scholarly journals A Survey of Copy Number Variants Associated with Neurodevelopmental Disorders in a Large-Scale, Multi-Ancestry Biobank

2021 ◽  
Author(s):  
Rebecca Birnbaum ◽  
Behrang Mahjani ◽  
Ruth Loos ◽  
Andrew Sharp
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Large Scale ◽  
Clinical Presentation ◽  
Copy Number Variants ◽  
P Value ◽  
Congenital Disorders ◽  
Major Depressive ◽  
Clinical Assessments ◽  
Obstructive Sleep

BACKGROUND: Past clinical genetic studies have identified rare, copy number variants (CNVs) as risk factors for multiple, neurodevelopmental disorders (NDD), including autism spectrum disorder and schizophrenia. However, the broad, clinical characterization of these NDD-CNVs in large population cohorts, especially of diverse ancestry, is relatively understudied. We characterized the clinical presentation of NDD-CNVs in the BioMe biobank, comprising ~25,000 individuals across diverse ancestry, medical and neuropsychiatric clinical presentation, with a mean age of 50.3 years. METHODS: Individuals within the BioMe biobank harboring NDD-CNVs were identified using a consensus of two CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by a series of novel, in-silico clinical assessments. RESULTS: The overall prevalence of a set of 64 NDD-CNVs was calculated at ~2.5%, with prevalence varying by locus, corroborating the presence of some relatively, highly-prevalent NDD-CNVs (i.e., 15q11.2 deletion/duplication, 2q13(NPHP1) deletion/duplication). An aggregate set of rare, NDD-CNVs were enriched for congenital disorders (OR=1.8, p-value=0.02) and major depressive disorders (OR=1.3, p-value=0.04) in multi-ancestry analyses, and major depressive-disorder in an African ancestry-stratified group (OR=1.8, p-value=0.01). In a meta-analysis of medical diagnoses (n=195 hierarchically-clustered diagnostic codes), an aggregated set of rare, NDD-CNVs was significantly associated with obstructive sleep apnea (Z-score=3.6 p=3.2x10-4). Further, an aggregated set of rare, NDD-CNVs was associated with increased body mass index (BMI) in a multi-ancestry analysis (Beta=0.14, p-value=0,04), and in Hispanic-stratified analyses (Beta=0.30, p-value=4.2x10-3). For 38 common serum laboratory tests, there was no identified association with the aggregate set of NDD-CNVs. CONCLUSION: The current analyses elucidated clinical features of individuals harboring NDD-CNVs, in a large-scale, multi-ancestry biobank, identifying enrichments for congenital disorders and major depressive disorder, as well as identifying associations with obesity-related phenotypes, obstructive sleep apnea and increased BMI. Future recall of individuals harboring NDD-CNVs will allow for further clinical assessments beyond the electronic health records (EHR) presently analyzed, including neurocognitive and neuroimaging outcomes.

0306 Exploring the feasibility of using copy number variants as genetic markers through large-scale whole genome sequencing experiments

2016 ◽  
Vol 94 (suppl_5) ◽  
pp. 146-146
Author(s):  
D. M. Bickhart ◽  
L. Xu ◽  
J. L. Hutchison ◽  
J. B. Cole ◽  
D. J. Null ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genetic Markers ◽  
Genome Sequencing ◽  
Copy Number ◽  
Large Scale ◽  
Copy Number Variants ◽  
Whole Genome

scholarly journals Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders

2014 ◽  
Author(s):  
Janani Iyer ◽  
Santhosh Girirajan
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Molecular Genetic ◽  
Copy Number Variants ◽  
Fruit Fly ◽  
Functional Evaluation ◽  
Rare Cnvs ◽  
Molecular Genetic Basis ◽  
Causal Genes ◽  
Genomic Regions

Rare copy-number variants (CNVs) are a significant cause of neurodevelopmental disorders. The sequence architecture of the human genome predisposes certain individuals to deletions and duplications within specific genomic regions. While assessment of individuals with different breakpoints has identified causal genes for certain rare CNVs, deriving gene-phenotype correlations for rare CNVs with similar breakpoints has been challenging. We present a comprehensive review of the literature related to genetic architecture that is predisposed to recurrent rearrangements, and functional evaluation of deletions, duplications, and candidate genes within rare CNV intervals using mouse, zebrafish, and fruit fly models. It is clear that phenotypic assessment and complete genetic evaluation of large cohorts of individuals carrying specific CNVs and functional evaluation using multiple animal models are necessary to understand the molecular genetic basis of neurodevelopmental disorders.

scholarly journals Bayesian copy number detection and association in large-scale studies

2020 ◽  
Author(s):  
Stephen Cristiano ◽  
David McKean ◽  
Jacob Carey ◽  
Paige Bracci ◽  
Paul Brennan ◽  
...  
Keyword(s):  
Copy Number ◽  
Large Scale ◽  
Disease Risk ◽  
Copy Number Variants ◽  
Regulatory Elements ◽  
Cancer Case ◽  
Tumor Supressor ◽  
Increase Risk ◽  
Control Study

AbstractGermline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.

Genomic Syndromes in Schizophrenia

2013 ◽  
pp. 247-255
Author(s):  
George Kirov ◽  
Michael C. O’Donovan ◽  
Michael J. Owen
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Individual Risk ◽  
Genomic Deletions ◽  
Pathogenic Cnvs ◽  
Cognition And Learning

Several submicroscopic genomic deletions and duplications known as copy number variants (CNVs) have been reported to increase susceptibility to schizophrenia. Those for which the evidence is particularly strong include deletions at chromosomal segments 1q21.1, 3q29, 15q11.2, 15q13.3, 17q12 and 22q11.2, duplications at 15q11.2-q13.1, 16p13.1, and 16p11.2, and deletions atthe gene NRXN1. The effect of each on individual risk is relatively large, but it does not appear that any of them is alone sufficient to cause disorder in carriers. These CNVs often arise as new mutations(de novo). Analyses of genes enriched among schizophrenia implicated CNVs highlight the involvement in the disorder of post-synaptic processes relevant to glutamatergicsignalling, cognition and learning. CNVs that contribute to schizophrenia risk also contribute to other neurodevelopmental disorders, including intellectual disability, developmental delay and autism. As a result of selection, all known pathogenic CNVs are rare, and none makes a sizeable contribution to overall population risk of schizophrenia, although the study of these mutations is nevertheless providing important insights into the origins of the disorder.

scholarly journals Copy number variation analysis of twin pairs discordant for cleft lip with or without cleft palate

2019 ◽  
Vol 33 ◽  
pp. 205873841985587
Author(s):  
Luca Scapoli ◽  
Francesco Carinci ◽  
Annalisa Palmieri ◽  
Francesca Cura ◽  
Alessandro Baj ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Copy Number ◽  
Large Scale ◽  
Cleft Lip ◽  
Small Sample Size ◽  
Copy Number Variants ◽  
Monozygotic Twins ◽  
Monozygotic Twin ◽  
Small Sample ◽  
High Level

Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a frequent orofacial malformation. The comparison of concordance rate observed in monozygotic and dizygotic twins supports high level of heritability and a strong genetic component. However, phenotype concordance for orofacial cleft in monozygotic twins is about 50%. The aim of the present investigation was to detect postzygotic events that may account for discordance in monozygotic twins. High-density SNP microarrays hybridization was used to genotype two pairs of monozygotic twins discordant for nsCL/P. Discordant SNP genotypes and copy number variants were analyzed to identify genetic differences responsible of phenotype discrepancy. A number of differences were observed, none involving known nsCL/P candidate genes or genomic regions. Considering the limitation of the study, related to the small sample size and to the large-scale investigation method, the results suggest that the detection of discordant events in other monozygotic twin pairs would be remarkable and warrant further investigations.

scholarly journals Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4–BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature

2020 ◽  
Vol 17 (24) ◽  
pp. 9253
Author(s):  
Natália Oliva-Teles ◽  
Maria Chiara de Stefano ◽  
Louise Gallagher ◽  
Severin Rakic ◽  
Paula Jorge ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Chromosomal Region ◽  
Current Knowledge ◽  
Copy Number Variants ◽  
Inclusion Criteria ◽  
Rare Disorders ◽  
Number Variation ◽  
Malformation Syndromes ◽  
Neuropsychiatric Conditions

Copy number variants (CNVs) play an important role in the genetic underpinnings of neuropsychiatric/neurodevelopmental disorders. The chromosomal region 16p11.2 (BP4–BP5) harbours both deletions and duplications that are associated in carriers with neurodevelopmental and neuropsychiatric conditions as well as several rare disorders including congenital malformation syndromes. The aim of this article is to provide a review of the current knowledge of the diverse neurodevelopmental disorders (NDD) associated with 16p11.2 deletions and duplications reported in published cohorts. A literature review was conducted using the PubMed/MEDLINE electronic database limited to papers published in English between 1 January 2010 and 31 July 2020, describing 16p11.2 deletions and duplications carriers’ cohorts. Twelve articles meeting inclusion criteria were reviewed from the 75 articles identified by the search. Of these twelve papers, eight described both deletions and duplications, three described deletions only and one described duplications only. This study highlights the heterogeneity of NDD descriptions of the selected cohorts and inconsistencies concerning accuracy of data reporting.

Corrigendum to “Challenges in the clinical interpretation of small de novo copy number variants in neurodevelopmental disorders” [Gene 706 (2019) 162–171]

Gene ◽  
2020 ◽  
Vol 735 ◽  
pp. 144393
Author(s):  
Pamela Magini ◽  
Emanuela Scarano ◽  
Ilaria Donati ◽  
Alberto Sensi ◽  
Laura Mazzanti ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Clinical Interpretation

scholarly journals What a psychiatrist needs to know about copy number variants

2015 ◽  
Vol 21 (3) ◽  
pp. 157-163 ◽  
Author(s):  
George Kirov ◽  
Elliott Rees ◽  
James Walters
Keyword(s):  
Risk Factors ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Early Onset ◽  
Copy Number ◽  
Structural Changes ◽  
Developmental Disorder ◽  
Copy Number Variants ◽  
Clinical Genetics

SummaryCopy number variants (CNVs) are structural changes in chromosomes that result in deletions, duplications, inversions or translocations of large DNA segments. Eleven confirmed CNV loci have been identified as rare but important risk factors in schizophrenia. These CNVs are also associated with other neurodevelopmental disorders and medical/physical comorbidities. Although the penetrance of the CNVs for schizophrenia (the chance that CNV carriers will develop the disorder) is modest, the penetrance of CNVs for any early-onset developmental disorder (e.g. intellectual disability or autism) is much higher. Testing for CNVs is now affordable and being used in clinical genetics and neurodevelopmental disorders clinics. It is possible that testing will be expanded to psychiatric clinics. This article provides a clinically relevant overview of recent CNV findings in schizophrenia and related disorders.

Copy-number variants in neurodevelopmental disorders: promises and challenges

2009 ◽  
Vol 25 (12) ◽  
pp. 536-544 ◽  
Author(s):  
Alison K. Merikangas ◽  
Aiden P. Corvin ◽  
Louise Gallagher
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Copy Number Variants
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