copy number variant
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2021 ◽  
Vol 12 ◽  
Author(s):  
Haimeng Bai ◽  
Harpreet Kaur ◽  
Asha R. Kallianpur ◽  
Todd Hulgan ◽  
Donald R. Franklin ◽  
...  

A common two-exon deletion distinguishes the gene encoding the free hemoglobin capturing protein—haptoglobin (HP)–into two alleles: HP1 and HP2. To evaluate the impact of this copy number variant (CNV) on neurocognitive impairment (NCI) in people living with HIV, we imputed this variant in 432 European-descent (EUR) and 491 African-descent (AFR) participants from the CNS HIV Antiretroviral Therapy Effects Research Study using an optimized imputation pipeline and evaluated its associations with NCI. At baseline, in AFR, the HP2 allele decreased the odds of NCI (defined by a global deficit score, GDS, ⩾0.5; Odds Ratio, OR = 0.584, p = 0.022). However, in EUR, HP2 increased the odds (OR = 2.081, p = 0.040) of NCI suggesting a detrimental effect. These effects were extended to longitudinal analyses using repeated measurements where the protective effect of the HP2 allele in AFR became marginally significant (p = 0.054) and in EUR the detrimental effect increased in significance (p = 0.037). In EUR, the HP2 allele slightly reduced the risk of NCI over time (OR = 0.028 per allele per year, p = 0.024). Further analyses of cognitive domain-specific impairment revealed that the HP-NCI effect was based on changes in learning, speed of information processing, and verbal domains over time differing by ancestry groups. Overall, these findings suggest that these functional HP CNV alleles influence the likelihood of NCI and contribute to changes in neurocognitive function over time in people living with HIV.


Author(s):  
Juergen Hench ◽  
Tatjana Vlajnic ◽  
Savas Deniz Soysal ◽  
Ellen C Obermann ◽  
Stephan Frank ◽  
...  

Fibroepithelial lesions (FL) of the breast, in particular Phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT, and FA. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including "The Cancer Genome Atlas" (TCGA) and "Gene Expression Omnibus" (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions and EGFR amplifications may inform therapeutic decision-making.


2021 ◽  
Vol 12 ◽  
Author(s):  
Meiying Cai ◽  
Xianguo Fu ◽  
Liangpu Xu ◽  
Na Lin ◽  
Hailong Huang

Smith-Magenis syndrome and Potocki-Lupski syndrome are rare autosomal dominant diseases. Although clinical phenotypes of adults and children have been reported, fetal ultrasonic phenotypes are rarely reported. A retrospective analysis of 6,200 pregnant women who received invasive prenatal diagnosis at Fujian Provincial Maternal and Child Health Hospital between October 2016 and January 2021 was performed. Amniotic fluid or umbilical cord blood was extracted for karyotyping and single nucleotide polymorphism array analysis. Single nucleotide polymorphism array analysis revealed six fetuses with copy number variant changes in the 17p11.2 region. Among them, one had a copy number variant microdeletion in the 17p11.2 region, which was pathogenically analyzed and diagnosed as Smith-Magenis syndrome. Five fetuses had copy number variant microduplications in the 17p11.2 region, which were pathogenically analyzed and diagnosed as Potocki-Lupski syndrome. The prenatal ultrasound phenotypes of the six fetuses were varied. The parents of two fetuses with Potocki-Lupski syndrome refused verification. Smith-Magenis syndrome in one fetus and Potocki-Lupski in another were confirmed as de novo. Potocki-Lupski syndrome in two fetuses was confirmed to be from maternal inheritance. The prenatal ultrasound phenotypes of Smith-Magenis syndrome and Potocki-Lupski syndrome in fetuses vary; single nucleotide polymorphism array analysis is a powerful diagnostic tool for these diseases. The ultrasonic phenotypes of these cases may enrich the clinical database.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Nastaran Maus Esfahani ◽  
Daniel Catchpoole ◽  
Javed Khan ◽  
Paul J. Kennedy

Abstract Background Copy 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. Results We 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. Conclusion A multi-dimensional copy number variant kernel association test can detect statistically significant associated CNV regions with any disease-related trait. MCKAT can provide biologists with CNV hot spots at the cytogenetic band level that CNVs on them may have a significant association with disease-related traits. Using MCKAT, biologists can narrow their investigation from the whole genome, including many genes and CNVs, to more specific cytogenetic bands that MCKAT identifies. Furthermore, MCKAT can help biologists detect significantly associated CNVs with disease-related traits across a patient group instead of examining each subject’s CNVs case by case.


2021 ◽  
Author(s):  
Milos Kostic ◽  
Joe J. Raymond ◽  
Beata Henry ◽  
Tayfun Tumkaya ◽  
Jivan Khlghatyan ◽  
...  

Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, like human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 18 patients and controls, profiling 167,958 cells with single cell (sc)RNA-seq. Analysis revealed neuronal-specific differential expression of genes outside of the 16p11.2 region that were related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene which can also harbor CNVs linked to neurodevelopmental phenotypes. We found that many genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with 16p11.2 deletion syndrome, and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Beatriz Carvalho Henriques ◽  
Avery Buchner ◽  
Xiuying Hu ◽  
Yabing Wang ◽  
Vasyl Yavorskyy ◽  
...  

AbstractMany antidepressants, atomoxetine, and several antipsychotics are metabolized by the cytochrome P450 enzymes CYP2D6 and CYP2C19, and guidelines for prescribers based on genetic variants exist. Although some laboratories offer such testing, there is no consensus regarding validated methodology for clinical genotyping of CYP2D6 and CYP2C19. The aim of this paper was to cross-validate multiple technologies for genotyping CYP2D6 and CYP2C19 against each other, and to contribute to feasibility for clinical implementation by providing an enhanced range of assay options, customizable automated translation of data into haplotypes, and a workflow algorithm. AmpliChip CYP450 and some TaqMan single nucleotide variant (SNV) and copy number variant (CNV) data in the Genome-based therapeutic drugs for depression (GENDEP) study were used to select 95 samples (out of 853) to represent as broad a range of CYP2D6 and CYP2C19 genotypes as possible. These 95 included a larger range of CYP2D6 hybrid configurations than have previously been reported using inter-technology data. Genotyping techniques employed were: further TaqMan CNV and SNV assays, xTAGv3 Luminex CYP2D6 and CYP2C19, PharmacoScan, the Ion AmpliSeq Pharmacogenomics Panel, and, for samples with CYP2D6 hybrid configurations, long-range polymerase chain reactions (L-PCRs) with Sanger sequencing and Luminex. Agena MassARRAY was also used for CYP2C19. This study has led to the development of a broader range of TaqMan SNV assays, haplotype phasing methodology with TaqMan adaptable for other technologies, a multiplex genotyping method for efficient identification of some hybrid haplotypes, a customizable automated translation of SNV and CNV data into haplotypes, and a clinical workflow algorithm.


2021 ◽  
Author(s):  
Takeshi Hiramoto ◽  
Shuken Boku ◽  
Gina Kang ◽  
Seiji Abe ◽  
Mariel Barbachan e Silva ◽  
...  

Rare gene variants confer a high level of penetrance to neurodevelopmental disorders, but their developmental origin and cellular substrates remain poorly understood. To address this limitation, we explored the role of TBX1, a gene encoded in a rare copy number variant, in cell and mouse models. Here, we report that neonatal Tbx1 deficiency contributes to defective peripubertal social behavior and impairs the proliferation of neonatal neural stem/progenitor cells. Moreover, TBX1 transcriptionally regulates genes linked to post-embryonic neurogenesis and neurodevelopmental disorders associated with other rare gene variants. Our data indicate a precise time window and cell type through which the social dimension is altered by a gene encoded in a rare CNV and provide a potential common mechanistic basis for a group of neurodevelopmental disorders.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2599-2599
Author(s):  
Nieves Garcia-Gisbert ◽  
Brayan Merchan ◽  
Sara Garcia-Avila ◽  
Marta Salido ◽  
Concepción Fernández-Rodríguez ◽  
...  

Abstract Introduction. Myelodysplastic syndromes (MDS) are clonal heterogeneous disorders in which molecular studies and cytogenetics are essential for diagnosis, classification and prognosis. Cell-free DNA (cfDNA) analysis has been reported as a reliable non-invasive approach for detecting molecular abnormalities in MDS. However, there is limited information about cytogenetic alterations and monitoring in cfDNA from MDS patients. Objective. To assess and monitor the molecular and cytogenetic abnormalities by next generation sequencing (NGS) using cfDNA from patients with MDS. Patients and methods. Bone marrow (BM) aspirates and peripheral blood (PB) samples were collected from 70 newly diagnosed or treatment-naïve patients with MDS (Table). PB samples from 21 healthy controls were also studied. Molecular characterization was performed in paired samples of BM DNA and cfDNA by NGS in all patients. Libraries were prepared using a custom panel including 48 myeloid-associated genes and genomic regions localized at the most frequently altered chromosomes in MDS (QIAseq Custom DNA Panels, Qiagen) and sequenced using Illumina. 20/70 (28.6%) showed cytogenetic/FISH alterations at diagnosis, 2 of them with infrequent alterations in MDS, not covered by the panel (+14, del(9q)). 6 cases presented chromosome Y loss as a single alteration, not covered by the NGS panel. Copy number variant (CNV) analysis was performed by NGS to detect cytogenetic alterations in both cfDNA and BM, and confirmed by chromosomal microarrays (CMA) in BM DNA (CytoScan/OncoScan, ThermoFisher). Results. We obtained a median amount of cfDNA of 58.4 ng/ml in MDS patients that was significantly higher than that obtained in healthy controls (median 32.4 ng/ml, P=0.023). Sequencing of BM DNA and cfDNA showed a comparable mutational profile (187/201 mutations, 93.0% concordance). The most frequently mutated genes were TET2 (44.3%), SF3B1 (37.1%), ASXL1 (20.0%), DNMT3A (20.0%), SRSF2 (15.7%), ZRSR2 (12.9%) and U2AF1 (12.9%). A strong correlation was observed between the VAFs of BM DNA and cfDNA (r s=0.797, P<0.001). VAFs of SF3B1 mutations detected in cfDNA were significantly higher than VAFs in BM DNA (P=0.016). The analysis of cytogenetic alterations by NGS showed abnormalities in 10/70 MDS patients in both BM DNA and cfDNA. Interestingly, in a patient without analyzable metaphases in karyotype, del(20q) was found by NGS and confirmed by CMA. Overall, CMA and NGS were highly concordant to detect chromosomal aberrations although they do not reach the sensitivity achieved by karyotype/FISH (Figure 1). However, all cytogenetic aberrations detected by NGS in BM DNA were also detected in cfDNA. Molecular and cytogenetic alterations were monitored in sequential samples from 7 cases (median follow up: 13 months, range 10-30). We observed an excellent correlation between the VAF of mutations in BM DNA and ctDNA across multiple matched time points. A decrease in the VAF was detected in patients responding to therapy (either hypomethylating agents or chemotherapy), but not in non-responding patients (Figure 2). Of note, cfDNA analysis also showed cytogenetic evolution in 2 cases not responding to azacitidine (del(12p) and +21). From the two untreated patients, one acquired a subclonal del(7q) not detected by NGS and observed only in few metaphases, and the second patient showed a clonal expansion of the NF1 mutation at the time of AML transformation. Conclusions. Analysis of cfDNA allows the characterization and monitoring of molecular abnormalities in patients with MDS. Cytogenetic alterations were detectable in most cases by NGS in both BM DNA and cfDNA although with a lower detection rate than karyotype/FISH. Acknowledgements. ISCIII-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure/Table legends: Table. MDS patients included, classified by disease subtype. (SLD: single lineage dysplasia; MLD: multilineage dysplasia; RS: ring sideroblasts; EB: excess blasts; MDS-U: MDS-unclassifiable) Figure 1. Detection of cytogenetic alterations by conventional karyotype, FISH, CMA and NGS. Figure 2. Monitoring of molecular and cytogenetic alterations in 7 patients with MDS. 5 patients receiving treatment (3 azacitidine, 1 FLAG-IDA + HCT, 1 inhibitor of hypoxia-inducible factor (HIF)) and 2 untreated cases were included. BM VAF dynamics are shown with a dotted line and cfDNA dynamics are shown with a solid line. Figure 1 Figure 1. Disclosures Besses: Gilead: Research Funding. Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau.


Author(s):  
Takeshi Hiramoto ◽  
Akira Sumiyoshi ◽  
Takahira Yamauchi ◽  
Kenji Tanigaki ◽  
Qian Shi ◽  
...  

AbstractCopy number variants (CNVs) have provided a reliable entry point to identify the structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which the CNVs contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in mice with a heterozygous deletion of Tbx1, one of the 22q11.2-encoded genes. Ex vivo whole-brain diffusion-tensor imaging (DTI)–magnetic resonance imaging (MRI) in Tbx1 heterozygous mice indicated that the fimbria was the only region with significant myelin alteration. Electron microscopic and histological analyses showed that Tbx1 heterozygous mice exhibited an apparent absence of large myelinated axons and thicker myelin in medium axons in the fimbria, resulting in an overall decrease in myelin. The fimbria of Tbx1 heterozygous mice showed reduced mRNA levels of Ng2, a gene required to produce oligodendrocyte precursor cells. Moreover, postnatal progenitor cells derived from the subventricular zone, a source of oligodendrocytes in the fimbria, produced fewer oligodendrocytes in vitro. Behavioral analyses of these mice showed selectively slower acquisition of spatial memory and cognitive flexibility with no effects on their accuracy or sensory or motor capacities. Our findings provide a genetic and cellular basis for the compromised cognitive speed in patients with 22q11.2 hemizygous deletion.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi39-vi39
Author(s):  
Charlotte Eaton ◽  
Abrar Choudhury ◽  
Timothy Casey-Clyde ◽  
Danielle Swaney ◽  
Nevan Krogan ◽  
...  

Abstract BACKGROUND Alterations in NF2 underlie meningioma tumorigenesis, but tumor suppressor functions of the NF2 gene product, Merlin, are incompletely understood in meningiomas. Here we integrate proteomic proximity-labelling mass spectrometry with CRISPR interference (CRISPRi), RNA sequencing, and biochemical approaches to discover Merlin drives meningioma apoptosis and susceptibility to cytotoxic therapy. METHODS RNA sequencing was performed on triplicate M10G meningioma cells stably expressing CRISPRi machinery and either non-targeting control sgRNAs, sgRNAs suppressing NF2, or sgRNAs suppressing NF2 with Merlin rescue. QPCR in IOMM-Lee and MSC1 meningioma cells expressing non-targeting control shRNAs or shRNAs suppressing NF2 was used for orthogonal validation in vitro. RNA sequencing of euploid meningiomas (n=52) or meningiomas with loss of NF2 as the only copy number variant (n=28) was used for orthogonal validation in vivo. Merlin interactors in meningioma cells were identified using APEX proteomic proximity-labelling mass spectrometry. Mechanistic and functional studies were performed using biochemical, molecular, and cell biology approaches in meningioma cells and CH-157MN meningioma xenografts treated with cytotoxic chemotherapy or ionizing radiation. RESULTS Merlin suppression in meningioma cells and xenografts inhibited pro-apoptotic interferon regulatory factor (IRF) target genes and attenuated meningioma apoptosis. Merlin suppression did not alter IRF stability or subcellular localization in meningioma cells, and proteomic proximity-labelling mass spectrometry revealed a novel interaction between wildtype Merlin and ARHGAP35, a DNA binding factor that inhibits glucocorticoid receptor expression (NR3C1). NR3C1 inhibits IRF activity to prevent apoptosis, and Merlin suppression in meningioma cells induced NR3C1expression, which was inhibited by Merlin rescue. Further, NR3C1 suppression rescued meningioma cell apoptosis in the absence of Merlin, and NR3C1 expression was increased in human meningiomas with loss of NF2 compared to euploid meningiomas. CONCLUSIONS These data shed light on a novel pro-apoptotic tumor suppressor function of Merlin regulating glucocorticoid signalling and susceptibility to cytotoxic therapy in meningiomas.


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