scholarly journals Single-nucleotide and Copy-number variance related to severity of Hypospadias

2018 ◽  
Author(s):  
Neetu Singh ◽  
Devendra Kumar Gupta ◽  
Shilpa Sharma ◽  
Dinesh Kumar Sahu ◽  
Archana Mishra ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
North India ◽  
Taqman Assay ◽  
Comparative Genomic ◽  
Chinese Han ◽  
Significance Levels ◽  
Grade 3 ◽  
Severity Of The Disease ◽  
Penoscrotal Hypospadias

AbstractThe genetic association of Hypospadias-risk studies has been conducted in Caucasians, Chinese-Han populations and few in Indian populations. Although no comprehensive approach has been followed to assess genetic involvement in the severity of the disorder. The study evaluated to establish the correlation between genotyped SNPs/CNVs and Hypospadias-severity by an association in a total 30 SNPs in genes related to sex hormone-biosynthesis and metabolism; embryonic-development and Phospholipase-D-signalling pathways on 138 surgery-confirmed hypospadias-cases from North-India (84 Penile and 28 cases of Penoscrotal-Hypospadias compared against 31 cases of Glanular+Coronal), and analyzed and identified copy number variants (CNVs) in four Familial samples (18 members) and three paired-sporadic cases (6 samples) using array-based comparative-genomic-hybridization and validated in 32 Hypospadias samples by TaqMan assay. Based on Odds Ratio at 95% CI, Z Statistic and Significance Levels, STS gene-rs17268974 was associated with Penile-Hypospadias and 9-SNPs (seven-SNPs (rs5934740; rs5934842; rs5934913; rs6639811; rs3923341; rs17268974; rs5934937) of STS gene; rs7562326-SRD5A2 and rs1877031-STARD3 were associated with Penoscrotal-Hypospadias. On aggregate analysis with p <0.001, we identified homozygous-loss of Ch7:q34 (PRSS3P2, PRSS2). On validation in previously CNV-characterized and new (32-hypospadias-cases), we identified PRSS3P2-loss in most of the grade 3 and 4 hypospadias. Hence, Grade 1 and 2 (coronal and granular) show no-PRSS3P2-loss and no-association with SNPs in STS; SRD5A2; STARD3-gene but Grade 3 and 4 (Penile and Penoscrotal) show PRSS3P2-loss accompanied with the association of SNPs in STS; SRD5A2; STARD3. Hence, homozygous-loss of PRSS3P2 accompanied with the association of STS; SRD5A2; STARD3 may link to the severity of the disease.

Molecular karyotyping in routine diagnostics – a view back and forth1)

2013 ◽  
Vol 36 (5) ◽  
Author(s):  
Uwe Heinrich ◽  
Meike Gabert ◽  
Imma Rost
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Uniparental Disomy ◽  
Simultaneous Detection ◽  
Molecular Karyotyping ◽  
Comparative Genomic ◽  
Detection Rates ◽  
Routine Diagnostics ◽  
Indispensable Tool

AbstractSince its introduction in the routine diagnostics of patients with mental retardation/developmental delay, array-comparative genomic hybridization (aCGH) has become an indispensable tool for the detection of clinically relevant copy number variants (CNVs). Despite the current tendency for higher resolution arrays, the growing number of public internet databases as well as better calling algorithms allow save reporting and a better classification of CNVs. The application of combined aCGH plus single nucleotide polymorphism (SNP) arrays will increase detection rates by revealing copy number neutral changes, such as uniparental disomy. In the future, next generation sequencing techniques will lead to a further increase in resolution with the simultaneous detection of unbalanced and even balanced chromosomal aberrations.

scholarly journals Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

2014 ◽  
Vol 171 (2) ◽  
pp. 253-262 ◽  
Author(s):  
Ana P M Canton ◽  
Sílvia S Costa ◽  
Tatiane C Rodrigues ◽  
Debora R Bertola ◽  
Alexsandra C Malaquias ◽  
...  
Keyword(s):  
Short Stature ◽  
Candidate Genes ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Comparative Genomic ◽  
Growth Disorders ◽  
Genomic Regions

BackgroundThe etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders.ObjectiveTo analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause.Patients and methodsA total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature.ResultsIn 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation.ConclusionPathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.

scholarly journals Combining callers improves the detection of copy number variants from whole-genome sequencing

2021 ◽  
Author(s):  
Marie Coutelier ◽  
Manuel Holtgrewe ◽  
Marten Jäger ◽  
Ricarda Flöttman ◽  
Martin A. Mensah ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Copy Number Variants ◽  
Computation Time ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Base Pairs ◽  
Whole Exome ◽  
Human Pathology

AbstractCopy Number Variants (CNVs) are deletions, duplications or insertions larger than 50 base pairs. They account for a large percentage of the normal genome variation and play major roles in human pathology. While array-based approaches have long been used to detect them in clinical practice, whole-genome sequencing (WGS) bears the promise to allow concomitant exploration of CNVs and smaller variants. However, accurately calling CNVs from WGS remains a difficult computational task, for which a consensus is still lacking. In this paper, we explore practical calling options to reach the best compromise between sensitivity and sensibility. We show that callers based on different signal (paired-end reads, split reads, coverage depth) yield complementary results. We suggest approaches combining four selected callers (Manta, Delly, ERDS, CNVnator) and a regenotyping tool (SV2), and show that this is applicable in everyday practice in terms of computation time and further interpretation. We demonstrate the superiority of these approaches over array-based Comparative Genomic Hybridization (aCGH), specifically regarding the lack of resolution in breakpoint definition and the detection of potentially relevant CNVs. Finally, we confirm our results on the NA12878 benchmark genome, as well as one clinically validated sample. In conclusion, we suggest that WGS constitutes a timely and economically valid alternative to the combination of aCGH and whole-exome sequencing.

High Resolution Array-Based CGH and SNP Studies of AML Genomes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 107-107
Author(s):  
Matthew J. Walter ◽  
R. Ries ◽  
X. Li ◽  
W. Shannon ◽  
J. Payton ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Neutral Loss ◽  
Copy Number Variants ◽  
Uniparental Disomy ◽  
Cell Receptor ◽  
Homozygous Deletion ◽  
Comparative Genomic ◽  
Snp Arrays ◽  
Gains And Losses

Abstract To test if small deletions or amplifications (ie. below the resolution of cytogenetics) exist in bone marrow-derived tumor DNA from acute myeloid leukemia (AML) patients (pts), we used a dense tiling path array comparative genomic hybridization (aCGH) platform consisting of 386,165 unique oligomers spaced evenly at ∼6Kb intervals across the genome. We analyzed 144 adult de novo AML pts; 64 had normal karyotypes, and 80 had 1 or 2 clonal aberrations. Similar numbers of FAB M0/1, M2, M3, and M4 pts were included, and all samples had >30% blasts (median=72%). To generate a cancer-free control set of data, we also analyzed 23 DNA samples from normal individuals matched for age and ethnicity, and with no history of cancer. Both the tumor and cancer-free control DNA samples were co-hybridized with a pool of control DNAs from blood of 4 healthy young males. To define the sensitivity and specificity of the aCGH platform, we examined its ability to detect cytogenetically defined chromosome gains and losses. Of the 33 gains and losses present in >20% of metaphases, 29 (88%) were detected by aCGH. Of the 20 gains and losses present in ≤20% of metaphases, aCGH detected only 5 (25%). Three of 63 (4.8%) balanced translocations [t(15;17), t(8;21), t(9;11)] were detected using aCGH, indicating that breakpoints of some translocations contained small deletions. Further, we identified many previously described germline copy number variants (CNVs) in both the AML pts and cancer-free controls. To improve our ability to define even smaller somatic microdeletions and amplifications, we tested 20 AML pts using CGH arrays containing 1.5 million probes per genome (average probe spacing 1.5 Kb). To preclude detection of germline CNVs, the higher resolution CGH experiments were performed comparing tumor and skin-derived DNA from the same patient. These same sample pairs were also analyzed individually with the Affymetrix 500K SNP arrays. Using stringent criteria to define abnormal segments, we identified 64 altered loci in the 20 AML pts that were not apparent cytogenetically, and that contained ≥1 gene. SNP arrays confirmed aCGH findings in 7/9 loci >100 Kb, and in 1/55 loci <100 Kb in size. In addition, SNP arrays revealed copy number neutral loss of heterozygosity of the 11p arm in 2/20 AML pts, indicating partial uniparental disomy (UPD) involving this region. We also detected somatic deletions in the T cell receptor (TCR) (n=3/20) and immunoglobulin heavy chain (n=1/20) genes, including a homozygous deletion measuring 4.3 Kb in size. The remaining loci identified with the 1.5M oligo aCGH platform were validated using quantitative PCR with matched tumor and germline DNA. Only 5/60 putative calls were validated using this approach, and include a deletion of IGFBP2, and amplifications of CROP, CPEB4, HOMER1, and ZNF148. In summary, 13 loci containing genes have been validated by SNP arrays or qPCR. No recurrent deletions or amplifications were found in the 20 AML pts. Thus, an additional 74 AML pts are being screened for evidence of recurrence at these loci. Our data suggest that an ultra-dense platform may be required to detect the majority of somatic copy number changes in AML genomes, and that UPD is relatively rare in AML pts, occurring in ∼10% of pts, and recurrent only in the 11p region.

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

Genes ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 524 ◽  
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.

scholarly journals Genomic Copy Number Variants in CML Patients With the Philadelphia Chromosome (Ph+): An Update

2021 ◽  
Vol 12 ◽  
Author(s):  
Heyang Zhang ◽  
Meng Liu ◽  
Xiaoxue Wang ◽  
Yuan Ren ◽  
Young Mi Kim ◽  
...  
Keyword(s):  
Copy Number ◽  
Array Cgh ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Copy Number Variants ◽  
Chromosomal Anomaly ◽  
Comparative Genomic ◽  
Ph Chromosome ◽  
Patient Prognosis

BackgroundSubmicroscopic segmental imbalances detected by array-comparative genomic hybridization (array-CGH) were discovered to be common in chronic myeloid leukemia (CML) patients with t(9;22) as the sole chromosomal anomaly. To confirm the findings of the previous study and expand the investigation, additional CML patients with t(9;22) as the sole chromosomal anomaly were recruited and copy number variants (CNVs) were searched for.MethodsKaryotyping tests were performed on 106 CML patients during January 2010–September 2019 in our Genetics Laboratory. Eighty-four (79.2%) patients had the Philadelphia (Ph) chromosome as the sole chromosomal anomaly. Only 49(58.3%) of these 84 patients had sufficient marrow or leukemia blood materials to additionally be included in the array-CGH analysis. Fluorescence in situ hybridization (FISH) was carried out to confirm the genes covered by the deleted or duplicated regions of the CNVs.Results11(22.4%) out of the 49 patients were found to have one to three somatic segmental somatic segmental (CNVs), including fourteen deletions and three duplications. The common region associated with deletions was on 9q33.3-34.12. Identified in five (45.5%) of the 11 positive patients with segmental CNVs, the deletions ranged from 106 kb to 4.1 Mb in size. Two (18.2%) cases had a deletion in the ABL1-BCR fusion gene on der (9), while three (27.3%) cases had a deletion in the ASS1 gene. The remaining CNVs were randomly distributed on different autosomes.ConclusionSubtle genomic CNVs are relatively common in CML patients without cytogenetically visible additional chromosomal aberrations (ACAs). Long-term studies investigating the potential impact on patient prognosis and treatment outcome is underway.

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