scholarly journals Whole genome sequencing of apparently mutation-negative MEN1 patients

2020 ◽  
Vol 182 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Samuel Backman ◽  
Duska Bajic ◽  
Joakim Crona ◽  
Per Hellman ◽  
Britt Skogseid ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Missense Variant ◽  
Endocrine Tumors ◽  
Whole Genome ◽  
Loss Of Function ◽  
Chromosome 1Q ◽  
Pathogenic Variants ◽  
Sporadic Disease ◽  
Tumor Dna

Objective Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1 gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1 mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. Design Fourteen patients with a clinical diagnosis (n = 13) or suspicion (n = 1) of MEN1 who had negative genetic screening of the MEN1 gene were included. Methods Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. Results Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson’s two-hit model. Conclusion These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation-negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

scholarly journals Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate

2021 ◽  
Author(s):  
Waheed Awotoye ◽  
Peter A. Mossey ◽  
Jacqueline B. Hetmanski ◽  
Lord Jephthah Joojo Gowans ◽  
Mekonen A. Eshete ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cleft Lip ◽  
De Novo ◽  
Association Studies ◽  
Whole Genome ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Pathogenic Variants ◽  
Cleft Lip Palate

Abstract The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.

BIOM-23. A PILOT STUDY OF WHOLE GENOME SEQUENCING (WGS) OF PLASMA CELL-FREE DNA (cfDNA) FOR ULTRASENSITIVE DETECTION OF TUMOR DNA IN PATIENTS WITH GLIOBLASTOMA (GBM)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi15-vi15
Author(s):  
Stephen J Bagley ◽  
Jacob Till ◽  
Aseel Abdalla ◽  
MacLean Nasrallah ◽  
Tomer Lauterman ◽  
...  
Keyword(s):  
Pilot Study ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Tumor Tissue ◽  
Methylation Status ◽  
Tumor Burden ◽  
Whole Genome ◽  
Newly Diagnosed ◽  
Genome Wide ◽  
Tumor Dna

Abstract BACKGROUND Plasma circulating tumor DNA (ctDNA) is rarely detectable by traditional methods in patients with GBM. As a result, unlike in lung and other cancers, serial next generation sequencing of ctDNA for monitoring GBM tumor burden has been challenging. In light of the low tumor fraction (TF) of DNA fragments in GBM patient plasma and the urgent need to improve upon MRI for tracking GBM tumor burden, we conducted a pilot study in patients with newly diagnosed GBM using the C2 intelligence platform (C2i Genomics), which leverages genome-wide mutational integration for highly sensitive ctDNA detection. METHODS Plasma was collected pre- and post-operatively in patients with newly diagnosed GBM undergoing surgical resection/biopsy. cfDNA was extracted, quantified, and analyzed for fragment size. Genomic DNA (gDNA) was extracted from matched tumor tissue. Whole genome sequencing (WGS) was performed on both gDNA and cfDNA. A specific copy number alteration (CNA) compendium was created for each patient to generate a readout of TF (Zviran, Nat Medicine 2020). We assessed the association between TF at post-operative day 1 (a surrogate for residual disease) and OS, adjusting for other prognostic factors using Cox regression. RESULTS 37 patients were enrolled. For samples with high tumor fraction (n=5), a statistically significant (p< 1e-4) correlation between CNA profiles of tumor tissue and plasma samples was observed. Post-operative TF above the median value was associated with inferior OS (median 7.7 vs. 19.3 months, p=0.019). This association persisted after adjusting for age, O6-methylguanine-DNA methyltransferase methylation status, extent of resection, and performance status (adjusted HR 2.5, 95% CI 1.1-5.6, p=0.03). CONCLUSION Genome-wide mutational integration enables ultra-sensitive detection of ctDNA in GBM patient plasma. Post-operative TF measured by the C2i test is independently associated with OS in newly diagnosed GBM, providing the foundation to evaluate this technology for personalized prognostication and disease monitoring.

scholarly journals A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

2020 ◽  
Vol 29 (6) ◽  
pp. 967-979 ◽  
Author(s):  
Revital Bronstein ◽  
Elizabeth E Capowski ◽  
Sudeep Mehrotra ◽  
Alex D Jansen ◽  
Daniel Navarro-Gomez ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Diagnosis ◽  
Genetic Diagnostics ◽  
Whole Genome ◽  
Unique Challenge ◽  
Coding Regions ◽  
Pathogenic Variants ◽  
Number Of Patients ◽  
Coding Variants

Abstract Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a genetic treatment such as gene therapy to be successful, an accurate genetic diagnostic is required. Genetic diagnostics relies on the assessment of the probability that a given DNA variant is pathogenic. Non-coding variants present a unique challenge for such assessments as compared to coding variants. For one, non-coding variants are present at much higher number in the genome than coding variants. In addition, our understanding of the rules that govern the non-coding regions of the genome is less complete than our understanding of the coding regions. Methods that allow for both the identification of candidate non-coding pathogenic variants and their functional validation may help overcome these caveats allowing for a greater number of patients to benefit from advancements in genetic therapeutics. We present here an unbiased approach combining whole genome sequencing (WGS) with patient-induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs) transcriptome analysis. With this approach, we identified and functionally validated a novel pathogenic non-coding variant in a small family with a previously unresolved genetic diagnosis.

Author response for "Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability"

2018 ◽  
Author(s):  
Ann-Charlotte Thuresson ◽  
Cecilia Soussi Zander ◽  
Jin J. Zhao ◽  
Jonatan Halvardson ◽  
Khurram Maqbool ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Author Response ◽  
Whole Genome ◽  
Pathogenic Variants

scholarly journals Pathogenic variants in KPTN gene identified by clinical whole-genome sequencing

2020 ◽  
Vol 6 (3) ◽  
pp. a003970
Author(s):  
Isabelle Thiffault ◽  
Andrea Atherton ◽  
Bryce A. Heese ◽  
Ahmed T. Abdelmoity ◽  
Kailash Pawar ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Pathogenic Variants

Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13113-e13113
Author(s):  
Howard John Lim ◽  
Kasmintan A Schrader ◽  
Sean Young ◽  
Jessica Nelson ◽  
Alexandra Fok ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genomic Research ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.

scholarly journals NyuWa Genome Resource: Deep Whole Genome Sequencing Based Chinese Population Variation Profile and Reference Panel

2020 ◽  
Author(s):  
Peng Zhang ◽  
Huaxia Luo ◽  
Yanyan Li ◽  
You Wang ◽  
Jiajia Wang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Chinese Population ◽  
Population Variation ◽  
Reference Panel ◽  
Specific Reference ◽  
Whole Genome ◽  
Loss Of Function ◽  
Southern Chinese ◽  
Novel Variants

AbstractThe lack of Chinese population specific haplotype reference panel and whole genome sequencing resources has greatly hindered the genetics studies in the world’s largest population. Here we presented the NyuWa genome resource of 71.1M SNPs and 8.2M indels based on deep (26.2X) sequencing of 2,999 Chinese individuals, and constructed NyuWa reference panel of 5,804 haplotypes and 19.3M variants, which is the first publicly available Chinese population specific reference panel with thousands of samples. There were 25.0M novel variants in NyuWa genome resource, and 3.2M specific variants in NyuWa reference panel. Compared with other panels, NyuWa reference panel reduces the Han Chinese imputation error rate by the range of 30% to 51%. Population structure and imputation simulation tests supported the applicability of one integrated reference panel for both northern and southern Chinese. In addition, a total of 22,504 loss-of-function variants in coding and noncoding genes were identified, including 11,493 novel variants. These results highlight the value of NyuWa genome resource to facilitate genetics research in Chinese and Asian populations.

scholarly journals Exploring the Missing Heritability in Subjects With Hearing Loss, Enlarged Vestibular Aqueducts, and A Single or No Pathogenic SLC26A4 Variant

2021 ◽  
Author(s):  
Jeroen Smits ◽  
Suzanne E. de Bruijn ◽  
Cornelis P. Lanting ◽  
Jaap Oostrik ◽  
Luke O’Gorman ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genome Mapping ◽  
Copy Number Variants ◽  
Whole Genome ◽  
Missing Heritability ◽  
Vestibular Aqueduct ◽  
Pathogenic Variants ◽  
Long Read

Abstract Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype-phenotype correlation, a significant part of SLC26A4 cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, short- and long-read whole genome sequencing and optical genome mapping were performed. We found a previously described EVA-associated haplotype (Caucasian EVA (CEVA)) to be significantly enriched in our M1 patient cohort. The haplotype was also present in two M0 cases. Despite extensive genetic analyses, we were not able to prioritize any of the variants present within the haplotype as the likely pathogenic defect, and therefore additional analyses addressing the defect(s) at the RNA, protein, or epigenetic level are required. Whole genome sequencing also revealed splice-altering SLC26A4 variants in two M1 cases, which are now genetically explained, but no deep-intronic or copy number variants. With these findings, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases.

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