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

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.

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Duplications at 19q13.33 in patients with neurodevelopmental disorders

Neurology Genetics ◽

10.1212/nxg.0000000000000210 ◽

2018 ◽

Vol 4 (1) ◽

pp. e210 ◽

Cited By ~ 1

Author(s):

Eduardo Pérez-Palma ◽

Elmo Saarentaus ◽

Marie Ravoet ◽

Giancarlo V. De Ferrari ◽

Peter Nürnberg ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Copy Number ◽

De Novo ◽

Gene Dosage ◽

Copy Number Variants ◽

Clinical Databases ◽

Consensus Region ◽

Reference Databases ◽

Copy Number Changes ◽

Future Evaluation

ObjectiveAfter the recent publication of the first patients with disease-associated missense variants in the GRIN2D gene, we evaluate the effect of copy number variants (CNVs) overlapping this gene toward the presentation of neurodevelopmental disorders (NDDs).MethodsWe explored ClinVar (number of CNVs = 50,794) and DECIPHER (number of CNVs = 28,085) clinical databases of genomic variations for patients with copy number changes overlapping the GRIN2D gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content, and expression, with publicly available reference databases.ResultsWe identified 11 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo, and comparable CNVs are not present in control databases. All patients were reported to have NDDs and dysmorphic features as the most common clinical phenotype (N = 8/11), followed by seizures (N = 6/11) and intellectual disability (N = 5/11). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression, and gene dosage sensitivity analysis, we highlight 4 genes for future evaluation: CARD8, C19orf68, KDELR1, and GRIN2D, which are promising candidates for disease causality. Furthermore, investigation of the literature especially supports GRIN2D as the best candidate gene.ConclusionsOur study presents dup19q13.33 as a novel duplication syndrome locus associated with NDDs. CARD8, C19orf68, KDELR1, and GRIN2D are promising candidates for functional follow-up.

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A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

10.1101/2019.12.12.19014555 ◽

2019 ◽

Cited By ~ 1

Author(s):

Joanna Martin ◽

Grace Hosking ◽

Megan Wadon ◽

Sharifah Shameem Agha ◽

Kate Langley ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Neurodevelopmental Disorders ◽

Copy Number ◽

De Novo ◽

Copy Number Variants ◽

Case Control ◽

Genetic Studies ◽

Hyperactivity Disorder ◽

Risk Alleles ◽

Tourette Disorder

AbstractBackgroundRecent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability, and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD.MethodsChildren with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200kb) CNVs and identified those calls that were present in the proband and absent in both biological parents.ResultsIn 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at 4 genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies.ConclusionsOur study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.

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Faculty Opinions recommendation of rDNA Copy Number Variants Are Frequent Passenger Mutations in Saccharomyces cerevisiae Deletion Collections and de Novo Transformants.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726580404.793522980 ◽

2016 ◽

Author(s):

Judith Berman

Keyword(s):

Saccharomyces Cerevisiae ◽

Copy Number ◽

De Novo ◽

Copy Number Variants ◽

Passenger Mutations ◽

Rdna Copy ◽

Rdna Copy Number

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An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

Scientific Reports ◽

10.1038/srep22851 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 9

Author(s):

Leandro de Araújo Lima ◽

Ana Cecília Feio-dos-Santos ◽

Sintia Iole Belangero ◽

Ary Gadelha ◽

Rodrigo Affonseca Bressan ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Copy Number ◽

De Novo ◽

Copy Number Variants ◽

Integrative Approach ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Hyperactivity Disorder ◽

New Genes

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

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

10.1101/011510 ◽

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.

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De Novo Sequence and Copy Number Variants are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

SSRN Electronic Journal ◽

10.2139/ssrn.3188485 ◽

2018 ◽

Author(s):

Sheng Wang ◽

Jeffrey D. Mandelll ◽

Yogesh Kumarr ◽

Nawei Sunn ◽

Montana T. Morris ◽

...

Keyword(s):

Cell Polarity ◽

Copy Number ◽

De Novo ◽

Copy Number Variants ◽

Tourette Disorder

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The prenatal diagnosis and clinical outcomes of fetuses with 15q11.2 copy number variants: a case series of 36 patients

10.22541/au.161956845.50551129/v1 ◽

2021 ◽

Author(s):

Jessica Kang ◽

Chien Nan Lee ◽

Yi-Ning Su ◽

Ming-Wei Lin ◽

Yi-Yun Tai ◽

...

Keyword(s):

Pregnant Women ◽

Developmental Delay ◽

Copy Number ◽

De Novo ◽

Copy Number Variants ◽

Case Series ◽

Copy Number Variant ◽

University Hospital ◽

Limited Information ◽

Ultrasound Findings

Objective: The prenatal genetic counseling of fetus diagnosed with the 15q11.2 copy number variant (CNV) involving the BP1-BP2 region has been difficult due to limited information and controversial opinion on prognosis. Design: Case series. Setting: This study uses data from National Taiwan University Hospital. Sample: Data of 36 pregnant women who underwent prenatal microarray analysis from 2012 to 2017 and were assessed at National Taiwan University Hospital. Methods: Data were collected by reviewing patients’ medical record. Comparison of patient characteristics, prenatal ultrasound findings and postnatal outcomes between different cases involving the 15q11.2 BP1-BP2 region were presented. Main outcome measured: Postnatal prognosis. Results: Out of the 36 patients diagnosed with CNVs involving the BP1-BP2 region, 5 were diagnosed with microduplication and 31 with microdeletion. Abnormal ultrasound findings were recorded in 12 cases prenatally. De novo microduplications were observed in 25% of the cases and microdeletions were found in 14%. Amongst the cases, 10 pregnant women received termination of pregnancy and 26 gave birth to healthy individuals (27 babies in total). Conclusion: The prognoses of 15q11.2 CNVs were controversial and recent studies have revealed its connection with developmental delay and autism. In our study, no obvious developmental delay or neurological disorders were detected postnatally in the 1 case of 15q11.2 microduplication and 25 cases of microdeletion.

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

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17249253 ◽

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.

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