44. Reevaluation of copy number variant (CNV) classifications in the clinical laboratory setting: challenges, insights, and experiences with a laboratory-initiated process

IntroductionFetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.MethodsWe reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.ResultsSeven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).ConclusionsThis study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

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Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2010.10.004 ◽

2010 ◽

Vol 87 (5) ◽

pp. 618-630 ◽

Cited By ~ 203

Author(s):

Daniel Moreno-De-Luca ◽

Jennifer G. Mulle ◽

Erin B. Kaminsky ◽

Stephan J. Sanders ◽

Scott M. Myers ◽

...

Keyword(s):

High Risk ◽

Copy Number ◽

Copy Number Variant

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Chromosome 22 Deletions and Suicidal Behavior in Schizophrenia

Neuropsychobiology ◽

10.1159/000513645 ◽

2021 ◽

pp. 1-8

Author(s):

Ali Bani-Fatemi ◽

Christopher Adanty ◽

Nasia Dai ◽

Ariel Graff ◽

Philip Gerretsen ◽

...

Keyword(s):

Suicide Attempt ◽

Suicidal Behavior ◽

Copy Number ◽

Rating Scale ◽

Copy Number Variant ◽

Chromosome 22 ◽

Suicide Attempters ◽

Severity Rating ◽

Neuropsychiatric Diseases ◽

Significant Difference

Background: Studies have shown that the overall copy number variant (CNV) load is associated with schizophrenia. Schizophrenia is a mental disorder that is frequently associated with suicidal behavior. Methods: We recruited 263 patients with schizophrenia from the Centre for Addiction and Mental Health. The Columbia Suicide Severity Rating Scale was used to assess the presence of lifetime suicide attempt. Genotyping was completed using the Illumina Omni 2.5 chip. We tested the association between deletion events on chromosome 22 with suicide attempt in our schizophrenia sample. Results: There was no significant difference between suicide attempters and non-attempters considering the presence/absence of deletion events on chromosome 22. Conclusion: Although our results did not show a significant association between deletions on chromosome 22 and suicide attempt in schizophrenia, CNV studies may reveal important, novel insights and open further investigation for the treatment of neuropsychiatric diseases.

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A novel rare copy number variant of the ABCF1 gene identified among dengue fever patients from Peninsular Malaysia

Genetics and Molecular Research ◽

10.4238/2014.february.19.9 ◽

2014 ◽

Vol 13 (1) ◽

pp. 980-985 ◽

Cited By ~ 3

Author(s):

B.P. Hoh ◽

S.S. Sam ◽

S.H. Umi ◽

M. Mahiran ◽

N.Y. Nik Khairudin ◽

...

Keyword(s):

Dengue Fever ◽

Copy Number ◽

Copy Number Variant ◽

Peninsular Malaysia

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Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0908584106 ◽

2009 ◽

Vol 106 (39) ◽

pp. 16746-16751 ◽

Cited By ~ 97

Author(s):

B. Xu ◽

A. Woodroffe ◽

L. Rodriguez-Murillo ◽

J. L. Roos ◽

E. J. van Rensburg ◽

...

Keyword(s):

Copy Number ◽

Genetic Architecture ◽

Copy Number Variant

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MCKAT, a multi-dimensional copy number variant kernel association test

10.1101/2021.03.13.435274 ◽

2021 ◽

Author(s):

Nastaran Maus Esfahani ◽

Daniel Catchpoole ◽

Javed Khan ◽

Paul J. Kennedy

Keyword(s):

Copy Number ◽

Kernel Method ◽

Random Effect ◽

Random Effect Model ◽

Score Test ◽

Copy Number Variant ◽

Association Test ◽

P Value ◽

Single Pair ◽

Related Trait

AbstractBackgroundCopy number variants (CNVs) are the gain or loss of DNA segments in the genome. Studies have shown that CNVs are linked to various disorders, including autism, intellectual disability, and schizophrenia.Consequently, the interest in studying a possible association of CNVs to specific disease traits is growing. However, due to the specific multi-dimensional characteristics of the CNVs, methods for testing the association between CNVs and the disease-related traits are still underdeveloped. We propose a novel multi-dimensional CNV kernel association test (MCKAT) in this paper. We aim to find significant associations between CNVs and disease-related traits using kernel-based methods.ResultsWe address the multi-dimensionality in CNV characteristics. We first design a single pair CNV kernel, which contains three sub-kernels to summarize the similarity between two CNVs considering all CNV characteristics. Then, aggregate single pair CNV kernel to the whole chromosome CNV kernel, which summarizes the similarity between CNVs in two or more chromosomes. Finally, the association between the CNVs and disease-related traits is evaluated by comparing the similarity in the trait with kernel-based similarity using a score test in a random effect model. We apply MCKAT on genome-wide CNV datasets to examine the association between CNVs and disease-related traits, which demonstrates the potential usefulness the proposed method has for the CNV association tests. We compare the performance of MCKAT with CKAT, a uni-dimensional kernel method. Based on the results, MCKAT indicates stronger evidence, smaller p-value, in detecting significant associations between CNVs and disease-related traits in both rare and common CNV datasets.ConclusionA multi-dimensional copy number variant kernel association test can detect significantly associated CNVs with any disease-related trait. MCKAT can help biologists detect significantly associated CNVs with any disease-related trait across a patient group instead of examining the CNVs case by case in each subject.

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Detection and characterization of copy number variants based on whole-genome sequencing by DNBSEQ platforms

10.1101/786962 ◽

2019 ◽

Author(s):

Junhua Rao ◽

Lihua Peng ◽

Fang Chen ◽

Hui Jiang ◽

Chunyu Geng ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Copy Number ◽

Copy Number Variants ◽

Copy Number Variant ◽

Whole Genome ◽

Genome Wide ◽

Wide Range ◽

Distribution Sensitivity ◽

Cnv Detection

AbstractBackgroundNext-generation sequence (NGS) has rapidly developed in past years which makes whole-genome sequencing (WGS) becoming a more cost- and time-efficient choice in wide range of biological researches. We usually focus on some variant detection via WGS data, such as detection of single nucleotide polymorphism (SNP), insertion and deletion (Indel) and copy number variant (CNV), which playing an important role in many human diseases. However, the feasibility of CNV detection based on WGS by DNBSEQ™ platforms was unclear. We systematically analysed the genome-wide CNV detection power of DNBSEQ™ platforms and Illumina platforms on NA12878 with five commonly used tools, respectively.ResultsDNBSEQ™ platforms showed stable ability to detect slighter more CNVs on genome-wide (average 1.24-fold than Illumina platforms). Then, CNVs based on DNBSEQ™ platforms and Illumina platforms were evaluated with two public benchmarks of NA12878, respectively. DNBSEQ™ and Illumina platforms showed similar sensitivities and precisions on both two benchmarks. Further, the difference between tools for CNV detection was analyzed, and indicated the selection of tool for CNV detection could affected the CNV performance, such as count, distribution, sensitivity and precision.ConclusionThe major contribution of this paper is providing a comprehensive guide for CNV detection based on WGS by DNBSEQ™ platforms for the first time.

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HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of Copy Number Variant, Copy Number Variation Region, and Runs of Homozygosity

Frontiers in Genetics ◽

10.3389/fgene.2021.731355 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jinghang Zhou ◽

Liyuan Liu ◽

Thomas J. Lopdell ◽

Dorian J. Garrick ◽

Yuangang Shi

Keyword(s):

Copy Number ◽

Copy Number Variants ◽

Copy Number Variant ◽

R Package ◽

Copy Number Variation Region ◽

Runs Of Homozygosity ◽

Number Variation ◽

Genomic Studies ◽

Computing Platforms ◽

Analysis System

Detection of CNVs (copy number variants) and ROH (runs of homozygosity) from SNP (single nucleotide polymorphism) genotyping data is often required in genomic studies. The post-analysis of CNV and ROH generally involves many steps, potentially across multiple computing platforms, which requires the researchers to be familiar with many different tools. In order to get around this problem and improve research efficiency, we present an R package that integrates the summarization, annotation, map conversion, comparison and visualization functions involved in studies of CNV and ROH. This one-stop post-analysis system is standardized, comprehensive, reproducible, timesaving, and user-friendly for researchers in humans and most diploid livestock species.

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