scholarly journals Copy Number Changes Identified Using Whole Exome Sequencing in Nonsyndromic Cleft Lip and Palate in a Honduran Population

2017 ◽  
Vol 109 (16) ◽  
pp. 1257-1267 ◽  
Author(s):  
Yi Cai ◽  
Karynne E. Patterson ◽  
Frederic Reinier ◽  
Sarah E. Keesecker ◽  
Elizabeth Blue ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Whole Exome ◽  
Copy Number Changes

Whole-exome tumor sequencing study in patients with biliary cancer with a response to MEK inhibitors.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 253-253
Author(s):  
Daniel H. Ahn ◽  
Hatice Gulcin Ozer ◽  
Baris Hancioglu ◽  
Gregory B. Lesinski ◽  
Cynthia Dawn Timmers ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Mapk Pathway ◽  
Objective Response ◽  
Erk Signaling ◽  
Chromosome 11 ◽  
Whole Exome ◽  
Two Samples ◽  
Copy Number Changes

253 Background: We conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC). The observed preliminary activity was confirmed with another MEK inhibitor (MEK162) that was tested in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response including a complete response to selumetinib. Methods: Normal and tumor DNA from available formalin-fixed paraffin-embedded tissue from biopsies of primary or metastatic tumor from two patients who experienced an objective response underwent whole-exome sequencing. Raw sequence reads were processed with GATK workflow and tumor-specific variants were identified using MuTect and VarScan 2. Following, we assessed the functional consequences of the variants. Copy number changes and potential gene fusion events were also screened. We compared the findings to assess for any commonality between the two samples. Ingenuity Pathway Analysis was used to assess whether the identified somatic variants were intrinsic to the MAPK pathway. Results: 1169 and 628 tumor-specific variants were identified in the two tumor samples. Further analysis demonstrated a similar number of functional and novel variants between the two samples, which were 60 and 53, respectively. No common variants or detectable fusion events were observed between the two samples. Copy number changes were found in chromosomes 1, 5, 6, 9, 10, 12, 17, 20, 21 and 22 in sample one, and in chromosome 11 and 12 on sample two with no common findings. Several variants in genes associated with ERK signaling were present in each tumor sample. Conclusions: Although no common tumor-specific somatic changes of significance several genes associated with ERK signaling were identified in the patients with an objective response. Confirmatory studies investigating the role of the identified genes need to be further investigated.

scholarly journals Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 833 ◽  
Author(s):  
Bénédicte Demeer ◽  
Nicole Revencu ◽  
Raphael Helaers ◽  
Cica Gbaguidi ◽  
Stéphanie Dakpe ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Candidate Gene Approach ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Wide Range ◽  
Primary Palate

Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity. When cleft of the palate is associated with cleft of the lip with preservation of the primary palate, it defines an atypical phenotype called discontinuous cleft. Although this phenotype may represent 5% of clefts of the lip and/or palate (CLP), it is rarely specifically referred to and its pathophysiology is unknown. We conducted whole exome sequencing (WES) and apply a candidate gene approach to non-syndromic discontinuous CLP individuals in order to identify genes and deleterious variants that could underlie this phenotype. We discovered loss-of-function variants in two out of the seven individuals, implicating FGFR1 and DLG1 genes, which represents almost one third of this cohort. Whole exome sequencing of clinically well-defined subgroups of CLP, such as discontinuous cleft, is a relevant approach to study CLP etiopathogenesis. It could facilitate more accurate clinical, epidemiological and fundamental research, ultimately resulting in better diagnosis and care of CLP patients. Non-syndromic discontinuous cleft lip and palate seems to have a strong genetic basis.

The Genome of Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 51-51
Author(s):  
Giulia Fabbri ◽  
Vladimir Trifonov ◽  
Davide Rossi ◽  
Oliver T Elliot ◽  
Joseph M Chan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Lymphocytic Leukemia ◽  
Gene Copy ◽  
Additional Patient ◽  
Array Analysis ◽  
Whole Exome ◽  
Copy Number Changes

Abstract Abstract 51 Chronic lymphocytic leukemia (CLL) is a malignancy of CD5+ mature B cells that includes two distinct subtypes marked by the differential presence of immunoglobulin gene mutations and a distinct clinical course. The pathogenesis of CLL is largely unknown: in contrast to other types of B cell malignancies, CLL is not associated with recurrent, balanced chromosomal translocations, nor genes have been found that are specifically targeted by somatic mutations, with the exception of ATM and p53 in 6–12% of cases. Instead, more than 80% of CLL patients carry genomic deletions of chromosomal regions 13q14, 11q22–23, and 17p13, or trisomy 12. Of these, the 13q14.3 deletion, encompassing the DLEU2/miR-15a/miR-16-1 cluster (Calin and Croce, Nat Rev Cancer 2006), has been recently shown to promote the development of CLL in mice (Klein et al., Cancer Cell 2010), suggesting its pathogenetic role in the human disease. To determine the extent of somatic genetic lesions (mutations and gene copy number changes) that are present in the CLL genome, we have integrated next generation whole-exome sequencing analysis (Nimblegen/Roche FLX454) and genome-wide high-density single nucleotide polymorphism array analysis (Affymetrix SNP 6.0) in 5 cases representative of the two CLL immunogenetic subgroups and their paired normal DNAs. Candidate tumor-specific nonsynonymous mutations were verified by Sanger sequencing in the same tumor/normal pairs, and all genes validated as mutated were then screened in an independent panel of 48 CLL DNAs by PCR amplification/direct sequencing of their entire coding region. The whole-exome sequencing approach revealed a total of 36 mutations, corresponding to 36 distinct genes at an average of 7 mutations/case (range, 5–9 mutations/case). The majority of these events were represented by single base pair substitutions (N=34, of which 30 missense mutations and 4 nonsense mutations), while frameshift insertion/deletions were rare (N=2 deletions of 4 and 32 base pairs, respectively; 5.5%). Analysis of the mutation features showed a prevalence of transitions versus transversions (64% vs 36%) and an elevated G+C over A+T ratio (66% vs 44%), analogous to the mutation spectrum observed in the genome of epithelial tumors such as colorectal, pancreatic and brain cancer. SNP array analysis in 4 of the 5 “discovery” cases confirmed the presence of the 13q14 deletion in 2 samples and identified 25 additional regions of copy number changes, corresponding to ∼7 lesions/case (range: 3 to 10) and mostly represented by deletions (N=16/27, ∼60%). When screened in the extended CLL panel, several of the 36 genes identified through the whole exome sequencing approach appeared to be mutated in at least one additional patient. Overall, these data indicate that the coding genome of CLL contains on average ∼14 somatic gene alterations per case. When classified based on functional annotation, most of these lesions appeared to converge on discrete signaling pathways, which likely represent important pathogenetic and possibly therapeutic targets in CLL. Disclosures: No relevant conflicts of interest to declare.

A Novel IRF6 Variant Detected in a Family With Nonsyndromic Cleft Lip and Palate by Whole Exome Sequencing

2020 ◽  
Vol 32 (1) ◽  
pp. 265-269
Author(s):  
Yanyang Wang ◽  
Cui Ma ◽  
Chanyuan Jiang ◽  
Yongbiao Zhang ◽  
Di Wu
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Whole Exome

scholarly journals Using Whole Exome Sequencing to Identify Candidate Genes With Rare Variants In Nonsyndromic Cleft Lip and Palate

2016 ◽  
Vol 40 (5) ◽  
pp. 432-441 ◽  
Author(s):  
Alana Aylward ◽  
Yi Cai ◽  
Andrew Lee ◽  
Elizabeth Blue ◽  
Daniel Rabinowitz ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Rare Variants ◽  
Whole Exome

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors

2021 ◽  
Author(s):  
Juan Chen ◽  
Yan Li ◽  
Jianlei Wu ◽  
Yakun Liu ◽  
Shan Kang
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Copy Number ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Deletion Region ◽  
Whole Exome

Abstract Background Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. Methods The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region. Results In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak–STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples. Conclusions Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2

2020 ◽  
Author(s):  
Piranit Nik Kantaputra ◽  
Prapai Dejkhamron ◽  
Worrachet Intachai ◽  
Chumpol Ngamphiw ◽  
Katsushige Kawasaki ◽  
...  
Keyword(s):  
Short Stature ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Upper Limb ◽  
Autosomal Recessive ◽  
Cleft Lip ◽  
Clinical Findings ◽  
Protein Model ◽  
Whole Exome ◽  
Cleft Lip Palate

Summary Background Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. Objective To report for the first time the molecular aetiology of JHS. Patient and methods Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed. Results Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect. Conclusions Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.

scholarly journals RefCNV: Identification of Gene-Based Copy Number Variants Using Whole Exome Sequencing

2016 ◽  
Vol 15 ◽  
pp. CIN.S36612 ◽  
Author(s):  
Lun-Ching Chang ◽  
Biswajit Das ◽  
Chih-Jian Lih ◽  
Han Si ◽  
Corinne E. Camalier ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Copy Number Variants ◽  
Estimation Methods ◽  
Single Nucleotide Variants ◽  
False Positive Error ◽  
Reference Set ◽  
Genome Wide ◽  
Whole Exome

With rapid advances in DNA sequencing technologies, whole exome sequencing (WES) has become a popular approach for detecting somatic mutations in oncology studies. The initial intent of WES was to characterize single nucleotide variants, but it was observed that the number of sequencing reads that mapped to a genomic region correlated with the DNA copy number variants (CNVs). We propose a method RefCNV that uses a reference set to estimate the distribution of the coverage for each exon. The construction of the reference set includes an evaluation of the sources of variability in the coverage distribution. We observed that the processing steps had an impact on the coverage distribution. For each exon, we compared the observed coverage with the expected normal coverage. Thresholds for determining CNVs were selected to control the false-positive error rate. RefCNV prediction correlated significantly ( r = 0.96–0.86) with CNV measured by digital polymerase chain reaction for MET (7q31), EGFR (7p12), or ERBB2 (17q12) in 13 tumor cell lines. The genome-wide CNV analysis showed a good overall correlation (Spearman's coefficient = 0.82) between RefCNV estimation and publicly available CNV data in Cancer Cell Line Encyclopedia. RefCNV also showed better performance than three other CNV estimation methods in genome-wide CNV analysis.

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