Structural variation in the human genome: the impact of copy number variants on clinical diagnosis

AbstractCopy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.

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Genotype-Phenotype correlation in Dravet Syndrome with SCN1A mutation increase efficiency of molecular diagnosis

Journal of Epilepsy and Clinical Neurophysiology ◽

10.1590/s1676-26492012000200009 ◽

2012 ◽

Vol 18 (2) ◽

pp. 60-62

Author(s):

MC Gonsales ◽

P Preto ◽

MA Montenegro ◽

MM Guerreiro ◽

I Lopes-Cendes

Keyword(s):

Protein Function ◽

Copy Number ◽

Mutation Screening ◽

Copy Number Variants ◽

Febrile Seizures ◽

Copy Number Variations ◽

Dravet Syndrome ◽

Missense Mutations ◽

The Impact ◽

Doose Syndrome

OBJECTIVES: The purpose of this study was to advance the knowledge on the clinical use of SCN1A testing for severe epilepsies within the spectrum of generalized epilepsy with febrile seizures plus by performing genetic screening in patients with Dravet and Doose syndromes and establishing genotype-phenotype correlations. METHODS: Mutation screening in SCN1A was performed in 15 patients with Dravet syndrome and 13 with Doose syndrome. Eight prediction algorithms were used to analyze the impact of the mutations in putative protein function. Furthermore, all SCN1A mutations previously published were compiled and analyzed. In addition, Multiplex Ligation-Dependent Probe Amplification (MLPA) technique was used to detect possible copy number variations within SCN1A. RESULTS: Twelve mutations were identified in patients with Dravet syndrome, while patients with Doose syndrome showed no mutations. Our results show that the most common type of mutation found is missense, and that they are mostly located in the pore region and the N- and C-terminal of the protein. No copy number variants in SCN1A were identified in our cohort. CONCLUSIONS: SCN1A testing is clinically useful for patients with Dravet syndrome, but not for those with Doose syndrome, since both syndromes do not seem to share the same genetic basis. Our results indicate that indeed missense mutations can cause severe phenotypes depending on its location and the type of amino-acid substitution. Moreover, our strategy for predicting deleterious effect of mutations using multiple computation algorithms was efficient for most of the mutations identified.

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Whole‐genome re‐sequencing reveals the impact of the interaction of copy number variants of the rhg1 and Rhg4 genes on broad‐based resistance to soybean cyst nematode

Plant Biotechnology Journal ◽

10.1111/pbi.13086 ◽

2019 ◽

Vol 17 (8) ◽

pp. 1595-1611 ◽

Cited By ~ 19

Author(s):

Gunvant B. Patil ◽

Naoufal Lakhssassi ◽

Jinrong Wan ◽

Li Song ◽

Zhou Zhou ◽

...

Keyword(s):

Copy Number ◽

Soybean Cyst Nematode ◽

Copy Number Variants ◽

Cyst Nematode ◽

Whole Genome ◽

The Impact

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Correlation of DNA Copy Number, Gene Expression, Protein Expression and Clinical Outcome in a Group of Patients with Diffuse Large B Cell Lymphoma (DLBCL) Treated with CHOP Plus Rituximab (CHOP-R).

Blood ◽

10.1182/blood.v108.11.2027.2027 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2027-2027

Author(s):

N.A. Johnson ◽

T. Relander ◽

P. Farinha ◽

T. Nayar ◽

D.E. Horsman ◽

...

Keyword(s):

Gene Expression ◽

Clinical Outcome ◽

Protein Expression ◽

B Cell ◽

Human Genome ◽

Copy Number ◽

B Cell Lymphoma ◽

Dna Copy Number ◽

The Impact ◽

Successes And Failures

Abstract Background: DLBCL is the most common subtype of Non-Hodgkin lymphoma and has a mortality rate of 40%. It is characterized by marked clinical and biological heterogeneity. Tumors with similar histology have different genetic abnormalities. The influence of many of these genetic changes on clinical outcome is unknown. Furthermore, treatment itself can influence the prognostic significance of certain biomarkers. Exploring the impact of genetic aberrations on gene expression, protein expression and clinical outcome is the focus of this investigation. Understanding the biology of DLBCL from patients treated with CHOP-R may lead to the discovery of novel biomarkers that are relevant in the CHOP-R era. Methods: RNA and DNA were extracted from frozen de novo DLBCL biopsies taken at the time of diagnosis from April 2001 to April 2005. Cases were selected based on their clinical outcome (11 patients with a >2 year remission with CHOP-R and 10 patients who progressed or relapsed after CHOP-R). We studied DNA amplifications and deletions using array comparative genomic hybridization (aCGH) comprising of >26,000 overlapping bacterial artificial chromosomes. This provides a >95% coverage of the human genome and the capability to reproducibly detect amplifications and deletions as small as 120 kb. We performed gene expression profiling (GEP) using the Affymetrix Human Genome U133 Plus 2 array. A tissue microarray was constructed to assess protein expression using paraffin active antibodies. BCL2, BCL6, P53 and MUM1 genes were assessed using all three platforms and results were correlated with clinical outcome. Results: DNA gains and losses were identified in all patients with an average of 19 alterations per tumor with amplifications being more frequent than deletions. GEP revealed a predominance (57%) of Activated B Cell (ABC) type. A supervised analysis identified a list of 471 genes that were differentially expressed (p<0.01) between treatment failures and successes, many of which are implicated in nucleic acid binding and cell cycle regulation. The correlation between DNA copy number and gene expression was poor especially in areas of DNA gain. The correlation between gene expression and copy number was greater for BCL2 and P53 than for BCL6 and MUM1 (r= 0.67 and 0.80 versus −0.02 and −0.08). The correlation between protein expression and gene expression were r = 0.22, 0.65, 0.66 and 0.53 for BCL2, P53, BCL6 and MUM1, respectively. In this small group of patients treated with CHOP-R, the international prognostic index (IPI) was higher in the patients “failing” CHOP-R (mean IPI 3.2 vs. 1.7). Deletions of 17p13.1 (P53) and high P53 protein expression were predominantly seen in the failures (7 vs 1). High BCL2 protein, low BCL6 protein and ABC signature were randomly distributed in both CHOP-R successes and failures. Conclusion: In this limited group of patients with DLBCL treated with CHOP-R, IPI had the strongest prognostic value. Candidate genes that could predict CHOP-R successes and failures will be validated by RT-PCR and TMA on a larger cohort of patients. The unpredictable correlation between gene expression and DNA copy number suggests that alternate mechanisms of gene regulation are involved in the pathogenesis of DLBCL.

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Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients

Genes ◽

10.3390/genes9110524 ◽

2018 ◽

Vol 9 (11) ◽

pp. 524 ◽

Cited By ~ 2

Author(s):

Teresa Giugliano ◽

Marco Savarese ◽

Arcomaria Garofalo ◽

Esther Picillo ◽

Chiara Fiorillo ◽

...

Keyword(s):

Copy Number ◽

Neuromuscular Disorders ◽

Copy Number Variants ◽

Dystrophin Gene ◽

Muscle Disease ◽

Comparative Genomic ◽

Disease Genes ◽

Inherited Disease ◽

Multicenter Cohort Study ◽

The Impact

Next-generation sequencing (NGS) technologies have led to an increase in the diagnosis of heterogeneous genetic conditions. However, over 50% of patients with a genetically inherited disease are still without a diagnosis. In these cases, different hypotheses are usually postulated, including variants in novel genes or elusive mutations. Although the impact of copy number variants (CNVs) in neuromuscular disorders has been largely ignored to date, missed CNVs are predicted to have a major role in disease causation as some very large genes, such as the dystrophin gene, have prone-to-deletion regions. Since muscle tissues express several large disease genes, the presence of elusive CNVs needs to be comprehensively assessed following an accurate and systematic approach. In this multicenter cohort study, we analyzed 234 undiagnosed myopathy patients using a custom array comparative genomic hybridization (CGH) that covers all muscle disease genes at high resolution. Twenty-two patients (9.4%) showed non-polymorphic CNVs. In 12 patients (5.1%), the identified CNVs were considered responsible for the observed phenotype. An additional ten patients (4.3%) presented candidate CNVs not yet proven to be causative. Our study indicates that deletions and duplications may account for 5–9% of genetically unsolved patients. This strongly suggests that other mechanisms of disease are yet to be discovered.

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Analysis of copy number variants and segmental duplications in the human genome: Evidence for a change in the process of formation in recent evolutionary history

Genome Research ◽

10.1101/gr.081422.108 ◽

2008 ◽

Vol 18 (12) ◽

pp. 1865-1874 ◽

Cited By ~ 92

Author(s):

P. M. Kim ◽

H. Y.K. Lam ◽

A. E. Urban ◽

J. O. Korbel ◽

J. Affourtit ◽

...

Keyword(s):

Human Genome ◽

Copy Number ◽

Evolutionary History ◽

Copy Number Variants ◽

Segmental Duplications

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M57 THE IMPACT OF COPY NUMBER VARIANTS ON BRAIN MORPHOMETRY

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2019.08.157 ◽

2019 ◽

Vol 29 ◽

pp. S196-S197

Author(s):

Claudia Modenato ◽

Kuldeep Kumar ◽

Clara Moreau ◽

Eloi Gagnon ◽

Catherine Schramm ◽

...

Keyword(s):

Copy Number ◽

Copy Number Variants ◽

Brain Morphometry ◽

The Impact

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Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0703834104 ◽

2007 ◽

Vol 104 (24) ◽

pp. 10110-10115 ◽

Cited By ~ 58

Author(s):

J. O. Korbel ◽

A. E. Urban ◽

F. Grubert ◽

J. Du ◽

T. E. Royce ◽

...

Keyword(s):

Human Genome ◽

Copy Number ◽

Copy Number Variants

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Structural and copy number variants in the human genome: implications for psychiatry

The British Journal of Psychiatry ◽

10.1192/bjp.bp.112.109579 ◽

2013 ◽

Vol 202 (1) ◽

pp. 5-6 ◽

Cited By ~ 7

Author(s):

David St Clair

Keyword(s):

Brain Development ◽

Human Genome ◽

Copy Number ◽

Copy Number Variants ◽

Adult Brain ◽

Normal Brain ◽

Brain Functioning ◽

Chromosomal Deletions ◽

Normal Brain Development

SummaryCopy number variants are small chromosomal deletions and duplications. When they alter the dose of genes critical for normal brain development and adult brain functioning they may cause severe disorders such as autism and schizophrenia. Numerous such loci have recently been identified. They are offering amazing leads for neuropsychiatric research.

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MONTAGE: a new tool for high-throughput detection of mosaic copy number variation

BMC Genomics ◽

10.1186/s12864-021-07395-7 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Joseph T. Glessner ◽

Xiao Chang ◽

Yichuan Liu ◽

Jin Li ◽

Munir Khan ◽

...

Keyword(s):

Copy Number Variation ◽

High Throughput ◽

Copy Number ◽

Copy Number Variants ◽

Cell Types ◽

Disease Phenotype ◽

Multiple Phenotypes ◽

Genome Wide ◽

Number Variation ◽

The Impact

Abstract Background Not all cells in a given individual are identical in their genomic makeup. Mosaicism describes such a phenomenon where a mixture of genotypic states in certain genomic segments exists within the same individual. Mosaicism is a prevalent and impactful class of non-integer state copy number variation (CNV). Mosaicism implies that certain cell types or subset of cells contain a CNV in a segment of the genome while other cells in the same individual do not. Several studies have investigated the impact of mosaicism in single patients or small cohorts but no comprehensive scan of mosaic CNVs has been undertaken to accurately detect such variants and interpret their impact on human health and disease. Results We developed a tool called Montage to improve the accuracy of detection of mosaic copy number variants in a high throughput fashion. Montage directly interfaces with ParseCNV2 algorithm to establish disease phenotype genome-wide association and determine which genomic ranges had more or less than expected frequency of mosaic events. We screened for mosaic events in over 350,000 samples using 1% allele frequency as the detection limit. Additionally, we uncovered disease associations of multiple phenotypes with mosaic CNVs at several genomic loci. We additionally investigated the allele imbalance observations genome-wide to define non-diploid and non-integer copy number states. Conclusions Our novel algorithm presents an efficient tool with fast computational runtime and high levels of accuracy of mosaic CNV detection. A curated mosaic CNV callset of 3716 events in 2269 samples is presented with comparability to previous reports and disease phenotype associations. The new algorithm can be freely accessed via: https://github.com/CAG-CNV/MONTAGE.

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