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 Structural disruption of genomic regions containing ultraconserved elements is associated with neurodevelopmental phenotypes

2017 ◽  
Author(s):  
Ruth B. McCole ◽  
Wren Saylor ◽  
Claire Redin ◽  
Chamith Y. Fonseka ◽  
Harrison Brand ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
Ultraconserved Elements ◽  
Genetic Perturbations ◽  
Number Variation ◽  
Balanced Chromosome Rearrangements ◽  
Genomic Regions ◽  
Structural Disruption

AbstractThe development of the human brain and nervous system can be affected by genetic or environmental factors. Here we focus on characterizing the genetic perturbations that accompany and may contribute to neurodevelopmental phenotypes. Specifically, we examine two types of structural variants, namely, copy number variation and balanced chromosome rearrangements, discovered in subjects with neurodevelopmental disorders and related phenotypes. We find that a feature uniting these types of genetic aberrations is a proximity to ultraconserved elements (UCEs), which are sequences that are perfectly conserved between the reference genomes of distantly related species. In particular, while UCEs are generally depleted from copy number variant regions in healthy individuals, they are, on the whole, enriched in genomic regions disrupted by copy number variants or breakpoints of balanced rearrangements in affected individuals. Additionally, while genes associated with neurodevelopmental disorders are enriched in UCEs, this does not account for the excess of UCEs either in copy number variants or close to the breakpoints of balanced rearrangements in affected individuals. Indeed, our data are consistent with some manifestations of neurodevelopmental disorders resulting from a disruption of genome integrity in the vicinity of UCEs.

Koduojančios ir nekoduojančios genomo sekos variantų bei kopijų skaičiaus pokyčių molekulinis ir funkcinis vertinimas

2020 ◽  
Author(s):  
◽  
Evelina Siavrienė
Keyword(s):  
Genome Sequence ◽  
Copy Number ◽  
Copy Number Variants ◽  
Sequence Variants ◽  
Functional Evaluation

A Molecular and Functional Evaluation of Coding and Non-Coding Genome Sequence Variants and Copy Number Variants

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.

Basic principles of genetic disease

ESC CardioMed ◽  
2018 ◽  
pp. 669-671
Author(s):  
Eric Schulze-Bahr
Keyword(s):  
Genetic Disease ◽  
Copy Number ◽  
Copy Number Variants ◽  
Single Nucleotide Variants ◽  
Individual Genome ◽  
Base Pairs ◽  
Single Nucleotide ◽  
Basic Principles ◽  
Bona Fide ◽  
Genomic Regions

The human genome consists of approximately 3 billion (3 × 109) base pairs of DNA (around 20,000 genes), organized as 23 chromosomes (diploid parental set), and a small mitochondrial genome (37 genes, including 13 proteins; 16,589 base pairs) of maternal origin. Most human genetic variation is natural, that is, common or rare (minor allele frequency >0.1%) and does not cause disease—apart from every true disease-causing (bona fide) mutation each individual genome harbours more than 3.5 million single nucleotide variants (including >10,000 non-synonymous changes causing amino acid substitutions) and 200–300 large structural or copy number variants (insertions/deletions, up to several thousands of base-pairs) that are non-disease-causing variations and scattered throughout coding and non-coding genomic regions.

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.

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.

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.

scholarly journals Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

2014 ◽  
Vol 171 (2) ◽  
pp. 253-262 ◽  
Author(s):  
Ana P M Canton ◽  
Sílvia S Costa ◽  
Tatiane C Rodrigues ◽  
Debora R Bertola ◽  
Alexsandra C Malaquias ◽  
...  
Keyword(s):  
Short Stature ◽  
Candidate Genes ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Comparative Genomic ◽  
Growth Disorders ◽  
Genomic Regions

BackgroundThe etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders.ObjectiveTo analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause.Patients and methodsA total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature.ResultsIn 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation.ConclusionPathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.

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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