura ◽  
Toru Nishikawa ◽  
Toru Takumi
Keyword(s):  
Autism Spectrum Disorder ◽  
Cell Fate ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Cellular Mechanisms ◽  
Common Features ◽  
Underlying Mechanisms ◽  
Glutamate System

Copy number variations (CNVs) in the distal 1q21.1 region, both deletion (1q del) and duplication (1q dup), are associated with autism spectrum disorder, epilepsy and schizophrenia. Besides common phenotypes, 1q del and 1q dup manifest opposite clinical phenotypes?e.g., microcephaly in 1q del and macrocephaly in 1q dup. However, molecular and cellular mechanisms are still elusive. We generate isogenic human ES (hES) cell lines with reciprocal 1q21.1 CNVs using CRISPR/Cas9 system and differentiate them into 2-dimensional (2-D) neurons and 3-D cortical organoids. Our study recapitulates opposite organoid size and shows dosage-dependent differentiation changes i.e., more mature and GABAergic components in 1q del and more proliferative state in 1q dup. In contrast, both CNVs show hyperexcitability and altered expressions of glutamate system as common features. These results demonstrate that 1q21.1 CNVs dramatically affect cell fate in the early neurodevelopmental periods. This is the first isogenic model of hES CNVs and our findings provide new insights into the underlying mechanisms of neurodevelopmental disorders.

scholarly journals Copy Number Variations in a Cohort of 420 Individuals with Neurodevelopmental Disorders From the South of Brazil

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tiago Fernando Chaves ◽  
Nathacha Baretto ◽  
Luan Freitas de Oliveira ◽  
Maristela Ocampos ◽  
Ingrid Tremel Barbato ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Facial Dysmorphism ◽  
Diagnostic Purpose ◽  
Chromosome 11 ◽  
The South ◽  
South Of Brazil

AbstractChromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = < 0.0001, OR = 0.32), obesity (p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.

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