What a psychiatrist needs to know about copy number variants

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.

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Genomic Syndromes in Schizophrenia

Neurobiology of Mental Illness ◽

10.1093/med/9780199934959.003.0019 ◽

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.

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Multiple copy number variants in a pediatric patient with Hb H disease and intellectual disability

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.37532 ◽

2016 ◽

Vol 170 (4) ◽

pp. 986-991 ◽

Cited By ~ 4

Author(s):

Karen G. Scheps ◽

Liliana Francipane ◽

Julián Nevado ◽

Nora Basack ◽

Myriam Attie ◽

...

Keyword(s):

Intellectual Disability ◽

Pediatric Patient ◽

Copy Number ◽

Copy Number Variants ◽

Multiple Copy ◽

Hb H Disease

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Copy number variants (CNVs) analysis in a deeply phenotyped cohort of individuals with intellectual disability (ID)

BMC Medical Genetics ◽

10.1186/1471-2350-15-82 ◽

2014 ◽

Vol 15 (1) ◽

Cited By ~ 8

Author(s):

Ying Qiao ◽

Eloi Mercier ◽

Jila Dastan ◽

Jane Hurlburt ◽

Barbara McGillivray ◽

...

Keyword(s):

Intellectual Disability ◽

Copy Number ◽

Copy Number Variants

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Advances in the genetics of schizophrenia: will high-risk copy number variants be useful in clinical genetics or diagnostics?

F1000 Medicine Reports ◽

10.3410/m1-61 ◽

2009 ◽

Vol 1 ◽

Cited By ~ 2

Author(s):

David A Collier ◽

Evangelos Vassos ◽

Simon Holden ◽

Christine Patch ◽

Philip McGuire ◽

...

Keyword(s):

High Risk ◽

Copy Number ◽

Copy Number Variants ◽

Clinical Genetics

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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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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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