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

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.

scholarly journals Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants

2021 ◽  
Author(s):  
Elmo Christian Saarentaus ◽  
Aki Samuli Havulinna ◽  
Nina Mars ◽  
Ari Ahola-Olli ◽  
Tuomo Tapio Johannes Kiiskinen ◽  
...  
Keyword(s):  
High Risk ◽  
Educational Attainment ◽  
Household Income ◽  
Copy Number ◽  
Copy Number Variants ◽  
Well Being ◽  
Subjective Health ◽  
Polygenic Risk Score ◽  
The Impact ◽  
Health Cognition

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.

scholarly journals Genome-Wide Copy Number Variation Association Study of Atrial Fibrillation Related Thromboembolic Stroke

2019 ◽  
Vol 8 (3) ◽  
pp. 332 ◽  
Author(s):  
Chia-Shan Hsieh ◽  
Pang-Shuo Huang ◽  
Sheng-Nan Chang ◽  
Cho-Kai Wu ◽  
Juey-Jen Hwang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Signaling Pathway ◽  
Copy Number ◽  
Genetic Factors ◽  
Copy Number Variations ◽  
Nucleotide Polymorphisms ◽  
Thromboembolic Stroke ◽  
Genome Wide ◽  
A Genome ◽  
The Impact

Atrial fibrillation (AF) is a common cardiac arrhythmia and is one of the major causes of ischemic stroke. In addition to the clinical factors such as CHADS2 or CHADS2-VASC score, the impact of genetic factors on the risk of thromboembolic stroke in patients with AF has been largely unknown. Single-nucleotide polymorphisms in several genomic regions have been found to be associated with AF. However, these loci do not contribute to all the genetic risks of AF or AF related thromboembolic risks, suggesting that there are other genetic factors or variants not yet discovered. In the human genome, copy number variations (CNVs) could also contribute to disease susceptibility. In the present study, we sought to identify CNVs determining the AF-related thromboembolic risk. Using a genome-wide approach in 109 patients with AF and thromboembolic stroke and 14,666 controls from the Taiwanese general population (Taiwan Biobank), we first identified deletions in chromosomal regions 1p36.32-1p36.33, 5p15.33, 8q24.3 and 19p13.3 and amplifications in 14q11.2 that were significantly associated with AF-related stroke in the Taiwanese population. In these regions, 148 genes were involved, including several microRNAs and long non-recoding RNAs. Using a pathway analysis, we found deletions in GNB1, PRKCZ, and GNG7 genes related to the alpha-adrenergic receptor signaling pathway that play a major role in determining the risk of an AF-related stroke. In conclusion, CNVs may be genetic predictors of a risk of a thromboembolic stroke for patients with AF, possibly pointing to an impaired alpha-adrenergic signaling pathway in the mechanism of AF-related thromboembolism.

scholarly journals Eight Y chromosome genes show copy number variations in horses

2018 ◽  
Vol 61 (3) ◽  
pp. 263-270
Author(s):  
Haoyuan Han ◽  
Xin Zhang ◽  
Xiaocheng Zhao ◽  
Xiaoting Xia ◽  
Chuzhao Lei ◽  
...  
Keyword(s):  
Y Chromosome ◽  
Copy Number ◽  
Distribution Patterns ◽  
Single Copy ◽  
Copy Number Variations ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Specific Transcript ◽  
Copy Numbers ◽  
The Impact

Abstract. Copy number variations (CNVs), which represent a significant source of genetic diversity on the Y chromosome in mammals, have been shown to be associated with the development of many complex phenotypes, such as reproduction and male fertility. The occurrence of CNVs has been confirmed on the Y chromosome in horses. However, the copy numbers (CNs) of Equus caballus Y chromosome (ECAY) genes are largely unknown. To demonstrate the copy number variations of Y chromosome genes in horses, the quantitative real-time polymerase chain reaction (qPCR) method was applied to measure the CNVs of the eukaryotic translation initiation factor 1A Y (EIF1AY), equine testis-specific transcript on Y 1 (ETSTY1), equine testis-specific transcript on Y 4 (ETSTY4), equine testis-specific transcript on Y 5 (ETSTY5), equine transcript Y4 (ETY4), ubiquitin activating enzyme Y (UBE1Y), sex determining region Y (SRY), and inverted repeat 2 Y (YIR2) across 14 Chinese domestic horse breeds in this study. Our results revealed that these eight genes were multi-copy; furthermore, some of the well acknowledged single-copy genes such as SRY and EIF1AY were found to be multi-copy in this research. The median copy numbers (MCNs) varied among different breeds for the same gene. The CNVs of Y chromosome genes showed different distribution patterns among Chinese horse breeds, indicating the impact of natural selection on copy numbers. Our results will provide fundamental information for future functional studies.

scholarly journals Chromosomal rearrangements are commonly post-transcriptionally attenuated in cancer

2016 ◽  
Author(s):  
Emanuel Gonçalves ◽  
Athanassios Fragoulis ◽  
Luz Garcia-Alonso ◽  
Thorsten Cramer ◽  
Julio Saez-Rodriguez ◽  
...  
Keyword(s):  
Copy Number ◽  
Protein Complexes ◽  
Chromosomal Rearrangements ◽  
Proteasome Inhibitors ◽  
Gene Signature ◽  
Copy Number Variations ◽  
Data Sets ◽  
Regulatory Interactions ◽  
The Impact ◽  
Rate Limiting

AbstractChromosomal rearrangements, despite being detrimental, are ubiquitous in cancer and often act as driver events. The effect of copy number variations (CNVs) on the cellular proteome of tumours is poorly understood. Therefore, we have analysed recently generated proteogenomic data-sets on 282 tumour samples to investigate the impact of CNVs in the proteome of these cells. We found that CNVs are post-transcriptionally attenuated in 23-33% of proteins with an enrichment for protein complexes. Complex subunits are highly co-regulated and some act as rate-limiting steps of complex assembly, indirectly controlling the abundance of other complex members. We identified 48 such regulatory interactions and experimentally validated AP3B1 and GTF2E2 as controlling subunits. Lastly, we found that a gene-signature of protein attenuation is associated with increased resistance to chaperone and proteasome inhibitors. This study highlights the importance of post-transcriptional mechanisms in cancer which allow cells to cope with their altered genomes.

scholarly journals RBV: Read balance validator, a tool for prioritising copy number variations in germline conditions

2018 ◽  
Author(s):  
Whitney Whitford ◽  
Klaus Lehnert ◽  
Russell G. Snell ◽  
Jessie C. Jacobsen
Keyword(s):  
Copy Number ◽  
High Throughput Sequencing ◽  
Sequence Data ◽  
Relative Proportion ◽  
Copy Number Variants ◽  
Read Depth ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Software Packages ◽  
Bioinformatic Tool

AbstractBackgroundThe popularisation and decreased cost of genome resequencing has resulted in an increased use in molecular diagnostics. While there are a number of established and high quality bioinfomatic tools for identifying small genetic variants including single nucleotide variants and indels, currently there is no established standard for the detection of copy number variants (CNVs) from sequence data. The requirement for CNV detection from high throughput sequencing has resulted in the development of a large number of software packages. These tools typically utilise the sequence data characteristics: read depth, split reads, read pairs, and assembly-based techniques. However the additional source of information from read balance, defined as relative proportion of reads of each allele at each position, has been underutilised in the existing applications.ResultsWe present Read Balance Validator (RBV), a bioinformatic tool which uses read balance for prioritisation and validation of putative CNVs. The software simultaneously interrogates nominated regions for the presence of deletions or multiplications, and can differentiate larger CNVs from diploid regions. Additionally, the utility of RBV to test for inheritance of CNVs is demonstrated in this report.ConclusionsRBV is a CNV validation and prioritisation bioinformatic tool for both genome and exome sequencing available as a python package from https://github.com/whitneywhitford/RBV

scholarly journals Dissecting Intra-Tumor Heterogeneity by the Analysis of Copy Number Variations in Single Cells: The Neuroblastoma Case Study

2019 ◽  
Vol 20 (4) ◽  
pp. 893 ◽  
Author(s):  
Federica Cariati ◽  
Francesca Borrillo ◽  
Varun Shankar ◽  
Marcella Nunziato ◽  
Valeria D’Argenio ◽  
...  
Keyword(s):  
Cell Lines ◽  
Copy Number ◽  
Tumor Heterogeneity ◽  
Single Cells ◽  
Neuroblastoma Cell ◽  
Copy Number Variants ◽  
Copy Number Variations ◽  
Cellular Heterogeneity ◽  
Genotypic Differences ◽  
Laboratory Protocol

Tumors often show intra-tumor heterogeneity because of genotypic differences between all the cells that compose it and that derive from it. Recent studies have shown significant aspects of neuroblastoma heterogeneity that may affect the diagnostic-therapeutic strategy. Therefore, we developed a laboratory protocol, based on the combination of the advanced dielectrophoresis-based array technology and next-generation sequencing to identify and sort single cells individually and carry out their copy number variants analysis. The aim was to evaluate the cellular heterogeneity, avoiding overestimation or underestimation errors, due to a bulk analysis of the sample. We tested the above-mentioned protocol on two neuroblastoma cell lines, SK-N-BE(2)-C and IMR-32. The presence of several gain or loss chromosomal regions, in both cell lines, shows a high heterogeneity of the copy number variants status of the single tumor cells, even if they belong to an immortalized cell line. This finding confirms that each cell can potentially accumulate different alterations that can modulate its behavior. The laboratory protocol proposed herein provides a tool able to identify prevalent behaviors, and at the same time highlights the presence of particular clusters that deviate from them. Finally, it could be applicable to many other types of cancer.

scholarly journals Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
L. D’Abate ◽  
S. Walker ◽  
R. K. C. Yuen ◽  
K. Tammimies ◽  
J. A. Buchanan ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Recurrence Prediction ◽  
Common Genetic Variants ◽  
Spectrum Disorders ◽  
Atypical Development ◽  
Research Consortium

AbstractIdentification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

A Study from Turkey: Identification of Copy Number Variants in Children and Adolescents with Autism Spectrum Disorder

2021 ◽  
Author(s):  
Ahmet Özaslan ◽  
Gülsüm Kayhan ◽  
Elvan İşeri ◽  
Mehmet Ali Ergün ◽  
Esra Güney ◽  
...  
Keyword(s):  
Copy Number ◽  
Diagnostic Yield ◽  
Venous Blood ◽  
Copy Number Variants ◽  
Clinical Importance ◽  
Turkish Population ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Turkish Children ◽  
Children With Asd

Abstract Recent studies suggest that copy number variations (CNVs) play a significant role in the aetiology of ASD. This study aims to investigate CNVs, which are thought to be an important factor in ASD etiology. In addition it was aimed to specify the clinical usefulness of chromosomal microarrays (CMA) in the examination of ASD patients in Turkish population. Of 47 children (60.34±25.60 months; 82.9% boys) with ASD were constructed the sample. The karyotype structure of all participants was found to be normal using conventional cytogenetic methods. DNA obtained from the venous blood samples of the participants was evaluated using SurePrint G3 ISCA V2 CGH 8x60K Array (Agilent Technologies Santa Clara, CA, USA). We have identified 8 CNVs, ranging in size from 55 kb to 6.5 Mb in 7 (5 boys) of 47 children with ASD of the 4 of 8 CNVs were classified as pathogenic, which were 9p24.3p24.2 deletion in 3 Mb size, 15q11-q13 duplication in 6.5 Mb size, 16p11.2 deletion in 598 kb size and 22q13.3 deletion in 55 kb size. According to results has been demonstrated that diagnostic yield of CMA in Turkish children with ASD was 8.5%. Our results indicate that CNVs contribute a part to the genetic aetiology of Turkish children with ASD. In accordance with the literature, these results emphasize the clinical importance of CMA to investigate the aetiology of ASD.

The Impact of Constitutional Copy Number Variants in Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 496-496
Author(s):  
Matthew W Jenner ◽  
David C Johnson ◽  
Paola E Leone ◽  
Brian A Walker ◽  
David Gonzalez ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Change ◽  
Copy Number Variations ◽  
Genomic Variation ◽  
Chromosome 21 ◽  
Nucleotide Polymorphisms ◽  
Copy Number Changes ◽  
The Impact ◽  
First Time ◽  
Tumor Dna

Abstract Single nucleotide polymorphisms (SNPs) have been long regarded as being important in determining variation and disease predisposition. Recently, chromosomal structural variation in the form of deletions, insertions and duplifications have been identified frequently in the genome of the general population. Such copy number variations (CNVs) have been shown to contribute to a range of human diseases. In recent studies we have utilized Affymetrix 50K and 500K arrays to identify acquired copy number change in myeloma tumor samples. In those studies we had access to paired constitutional DNA and in the present study have been able to report for the first time a CNV map of the constitutional genome of myeloma patients. Affymetrix 500K mapping arrays were used to identify copy number changes in 63 paired samples using DNA from peripheral blood and CD138 selected plasma cells. Tumor samples were analyzed in CNAG using both a paired and unpaired analysis to distinguish between inherited and acquired copy number change. Constitutional DNA was analyzed by both CNAG and GEMCA using 90 Caucasian samples from the Hapmap database as a reference set. For maximum calling accuracy, only those regions identified by both algorithms were called as CNVs. As with similar studies, overlapping CNVs identified using this approach were merged to generate a list of CNV regions (CNVRs) characteristic of the constitutional DNA of these myeloma cases. Using this approach, we identified 292 CNVs across 63 cases, with a median of 4 regions per sample. There were 155 discrete CNVRs, of which 46 were recurrent. The recurrent CNVRs were found most frequently in the pericentric regions of chromosome 14 and 15 in keeping with other studies. We then compared these recurrent CNVRs with a comparable dataset of normal individuals generated using Affymetrix 500K arrays. In this analysis, 25/46 recurrent CNVRs in the myeloma cases were novel. The two most frequent novel CNVRs in the myeloma cases were gains on chromosome 21 and 15. We also compared the characteristics of the constitutional CNVs with the acquired copy number changes in the corresponding tumor samples and identified that the constitutional CNVs were generally considerably smaller. However, using unpaired analysis it was possible to determine the presence of the constitutional CNV in the tumor sample, providing validation of the CNVs. We were also able to demonstrate that acquired copy number change in the tumor cells can either exaggerate or ameliorate the effect of the inherited CNV in the tumor genome, such as cases with acquired trisomy 15 and deletion or gain of regions of 15q in the constitutional DNA. These findings also reinforce the need for paired non-tumor DNA when undertaking copy number analysis of tumor DNA using SNP arrays. In this study we have been able to identify for the first time the presence of CNVs in the constitutional genome of individuals with myeloma. We have been able to systematically catalogue these CNVRs. These results provide the basis for future studies aimed at identifying how this type of genomic variation may influence the development of and outcome of myeloma and a broad range of other hematological conditions.

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