scholarly journals Pathogenic Variant Filtering for Mitochondrial Genome Haplotype Reporting

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1140
Author(s):  
Charla Marshall ◽  
Kimberly Sturk-Andreaggi ◽  
Joseph D. Ring ◽  
Arne Dür ◽  
Walther Parson
Keyword(s):  
Genetic Information ◽  
Variant Calling ◽  
Pathogenic Variant ◽  
Discriminatory Power ◽  
Coding Region ◽  
Legal Requirements ◽  
Random Match ◽  
Pathogenic Variants ◽  
Disease Information ◽  
Variant Filtering

Given the enhanced discriminatory power of the mitochondrial DNA (mtDNA) genome (mitogenome) over the commonly sequenced control region (CR) portion, the scientific merit of mitogenome sequencing is generally accepted. However, many laboratories remain beholden to CR sequencing due to privacy policies and legal requirements restricting the use of disease information or coding region (codR) information. In this report, we present an approach to obviate the reporting of sensitive codR data in forensic haplotypes. We consulted the MitoMap database to identify 92 mtDNA codR variants with confirmed pathogenicity. We determined the frequencies of these pathogenic variants in literature-quality and forensic-quality databases to be very low, at 1.2% and 0.36%, respectively. The observed effect of pathogenic variant filtering on random match statistics in 2488 forensic-quality mitogenome haplotypes from four populations was nil. We propose that pathogenic variant filtering should be incorporated into variant calling algorithms for mitogenome haplotype reporting to maximize the discriminatory power of the locus while minimizing the reveal of sensitive genetic information.

scholarly journals Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

scholarly journals Quantitative Approach to Fragmented QRS in Arrhythmogenic Cardiomyopathy: From Disease towards Asymptomatic Carriers of Pathogenic Variants

2020 ◽  
Vol 9 (2) ◽  
pp. 545 ◽  
Author(s):  
Rob W. Roudijk ◽  
Laurens P. Bosman ◽  
Jeroen F. van der Heijden ◽  
Jacques M. T. de Bakker ◽  
Richard N. W. Hauer ◽  
...  
Keyword(s):  
Early Stage ◽  
Pathogenic Variant ◽  
Observer Agreement ◽  
Arrhythmogenic Cardiomyopathy ◽  
Fragmented Qrs ◽  
Early Disease Detection ◽  
Pathogenic Variants ◽  
Disease Penetrance ◽  
Ecg Leads ◽  
And Control

Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM (n = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis (n = 57, 17%) and control subjects (n = 58, 17%) were included. Quantitative fQRS (Q-fQRS) was defined as the total amount of deflections in the QRS complex in all 12 electrocardiography (ECG) leads. Q-fQRS was scored by a single observer and reproducibility was determined by three independent observers. Q-fQRS count was feasible with acceptable intra- and inter-observer agreement. Q-fQRS count is significantly higher in patients with definite ACM (54 ± 15) and pathogenic variant carriers (55 ± 10) compared to controls (35 ± 5) (p < 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia (p = 0.701) at baseline or during follow-up (p = 0.335). Both definite ACM patients and pathogenic variant carriers not fulfilling ACM diagnosis have a higher Q-fQRS than controls. This may indicate that increased Q-fQRS is an early sign of disease penetrance. In concealed and early stages of ACM the role of Q-fQRS for risk stratification is limited.

scholarly journals Evaluation of serverless computing for scalable execution of a joint variant calling workflow

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254363
Author(s):  
Aji John ◽  
Kathleen Muenzen ◽  
Kristiina Ausmees
Keyword(s):  
Genetic Information ◽  
Best Practice ◽  
Workflow Management ◽  
Variant Calling ◽  
Phase Iii ◽  
1000 Genomes Project ◽  
1000 Genomes ◽  
Genomics Research ◽  
The Cost ◽  
Analysis Of Performance

Advances in whole-genome sequencing have greatly reduced the cost and time of obtaining raw genetic information, but the computational requirements of analysis remain a challenge. Serverless computing has emerged as an alternative to using dedicated compute resources, but its utility has not been widely evaluated for standardized genomic workflows. In this study, we define and execute a best-practice joint variant calling workflow using the SWEEP workflow management system. We present an analysis of performance and scalability, and discuss the utility of the serverless paradigm for executing workflows in the field of genomics research. The GATK best-practice short germline joint variant calling pipeline was implemented as a SWEEP workflow comprising 18 tasks. The workflow was executed on Illumina paired-end read samples from the European and African super populations of the 1000 Genomes project phase III. Cost and runtime increased linearly with increasing sample size, although runtime was driven primarily by a single task for larger problem sizes. Execution took a minimum of around 3 hours for 2 samples, up to nearly 13 hours for 62 samples, with costs ranging from $2 to $70.

scholarly journals Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0251639
Author(s):  
Camila Matzenbacher Bittar ◽  
Yasminne Marinho de Araújo Rocha ◽  
Igor Araujo Vieira ◽  
Clévia Rosset ◽  
Tiago Finger Andreis ◽  
...  
Keyword(s):  
Soft Tissue Sarcomas ◽  
Pathogenic Variant ◽  
Southern Brazil ◽  
Premenopausal Breast Cancer ◽  
Li Fraumeni Syndrome ◽  
Cancer Predisposition Syndrome ◽  
Pathogenic Variants ◽  
Li Fraumeni ◽  
Group B ◽  
Adrenocortical Carcinomas

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diagnosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chompret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p.Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and independent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligomerization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H heterozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants.

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

scholarly journals Germline MET pathogenic variants in papillary renal cell carcinomas type I: specific phenotype in French population and novel germline pathogenic variant MET c.3389T>C, p.(Leu1130Ser)

2021 ◽  
Author(s):  
Molka SEBAI ◽  
David TULASNE ◽  
Sandrine Caputo ◽  
Virginie VERKARRE ◽  
Marie FERNANDES ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Renal Cell ◽  
Kinase Domain ◽  
Pathogenic Variant ◽  
Renal Tumors ◽  
Tyrosine Kinase Domain ◽  
Functional Assay ◽  
Type I ◽  
Pathogenic Variants ◽  
Index Cases

Hereditary papillary renal cell carcinoma (HPRCC) is a rare inherited renal cancer syndrome characterized by bilateral and multifocal papillary type 1 renal tumors (PRCC1). Activating germline pathogenic variants of MET gene were identified in HPRCC families. We reviewed the medical and molecular records of a large French series of 158 patients screened for MET oncogenic variants (153 index-cases and five relatives). MET pathogenic variant rate was 10.4% (16/153) with 37.5% among patients with familial PRCC1 and 3.3% among patients with sporadic PRCC1 presentation. The phenotype in MET mutated cases was characteristic as PRCC1 tumors were mainly bilateral (82.3%) and multifocal (85.8%). Histologically, six out of seven patients with MET germline pathogenic variant harboured biphasic squamoid alveolar PRCC. Genetic screening identified in four index-cases a novel missense pathogenic variant within the tyrosine kinase domain: MET c.3389T>C, p.(Leu1130Ser). Functional assay confirmed its oncogenic effect with a constitutive phosphorylation of ERK protein and an abnormal focus formation induced. The genotype-phenotype correlation between MET pathogenic variants and PRCC1 presentation should encourage to widen the screening, especially toward non-familial PRCC1. This precise phenotype also constitutes a strong argument for the classification of novel missense variants within the tyrosine kinase domain when functional assays aren’t accessible.

scholarly journals Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Kodai Abe ◽  
Arisa Ueki ◽  
Yusaku Urakawa ◽  
Minoru Kitago ◽  
Tomoko Yoshihama ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
Genetic Analysis ◽  
Pathogenic Variant ◽  
Familial Pancreatic Cancer ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Pancreatic Cancers ◽  
Epidemiological Surveys ◽  
History Of

Abstract Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

Downstream Revenue Generated by a Cancer Genetic Counselor

2021 ◽  
pp. OP.20.00464 ◽  
Author(s):  
Caitlin B. Mauer ◽  
Brian D. Reys ◽  
Reece E. Hall ◽  
Connor L. Campbell ◽  
Sara M. Pirzadeh-Miller
Keyword(s):  
Genetic Counseling ◽  
Cancer Genetics ◽  
Healthcare Systems ◽  
Pathogenic Variant ◽  
Full Time ◽  
Cancer Genetic ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Relative Value ◽  
Management Recommendations

QUESTION ASKED: How much downstream revenue do cancer genetic counselors (GCs) generate when they identify patients with hereditary breast and ovarian cancer (HBOC) ( BRCA1/BRCA2) and Lynch syndrome (LS) pathogenic variants? SUMMARY ANSWER: Over a 10-year period, the downstream revenue generated from cancer GCs’ identification of patients with HBOC and LS was $32.79 million in US dollars (USD) (mean/year = $3.25 million USD and mean/patient = $77,000 USD). One full-time GC would generate $1.49-$1.86 million USD in revenue per year ($1.26-$1.58 million USD for HBOC-positive patients and $227-$284,000 USD for LS-positive patients per year). WHAT WE DID: Expected reimbursement and work relative value units (wRVUs) were collected from all hospital and ambulatory or outpatient encounters for patients with HBOC or LS identified in the Cancer Genetics clinic. Total revenue was calculated for each patient after they met with a GC; patients were stratified into categories of affected or unaffected status and new or established patients in the hospital system. WHAT WE FOUND: The downstream revenue generated from 425 patients with HBOC or LS mutations totaled $32,798,000 USD and 73,957 work relative value units after their cancer genetics appointments. Patients unaffected with cancer (n = 176) generated $8,453,000 USD, whereas naïve patients (n = 96), defined as those whose first visit to the institution was for a genetic counseling consultation, generated $5,933,000 USD. BIAS, CONFOUNDING FACTOR(S): This study solely focuses on revenue generated from patients with HBOC or LS. However, with the advent of next-generation sequencing panels, many pathogenic variants are being identified in other genes, resulting in enhanced management recommendations. Therefore, the revenue brought in by a GC likely surpasses the data provided here. Additionally, these data focus strictly on downstream revenue generated from patients receiving follow-up care at our institution. Patient adherence to compliance of management recommendations can affect the overall amount of revenue generated. REAL-LIFE IMPLICATIONS: To our knowledge, this is the first study to describe the amount of revenue generated for an institution downstream of the identification of pathogenic variant carriers in cancer susceptibility genes by a GC. These data will aid healthcare systems and oncology practices in determining if there is standalone fiscal value to the downstream effect of genetic counseling services or if services need to be supplemented through other avenues. By identifying clinic demographics and volumes, test uptake rate, and positive pathogenic variant rate, cancer GCs and healthcare systems or oncology practices can determine the expected revenue generated from HBOC and LS pathogenic variant carriers at their own institution to justify positions and growth of their genetic counseling departments ( Fig. 1 ).

scholarly journals Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene

2020 ◽  
Author(s):  
Flora Doffe ◽  
Vincent Carbonnier ◽  
Manon Tissier ◽  
Bernard Leroy ◽  
Isabelle Martins ◽  
...  
Keyword(s):  
Ethnic Diversity ◽  
Functional Characterization ◽  
Variant Calling ◽  
Asian Population ◽  
Tp53 Gene ◽  
Loss Of Function ◽  
Coding Region ◽  
Multiple Datasets ◽  
Novel Variants ◽  
Rare Genetic Variants

AbstractInfrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.

scholarly journals VariFAST: a variant filter by automated scoring based on tagged-signatures

2019 ◽  
Vol 20 (S22) ◽  
Author(s):  
Hang Zhang ◽  
Ke Wang ◽  
Juan Zhou ◽  
Jianhua Chen ◽  
Yizhou Xu ◽  
...  
Keyword(s):  
Best Practices ◽  
False Positive ◽  
Variant Calling ◽  
Sequencing Data ◽  
Novel Approach ◽  
Variant Filtering ◽  
Ngs Data Analysis ◽  
High Consistency ◽  
Ngs Data ◽  
Manual Review

Abstract Background Variant calling and refinement from whole genome/exome sequencing data is a fundamental task for genomics studies. Due to the limited accuracy of NGS sequencing and variant callers, IGV-based manual review is required for further false positive variant filtering, which costs massive labor and time, and results in high inter- and intra-lab variability. Results To overcome the limitation of manual review, we developed a novel approach for Variant Filter by Automated Scoring based on Tagged-signature (VariFAST), and also provided a pipeline integrating GATK Best Practices with VariFAST, which can be easily used for high quality variants detection from raw data. Using the bam and vcf files, VariFAST calculates a v-score by sum of weighted metrics causing false positive variations, and marks tags in the manner of keeping high consistency with manual review, for each variant. We validated the performance of VariFAST for germline variant filtering using the benchmark sequencing data from GIAB, and also for somatic variant filtering using sequencing data of both malignant carcinoma and benign adenomas as well. VariFAST also includes a predictive model trained by XGBOOST algorithm for germline variants refinement, which reveals better MCC and AUC than the state-of-the-art VQSR, especially outcompete in INDEL variant filtering. Conclusion VariFAST can assist researchers efficiently and conveniently to filter the false positive variants, including both germline and somatic ones, in NGS data analysis. The VariFAST source code and the pipeline integrating with GATK Best Practices are available at https://github.com/bioxsjtu/VariFAST.

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