scholarly journals Patient brain organoids identify a link between the 16p11.2 copy number variant and the RBFOX1 gene.

2021 ◽  
Author(s):  
Milos Kostic ◽  
Joe J. Raymond ◽  
Beata Henry ◽  
Tayfun Tumkaya ◽  
Jivan Khlghatyan ◽  
...  
Keyword(s):  
Copy Number ◽  
Neuronal Development ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
Small Region ◽  
Genomic Region ◽  
Deletion Syndrome ◽  
Protein Levels ◽  
Neurodevelopmental Disease ◽  
Expression Of Genes

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.

scholarly journals Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes

2019 ◽  
Vol 105 (4) ◽  
pp. 384-389 ◽  
Author(s):  
Adam Jackson ◽  
Heather Ward ◽  
Rebecca Louise Bromley ◽  
Charulata Deshpande ◽  
Pradeep Vasudevan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Copy Number ◽  
Developmental Disorders ◽  
Drug Exposure ◽  
Genetic Disorders ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
In Utero ◽  
Developmental Problems ◽  
Number Of Children

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.

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

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.

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

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.

scholarly journals The prenatal diagnosis and clinical outcomes of fetuses with 15q11.2 copy number variants: a case series of 36 patients

2021 ◽  
Author(s):  
Jessica Kang ◽  
Chien Nan Lee ◽  
Yi-Ning Su ◽  
Ming-Wei Lin ◽  
Yi-Yun Tai ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Developmental Delay ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Case Series ◽  
Copy Number Variant ◽  
University Hospital ◽  
Limited Information ◽  
Ultrasound Findings

Objective: The prenatal genetic counseling of fetus diagnosed with the 15q11.2 copy number variant (CNV) involving the BP1-BP2 region has been difficult due to limited information and controversial opinion on prognosis. Design: Case series. Setting: This study uses data from National Taiwan University Hospital. Sample: Data of 36 pregnant women who underwent prenatal microarray analysis from 2012 to 2017 and were assessed at National Taiwan University Hospital. Methods: Data were collected by reviewing patients’ medical record. Comparison of patient characteristics, prenatal ultrasound findings and postnatal outcomes between different cases involving the 15q11.2 BP1-BP2 region were presented. Main outcome measured: Postnatal prognosis. Results: Out of the 36 patients diagnosed with CNVs involving the BP1-BP2 region, 5 were diagnosed with microduplication and 31 with microdeletion. Abnormal ultrasound findings were recorded in 12 cases prenatally. De novo microduplications were observed in 25% of the cases and microdeletions were found in 14%. Amongst the cases, 10 pregnant women received termination of pregnancy and 26 gave birth to healthy individuals (27 babies in total). Conclusion: The prognoses of 15q11.2 CNVs were controversial and recent studies have revealed its connection with developmental delay and autism. In our study, no obvious developmental delay or neurological disorders were detected postnatally in the 1 case of 15q11.2 microduplication and 25 cases of microdeletion.

scholarly journals Peruvian Newborn Male with 3p13 Deletion Syndrome Encompassing the FOXP1 Gene: Review of the Literature

2020 ◽  
Vol 09 (04) ◽  
pp. 270-278
Author(s):  
Hugo H. Abarca-Barriga ◽  
Milana Trubnykova ◽  
Félix Chavesta-Velásquez ◽  
Claudia Barletta-Carrillo ◽  
Marco Ordoñez-Linares ◽  
...  
Keyword(s):  
Copy Number ◽  
Choanal Atresia ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Deletion Syndrome ◽  
Chromosomal Microarray ◽  
Facial Dysmorphism ◽  
Chromosomal Microarray Analysis ◽  
Heart Malformation ◽  
Number Variation

AbstractCopy number variation in loss of 3p13 is an infrequently reported entity characterized by hypertelorism, aniridia, microphthalmia, high palate, neurosensorial deafness, camptodactyly, heart malformation, development delay, autism spectrum disorder, seizures, and choanal atresia. The entity is caused probably by haploinsufficiency for FOXP1, UBA3, FAM19A1, and MITF. We report a newborn male with hypotonia, facial dysmorphism, heart malformation, and without clinical diagnosis; nevertheless, the use of appropriate genetic test, such us the chromosomal microarray analysis allowed identification of a copy number variant in loss of 5.5 Mb at chromosome 3 (p13-p14.1), that included 54 genes, encompassing FOXP1 gene. We compare the findings in our Peruvian patient to those of earlier reported patients; furthermore, add new signs for this entity.

scholarly journals Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome

2016 ◽  
Vol 135 (3) ◽  
pp. 273-285 ◽  
Author(s):  
Elisabeth E. Mlynarski ◽  
◽  
Michael Xie ◽  
Deanne Taylor ◽  
Molly B. Sheridan ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Copy Number ◽  
Congenital Heart ◽  
Heart Defects ◽  
Copy Number Variants ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion

scholarly journals Copy number variants in clinical WGS: deployment and interpretation for rare and undiagnosed disease

2018 ◽  
Author(s):  
Andrew M Gross ◽  
Subramanian S. Ajay ◽  
Vani Rajan ◽  
Carolyn Brown ◽  
Krista Bluske ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Genetic Disorders ◽  
Diagnostic Testing ◽  
Copy Number Variants ◽  
Uniparental Disomy ◽  
Copy Number Variant ◽  
Break Point ◽  
Clinically Significant ◽  
Family Based

AbstractPurposeCurrent diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, whole genome sequencing (WGS) has the potential to detect all genomic mutation types on a single platform and workflow. Here we sought to evaluate copy number variant (CNV) calling as part of a clinically accredited WGS test.MethodsUsing a depth-based copy number caller we performed analytical validation of CNV calling on a reference panel of 17 samples, compared the sensitivity of WGS-based variants to those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis, annotation, filtering, visualization of WGS based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases.ResultsWe found that CNV calls from WGS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed. This pipeline also enabled identification of cases of uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of some CNVs enabled break-point level resolution of genomic rearrangements and phasing of de-novo CNVs.ConclusionRobust identification of CNVs by WGS is possible within a clinical testing environment, and further developments will bring improvements in resolution of smaller and more complex CNVs.

T Cells of Patients with Myelodysplastic Syndrome Are Frequently Derived From the Malignant Clone

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2808-2808
Author(s):  
Suzanne Vercauteren ◽  
Daniel T. Starczynowski ◽  
Sandy Sung ◽  
Kelly McNeil ◽  
Chris Salski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Copy Number ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
Common Finding ◽  
Comparative Genomic ◽  
Trisomy 8 ◽  
T Cell Clonality ◽  
Cell Clonality

Abstract Abstract 2808 T cell clonality is a common finding in myelodysplastic syndromes (MDS), but is believed to be a reactive phenomenon. We compared copy number abnormalities in matched CD34+ progenitor cells and CD3+ T cells from 40 MDS patients by array comparative genomic hybridization. In 9 of 14 patients with large copy number variants, we detected the same aberration in CD34+ and CD3+ cells. Chromosome 20q (2 patients), isodicentric × chromosome (2 patients), trisomy 8 (2 patients), 11q abnormalities (1 patient), deletion 5q (1 patient) and partial trisomy 9 with trisomies 19 and 22 (1 patient) were detected in the CD34+ and CD3+ cells of these patients. The presence of deletion 20q, trisomy 8 and deletion of chromosome arm 11q in the T cells of 3 patients was confirmed by FISH. Multiplex PCR for TCR γ rearrangement was performed on 6 of the 14 MDS patients with large copy number variants. T cell clonality was detected in 3 of 4 and oligoclonality in 1 of 4 patients when the copy number variant was present in both CD34+ and CD3+ cells. In contrast, the 2 cases lacking the CD34+ copy number variant in the CD3+ population were polyclonal at the TCR γ locus. These data suggest that in a large proportion of MDS at least a proportion of the T cells are part of the malignant clone, and that CD3+ cells do not represent an appropriate patient normal control for genome-wide studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Copy Number Variant on Chromosome 20q13.3 Implicated in Thinness and Severe Obesity

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Sandra J. Hasstedt ◽  
Yuanpei Xin ◽  
Rong Mao ◽  
Tracey Lewis ◽  
Ted D. Adams ◽  
...  
Keyword(s):  
Copy Number ◽  
Severe Obesity ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
Null Alleles ◽  
Comparative Genomic ◽  
Likelihood Analysis ◽  
Severely Obese ◽  
Obese Subjects ◽  
Real Time Qpcr

Background/Objectives.To identify copy number variants (CNVs) which are associated with body mass index (BMI).Subjects/Methods.CNVs were identified using array comparative genomic hybridization (aCGH) on members of pedigrees ascertained through severely obese (BMI ≥ 35 kg/m2) sib pairs (86 pedigrees) and thin (BMI ≤ 23 kg/m2) probands (3 pedigrees). Association was inferred through pleiotropy of BMI with CNVlog⁡2intensity ratio.Results.A 77-kilobase CNV on chromosome 20q13.3, confirmed by real-time qPCR, exhibited deletions in the obese subjects and duplications in the thin subjects (P=2.2×10-6). Further support for the presence of a deletion derived from inference by likelihood analysis of null alleles for SNPs residing in the region.Conclusions.One or more of 7 genes residing in a chromosome 20q13.3 CNV region appears to influence BMI. The strongest candidate isARFRP1, which affects glucose metabolism in mice.

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