scholarly journals Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

BMJ ◽  
2021 ◽  
pp. n792
Keyword(s):  
Population Based ◽  
Diagnostic Evaluation ◽  
Pathogenic Variants

scholarly journals Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

BMJ ◽  
2021 ◽  
pp. n214
Author(s):  
Weedon MN ◽  
Jackson L ◽  
Harrison JW ◽  
Ruth KS ◽  
Tyrrell J ◽  
...  
Keyword(s):  
Positive Predictive Value ◽  
Predictive Value ◽  
Population Based ◽  
Genome Project ◽  
Personal Genome ◽  
Uk Biobank ◽  
Sequencing Data ◽  
Snp Chip ◽  
Pathogenic Variants ◽  
The Uk

Abstract Objective To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. Design Retrospective, population based diagnostic evaluation. Participants 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. Main outcome measures Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

scholarly journals Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1378
Author(s):  
Tú Nguyen-Dumont ◽  
James G. Dowty ◽  
Jason A. Steen ◽  
Anne-Laure Renault ◽  
Fleur Hammet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cumulative Risk ◽  
Population Based ◽  
Case Control ◽  
Cancer Information ◽  
Case Control Studies ◽  
Breast Cancer Family ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Control Family

Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

Population-Based Screening in Children For Early Diagnosis and Treatment of Familial Hypercholesterolemia: Design of The VRONI Study

2021 ◽  
Author(s):  
Veronika Sanin ◽  
Raphael Schmieder ◽  
Sara Ates ◽  
Lea Dewi Schlieben ◽  
Jens Wiehler ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Screening Program ◽  
Molecular Genetic ◽  
Population Based ◽  
Molecular Genetic Analysis ◽  
Cascade Screening ◽  
Screening Programs ◽  
Pathogenic Variants ◽  
Risk Indices ◽  
Training Courses

Abstract Background: Heterozygous Familial Hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce.Methods: In the VRONI study children aged 5 to 14 years in Bavaria are invited to participate in a FH screening program during regular pediatric visits. The screening is based on LDL-C measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first degree relatives, reverse cascade screening is recommended to identify and treat affected family members.Results: Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data-safety, legal and organisational aspects, which will be outlined in this paper. Recruitment started in January of 2021, within two months more than 280 pediatricians screened over 1,150 children. Approximately 60,000 children are expected to be enrolled in the VRONI study until 2024. Conclusion: VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nation-wide FH screening infrastructure. Further we aim to validate genetic variants of unclear significance, detect novel causative mutations, and contribute to polygenic risk indices. (German Clinical Trials Register: DRKS00022140; registered August 21st2020.)

SARS-CoV-2 Seroprevalence and Accuracy Diagnostic Evaluation During a Covid-19 Outbreak in a Major Penitentiary Complex in Brazil, June-July 2020: A Population-Based Study

2021 ◽  
Author(s):  
Fernando Augusto Gouvea-Reis ◽  
Danniely C.S. Silva ◽  
Lairton S. Borja ◽  
Patrícia O. Dias ◽  
Jadher Percio ◽  
...  
Keyword(s):  
Population Based ◽  
Diagnostic Evaluation ◽  
Population Based Study ◽  
June July

Development and assessment of an accessible communication system for population-based genetic testing: Method/design (Preprint)

2021 ◽  
Author(s):  
Tara Coffin ◽  
Deborah Bowen ◽  
Elizabeth Swisher ◽  
Karen Lu ◽  
Karen Lu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Communication System ◽  
Formative Evaluation ◽  
Online Communication ◽  
Implementation Process ◽  
Usability Testing ◽  
Population Based ◽  
Ovarian Cancer Risk ◽  
Online System ◽  
Pathogenic Variants

BACKGROUND Genetic testing uptake is low, despite the well-established connection between pathogenic variants in certain cancer-linked susceptibility genes and ovarian cancer risk. Given that most major insurers cover genetic testing for those with a family history suggestive of hereditary cancer, the issue may lie in access to genetic testing. OBJECTIVE To present the development and formative evaluation of the multi-step online communication system required to support the democratization of genetic testing. METHODS While designing the multi-step online communication system, we considered various barriers and facilitators to genetic testing, guided by Levesque et al.’s dimensions of accessibility. In addition to conducting usability testing, we performed ongoing assessments focusing on function of the online system and participant response rates, with the goal of continuing to make modifications to the online communication system as it is in use. RESULTS The combined approach of usability testing and expert user experience (UX) consultation resulted in several modifications to the multi-step online communication system, including changes that related to imagery and content, web-accessibility, and general organization of the online system. All recommendations were made with the goal of improving the overall accessibility of the online communication system. CONCLUSIONS A multi-step online communication system appears to be an effective way to address many potential barriers to access, which may otherwise make genetic testing difficult for at-risk individuals to participate in. Importantly, some dimensions of access were easy to assess prior to study recruitment opening, but other aspects of the communication system required ongoing assessment during the implementation process of the Making Genetic Testing Accessible (MAGENTA) study.

scholarly journals Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients

2019 ◽  
Vol 56 (10) ◽  
pp. 662-670 ◽  
Author(s):  
Yoshito Koyanagi ◽  
Masato Akiyama ◽  
Koji M Nishiguchi ◽  
Yukihide Momozawa ◽  
Yoichiro Kamatani ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Japanese Population ◽  
East Asian ◽  
Japanese Patients ◽  
Population Based ◽  
Genetic Profile ◽  
Genetic Characteristics ◽  
Pathogenic Variants ◽  
Recessive Genes ◽  
Dominant Genes

BackgroundThe genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.MethodsA total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.ResultsWe successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.ConclusionsEast Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

scholarly journals Repurposing Pathogenic Variants of DMD Gene and its Isoforms for DMD Exon Skipping Intervention

2020 ◽  
Vol 20 (7) ◽  
pp. 519-530 ◽  
Author(s):  
Rahul Tyagi ◽  
Sumit Kumar ◽  
Ashwin Dalal ◽  
Faruq Mohammed ◽  
Manju Mohanty ◽  
...  
Keyword(s):  
Exon Skipping ◽  
Population Based ◽  
Neuromuscular Disorder ◽  
Copy Number Variations ◽  
Reading Frame ◽  
The North ◽  
Pathogenic Variants ◽  
Mutation Database ◽  
Dmd Gene ◽  
Dependent Probe

Background: Duchenne Muscular Dystrophy (DMD) is a progressive, fatal neuromuscular disorder caused by mutations in the DMD gene. Emerging antisense oligomer based exon skipping therapy provides hope for the restoration of the reading frame. Objectives: Population-based DMD mutation database may enable exon skipping to be used for the benefit of patients. Hence, we planned this study to identify DMD gene variants in North Indian DMD cases. Methods: A total of 100 DMD cases were recruited and Multiplex ligation-dependent probe amplification (MLPA) analysis was performed to obtain the deletion and duplication profile. Results: Copy number variations (deletion/duplication) were found in 80.85% of unrelated DMD cases. Sixty-eight percent of cases were found to have variations in the distal hotspot region (Exon 45- 55) of the DMD gene. Exon 44/45 variations were found to be the most prominent among single exon variations, whereas exon 49/50 was found to be the most frequently mutated locations in single/ multiple exon variations. As per Leiden databases, 86.84% cases harboured out-of-frame mutations. Domain wise investigation revealed that 68% of mutations were localized in the region of spectrin repeats. Dp140 isoform was predicted to be absent in 62/76 (81.57%) cases. A total of 45/80 (56.25 %) and 23/80 (28.70%) DMD subjects were predicted to be amenable to exon 51 and exon 45 skipping trials, respectively. Conclusion: A major proportion of DMD subjects (80%) could be diagnosed by the MLPA technique. The data generated from our study may be beneficial for strengthening of mutation database in the North Indian population.

scholarly journals Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

2021 ◽  
Author(s):  
Siddhartha Yadav ◽  
Chunling Hu ◽  
Katherine L. Nathanson ◽  
Jeffrey N. Weitzel ◽  
David E. Goldgar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lobular Carcinoma ◽  
Population Based ◽  
Cancer Predisposition ◽  
Clinical Cohort ◽  
Breast Cancer Predisposition ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Multigene Panel

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

scholarly journals Standards-Based Clinical Decision Support Platform to Manage Patients Who Meet Guideline-Based Criteria for Genetic Evaluation of Familial Cancer

2020 ◽  
pp. 1-9 ◽  
Author(s):  
Guilherme Del Fiol ◽  
Wendy Kohlmann ◽  
Richard L. Bradshaw ◽  
Charlene R. Weir ◽  
Michael Flynn ◽  
...  
Keyword(s):  
Decision Support ◽  
Pilot Study ◽  
Clinical Decision Support ◽  
Familial Cancer ◽  
Family Health ◽  
Clinical Decision ◽  
Target Population ◽  
Population Based ◽  
Genetic Evaluation ◽  
Pathogenic Variants

PURPOSE The ubiquitous adoption of electronic health records (EHRs) with family health history (FHH) data provides opportunities for tailoring cancer screening strategies to individuals. We aimed to enable a standards-based clinical decision support (CDS) platform for identifying and managing patients who meet guidelines for genetic evaluation of hereditary cancer. METHODS The CDS platform ( www.opencds.org ) was used to implement algorithms based on the 2018 National Comprehensive Cancer Network guidelines for genetic evaluation of hereditary breast/ovarian and colorectal cancer. The platform was designed to be interfaced with different EHR systems via the Health Level Seven International Fast Healthcare Interoperability Resources standard. The platform was integrated with the Epic EHR and evaluated in a pilot study at an academic health care system. RESULTS The CDS platform was executed against a target population of 143,012 patients; 5,245 (3.7%) met criteria for genetic evaluation based on the FHH recorded in the EHR. In a clinical pilot study, genetic counselors attempted to reach out to 71 of the patients. Of those patients, 25 (35%) scheduled an appointment, 10 (14%) declined, 2 (3%) did not need genetic counseling, 7 (10%) said they would consider it in the future, and 27 (38%) were unreachable. To date, 13 (52%) of the scheduled patients completed visits, and 2 (15%) of those were found to have pathogenic variants in cancer predisposition genes. CONCLUSION A standards-based CDS platform integrated with EHR systems is a promising population-based approach to identify patients who are appropriate candidates for genetic evaluation of hereditary cancers.

Germline pathogenic variants in cancer predisposition genes among women with invasive lobular cancer of breast.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10581-10581
Author(s):  
Siddhartha Yadav ◽  
Chunling Hu ◽  
Susan M. Domchek ◽  
Jeffrey N. Weitzel ◽  
David Goldgar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Population Based ◽  
Cancer Predisposition ◽  
Clinical Cohort ◽  
Breast Cancer Predisposition ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Multigene Panel Testing ◽  
Multigene Panel

10581 Background: The prevalence of germline pathogenic variants (PVs) in cancer predisposition genes among women with invasive lobular breast cancer (ILC) and the risk of ILC in PV carriers is not well-defined. Methods: The study included 2,999 women with ILC and 32,544 unaffected controls from a population-based cohort; 3,796 women with ILC and 20,323 women with invasive ductal carcinoma (IDC) undergoing clinical multigene panel testing (clinical cohort); and 125,748 exome sequences from unrelated women without a cancer diagnosis in the gnomAD 3.0 dataset. Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected controls in both cohorts and between women with ILC and IDC in the clinical cohort. Results: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analyses, CDH1 and BRCA2 PVs were associated with high risks of ILC (Odds ratio (OR) > 4), and CHEK2, ATM and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. PV frequencies in these genes in ILC and IDC were similar except for PV frequencies in BRCA1 and CDH1. Conclusions: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2 and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. While, multigene panel testing may be appropriate for women with ILC, CDH1 should be specifically discussed in the context of low prevalence and attendant gastric cancer risk.

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