22 results on '"Durkie M"'
Search Results
2. Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease
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Durkie, M., Chong, J., Valluru, M.K., Harris, P.C., and Ong, A.C.M.
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urogenital system ,urologic and male genital diseases ,female genital diseases and pregnancy complications - Abstract
Purpose\ud \ud To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010–2020).\ud \ud \ud \ud Methods\ud \ud All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing.\ud \ud \ud \ud Results\ud \ud Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%).\ud \ud \ud \ud Conclusion\ud \ud We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.
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- 2021
3. SAT-334 GENETIC TESTING OF FAMILIES WITH VERY EARLY ONSET POLYCYSTIC KIDNEY DISEASE REVEALS THE FUNCTIONAL SIGNIFICANCE OF HYPOMORPHIC VARIANTS
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Durkie, M., primary, Chong, J., additional, and Ong, A., additional
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- 2019
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4. Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.
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Ellard S, Morgan S, Wynn SL, Walker S, Parrish A, Mein R, Juett A, Ahn JW, Berry I, Cassidy EJ, Durkie M, Fish L, Hall R, Howard E, Rankin J, Wright CF, Deans ZC, Scott RH, Hill SL, Baple EL, and Taylor RW
- Abstract
Purpose and Scope: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times., Methods of Statement Development: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute., Results and Conclusions: We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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5. The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification.
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Rowlands CF, Garrett A, Allen S, Durkie M, Burghel GJ, Robinson R, Callaway A, Field J, Frugtniet B, Palmer-Smith S, Grant J, Pagan J, McDevitt T, McVeigh TP, Hanson H, Whiffin N, Jones M, and Turnbull C
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- Humans, Likelihood Functions, Case-Control Studies, Phenotype, Penetrance, Genetic Predisposition to Disease, Genetic Variation
- Abstract
Background: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity., Methods: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1)., Results: PS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation., Conclusion: PS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
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- 2024
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6. Correction: EMQN best practice guidelines for genetic testing in hereditary breast and ovarian cancer.
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McDevitt T, Durkie M, Arnold N, Burghel GJ, Butler S, Claes KBM, Logan P, Robinson R, Sheils K, Wolstenholme N, Hanson H, Turnbull C, and Hume S
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- 2024
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7. Carrier testing for partners of MUTYH variant carriers: UK Cancer Genetics Group recommendations.
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McVeigh TP, Lalloo F, Monahan KJ, Latchford A, Durkie M, Mein R, Baple EL, and Hanson H
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- Humans, United Kingdom epidemiology, Genetic Carrier Screening methods, Neoplasms genetics, Genetic Testing methods, Heterozygote, Genetic Predisposition to Disease, Mutation genetics, DNA Glycosylases genetics
- Abstract
Competing Interests: Competing interests: None declared.
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- 2024
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8. Challenges in developing and implementing international best practice guidance for intermediate-risk variants in cancer susceptibility genes: APC c.3920T>A p.(Ile1307Lys) as an exemplar.
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McVeigh TP, Lalloo F, Frayling IM, Latchford A, Snape K, Durkie M, Monahan KJ, and Hanson H
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- Humans, Adenomatous Polyposis Coli Protein genetics, Neoplasms genetics, Practice Guidelines as Topic, Genetic Predisposition to Disease
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Competing Interests: Competing interests: None declared.
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- 2024
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9. The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.
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Pagnamenta AT, Yu J, Walker S, Noble AJ, Lord J, Dutta P, Hashim M, Camps C, Green H, Devaiah S, Nashef L, Parr J, Fratter C, Ibnouf Hussein R, Lindsay SJ, Lalloo F, Banos-Pinero B, Evans D, Mallin L, Waite A, Evans J, Newman A, Allen Z, Perez-Becerril C, Ryan G, Hart R, Taylor J, Bedenham T, Clement E, Blair E, Hay E, Forzano F, Higgs J, Canham N, Majumdar A, McEntagart M, Lahiri N, Stewart H, Smithson S, Calpena E, Jackson A, Banka S, Titheradge H, McGowan R, Rankin J, Shaw-Smith C, Evans DG, Burghel GJ, Smith MJ, Anderson E, Madhu R, Firth H, Ellard S, Brennan P, Anderson C, Taupin D, Rogers MT, Cook JA, Durkie M, East JE, Fowler D, Wilson L, Igbokwe R, Gardham A, Tomlinson I, Baralle D, Uhlig HH, and Taylor JC
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- Humans, Male, Female, Pedigree, Genome, Human, Whole Genome Sequencing, Methyl-CpG-Binding Protein 2 genetics, Mutation, Homeodomain Proteins genetics, Middle Aged, Rare Diseases genetics, Chromosome Inversion genetics
- Abstract
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts., Competing Interests: Declaration of interests H.H.U. declares research support or consultancy fees from Janssen, UCB Pharma, GSK, Eli Lilly, Bristol Myers Squibb BMS, OMass and Mestag. J.Y. is now employed by Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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10. Combining genotype with height-adjusted kidney length predicts rapid progression of ADPKD.
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Chen EWC, Chong J, Valluru MK, Durkie M, Simms RJ, Harris PC, and Ong ACM
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- Humans, Male, Female, Cross-Sectional Studies, Adult, Middle Aged, Prognosis, Follow-Up Studies, Body Height genetics, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology, Disease Progression, Genotype, Kidney pathology, Kidney diagnostic imaging, Glomerular Filtration Rate, TRPP Cation Channels genetics
- Abstract
Introduction: Our main objective was to identify baseline prognostic factors predictive of rapid disease progression in a large unselected clinical autosomal dominant polycystic kidney disease (ADPKD) cohort., Methods: A cross-sectional analysis was performed in 618 consecutive ADPKD patients assessed and followed-up for over a decade. A total of 123 patients (19.9%) had reached kidney failure by the study date. Data were available for the following: baseline eGFR (n = 501), genotype (n = 549), baseline ultrasound mean kidney length (MKL, n = 424) and height-adjusted baseline MKL (HtMKL, n = 377). Rapid disease progression was defined as an annualized eGFR decline (∆eGFR) of >2.5 mL/min/year by linear regression over 5 years (n = 158). Patients were further divided into slow, rapid and very rapid ∆eGFR classes for analysis. Genotyped patients were classified into several categories: PKD1 (T, truncating; or NT, non-truncating), PKD2, other genes (non-PKD1 or -PKD2), no mutation detected or variants of uncertain significance., Results: A PKD1-T genotype had the strongest influence on the probability of reduced baseline kidney function by age. A multivariate logistic regression model identified PKD1-T genotype and HtMKL (>9.5 cm/m) as independent predictors for rapid disease progression. The combination of both factors increased the positive predictive value for rapid disease progression over age 40 years and of reaching kidney failure by age 60 years to 100%. Exploratory analysis in a subgroup with available total kidney volumes showed higher positive predictive value (100% vs 80%) and negative predictive value (42% vs 33%) in predicting rapid disease progression compared with the Mayo Imaging Classification (1C-E)., Conclusion: Real-world longitudinal data confirm the importance of genotype and kidney length as independent variables determining ∆eGFR. Individuals with the highest risk of rapid disease progression can be positively selected for treatment based on this combination., (© Crown copyright 2024.)
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- 2024
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11. EMQN best practice guidelines for genetic testing in hereditary breast and ovarian cancer.
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McDevitt T, Durkie M, Arnold N, Burghel GJ, Butler S, Claes KBM, Logan P, Robinson R, Sheils K, Wolstenholme N, Hanson H, Turnbull C, and Hume S
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- Female, Humans, Breast Neoplasms genetics, Breast Neoplasms diagnosis, Genetic Predisposition to Disease, Hereditary Breast and Ovarian Cancer Syndrome genetics, Hereditary Breast and Ovarian Cancer Syndrome diagnosis, Practice Guidelines as Topic, Genetic Testing standards, Genetic Testing methods, Ovarian Neoplasms genetics, Ovarian Neoplasms diagnosis
- Abstract
Hereditary Breast and Ovarian Cancer (HBOC) is a genetic condition associated with increased risk of cancers. The past decade has brought about significant changes to hereditary breast and ovarian cancer (HBOC) diagnostic testing with new treatments, testing methods and strategies, and evolving information on genetic associations. These best practice guidelines have been produced to assist clinical laboratories in effectively addressing the complexities of HBOC testing, while taking into account advancements since the last guidelines were published in 2007. These guidelines summarise cancer risk data from recent studies for the most commonly tested high and moderate risk HBOC genes for laboratories to refer to as a guide. Furthermore, recommendations are provided for somatic and germline testing services with regards to clinical referral, laboratory analyses, variant interpretation, and reporting. The guidelines present recommendations where 'must' is assigned to advocate that the recommendation is essential; and 'should' is assigned to advocate that the recommendation is highly advised but may not be universally applicable. Recommendations are presented in the form of shaded italicised statements throughout the document, and in the form of a table in supplementary materials (Table S4). Finally, for the purposes of encouraging standardisation and aiding implementation of recommendations, example report wording covering the essential points to be included is provided for the most common HBOC referral and reporting scenarios. These guidelines are aimed primarily at genomic scientists working in diagnostic testing laboratories., (© 2024. The Author(s).)
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- 2024
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12. Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey.
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Allen S, Loong L, Garrett A, Torr B, Durkie M, Drummond J, Callaway A, Robinson R, Burghel GJ, Hanson H, Field J, McDevitt T, McVeigh TP, Bedenham T, Bowles C, Bradshaw K, Brooks C, Butler S, Del Rey Jimenez JC, Hawkes L, Stinton V, MacMahon S, Owens M, Palmer-Smith S, Smith K, Tellez J, Valganon-Petrizan M, Waskiewicz E, Yau M, Eccles DM, Tischkowitz M, Goel S, McRonald F, Antoniou AC, Morris E, Hardy S, and Turnbull C
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- Humans, Workflow, State Medicine, Genomics, United Kingdom, Laboratories, Neoplasms
- Abstract
Background: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission., Methods: In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4)., Results: Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored., Conclusion: The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation., Competing Interests: Competing interests: MD and TM have received honoraria from AstraZeneca and MSD for contributions as expert assessors in the GenQA/EMQN GTACT schemes: Ensuring accurate classification of BRCA1, BRCA2 and other HRR gene variants. ACA is the creator of BOADICEA, licensed by Cambridge Enterprise, and receives royalties from Cambridge University. TPM is a council member for the UK Cancer Genetics Group, and has received honoraria from AstraZeneca and Novartis, and consulting fees from Roche as an Expert Advisor for the National Molecular Tumour Board (Ireland). DME was co-applicant on an AstraZeneca Research Grant (2021–2023), is on the University of Southampton Executive Board and is the Non-Executive Director of UHS NHS Foundation Trust. CT has received honoraria from AstraZeneca and MSD for educational activities and scientific boards, which are donated in full to charity., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
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- 2024
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13. Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records.
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Loong L, Huntley C, McRonald F, Santaniello F, Pethick J, Torr B, Allen S, Tulloch O, Goel S, Shand B, Rahman T, Luchtenborg M, Garrett A, Barber R, Bedenham T, Bourn D, Bradshaw K, Brooks C, Bruty J, Burghel GJ, Butler S, Buxton C, Callaway A, Callaway J, Drummond J, Durkie M, Field J, Jenkins L, McVeigh TP, Mountford R, Nyanhete R, Petrides E, Robinson R, Scott T, Stinton V, Tellez J, Wallace AJ, Yarram-Smith L, Sahan K, Hallowell N, Eccles DM, Pharoah P, Tischkowitz M, Antoniou AC, Evans DG, Lalloo F, Norbury G, Morris E, Burn J, Hardy S, and Turnbull C
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- Humans, DNA Mismatch Repair genetics, Laboratories, Genomics, State Medicine, Neoplasms
- Abstract
Objective: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories., Design: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data., Results: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed., Conclusion: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry., Competing Interests: Competing interests: TPM has received grants in the last 36 months from Roche, Novartis and Hermitage Medical Group for support in educational materials, from MSD/Merck/AstraZeneca, Novartis, Iheed and RCPI for consultation as a subject matter expert, and has taken part in advisory boards for Roche, UK CGG (unpaid), Breast Cancer Now (unpaid), and Ovacare (unpaid). NH declares stock in GSK and AstraZeneca. FL has sat as an Expert Advisor for the NHSE&I Lynch Syndrome task and finish group. DE is chair of the Medical Research Council Clinical Academic Research partnership funding committee, and recipient of the Assessor Research Council of Norway Centres of Excellence Funding awards. CT has received honoraria for educational activities and advisory boards from AstraZeneca and Roche (all proceeds donated to registered charity 11511580)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2023
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14. UK recommendations for SDHA germline genetic testing and surveillance in clinical practice.
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Hanson H, Durkie M, Lalloo F, Izatt L, McVeigh TP, Cook JA, Brewer C, Drummond J, Butler S, Cranston T, Casey R, Tan T, Morganstein D, Eccles DM, Tischkowitz M, Turnbull C, Woodward ER, and Maher ER
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- Humans, Genetic Testing, Germ-Line Mutation genetics, United Kingdom, Genetic Predisposition to Disease, Electron Transport Complex II genetics, Paraganglioma genetics, Pheochromocytoma genetics, Adrenal Gland Neoplasms genetics
- Abstract
SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice., Competing Interests: Competing interests: RC has received speakers' honoraria from Novartis and Ipsen; DM has received speakers' honoraria from Roche and MSD and speakers' honoraria and consulting fees from Bristol Myers Squib., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
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- 2023
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15. Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK).
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Loong L, Garrett A, Allen S, Choi S, Durkie M, Callaway A, Drummond J, Burghel GJ, Robinson R, Torr B, Berry IR, Wallace AJ, Eccles DM, Ellard S, Baple E, Evans DG, Woodward ER, Kulkarni A, Lalloo F, Tischkowitz M, Lucassen A, Hanson H, and Turnbull C
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- Genetic Predisposition to Disease, Genetic Variation genetics, Humans, Laboratories, Genetic Testing, Neoplasms diagnosis, Neoplasms genetics
- Abstract
Purpose: Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely., Methods: Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification., Results: We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score., Conclusion: In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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16. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants.
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Loong L, Cubuk C, Choi S, Allen S, Torr B, Garrett A, Loveday C, Durkie M, Callaway A, Burghel GJ, Drummond J, Robinson R, Berry IR, Wallace A, Eccles DM, Tischkowitz M, Ellard S, Ware JS, Hanson H, and Turnbull C
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- BRCA1 Protein genetics, Codon, Genetic Predisposition to Disease, Humans, MutS Homolog 2 Protein genetics, Genetic Variation genetics, Mutation, Missense genetics
- Abstract
Purpose: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice., Methods: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset., Results: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62., Conclusion: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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17. Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.
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Garrett A, Loveday C, King L, Butler S, Robinson R, Horton C, Yussuf A, Choi S, Torr B, Durkie M, Burghel GJ, Drummond J, Berry I, Wallace A, Callaway A, Eccles D, Tischkowitz M, Tatton-Brown K, Snape K, McVeigh T, Izatt L, Woodward ER, Burnichon N, Gimenez-Roqueplo AP, Mazzarotto F, Whiffin N, Ware J, Hanson H, Pesaran T, LaDuca H, Buffet A, Maher ER, and Turnbull C
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- Germ-Line Mutation, Humans, Phenotype, Virulence, Adrenal Gland Neoplasms genetics, Adrenal Gland Neoplasms pathology, Succinate Dehydrogenase genetics
- Abstract
Purpose: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain., Methods: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features., Results: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD)., Conclusion: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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18. Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations.
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Garrett A, Durkie M, Callaway A, Burghel GJ, Robinson R, Drummond J, Torr B, Cubuk C, Berry IR, Wallace AJ, Ellard S, Eccles DM, Tischkowitz M, Hanson H, and Turnbull C
- Subjects
- Evidence-Based Medicine, Genetic Variation, Humans, Genes, Neoplasm, Genetic Predisposition to Disease genetics, Neoplasms genetics
- Abstract
Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical 'exponent score' (2) new combinations of evidence elements constituting likely pathogenic' and 'pathogenic' classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2021
- Full Text
- View/download PDF
19. Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease.
- Author
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Durkie M, Chong J, Valluru MK, Harris PC, and Ong ACM
- Subjects
- Child, Humans, Infant, Mutation, TRPP Cation Channels genetics, Exome Sequencing, Heredity, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant epidemiology, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Purpose: To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010-2020)., Methods: All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing., Results: Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%)., Conclusion: We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.
- Published
- 2021
- Full Text
- View/download PDF
20. Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network.
- Author
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Garrett A, Callaway A, Durkie M, Cubuk C, Alikian M, Burghel GJ, Robinson R, Izatt L, Talukdar S, Side L, Cranston T, Palmer-Smith S, Baralle D, Berry IR, Drummond J, Wallace AJ, Norbury G, Eccles DM, Ellard S, Lalloo F, Evans DG, Woodward E, Tischkowitz M, Hanson H, and Turnbull C
- Subjects
- Female, High-Throughput Nucleotide Sequencing, Humans, Ireland epidemiology, Male, Neoplasms epidemiology, Neoplasms pathology, United Kingdom epidemiology, Genetic Testing, Genetic Variation genetics, Genomics, Neoplasms genetics
- Abstract
Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic-high risk and benign-no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease-gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that 'national subspecialist multidisciplinary meetings' (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2020
- Full Text
- View/download PDF
21. Lineage-specific chimerism monitoring after allogeneic haematopoietic stem cell transplantation: do we really know what we are measuring?
- Author
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Watson MB, Clouston HJ, Snowden JA, Wilson G, Durkie M, Ward R, Kaur H, Travis D, and Barnett D
- Subjects
- Chimerism, Female, Humans, Male, Transplantation Conditioning mortality, Hematopoietic Stem Cell Transplantation methods, Transplantation Conditioning methods, Transplantation, Homologous methods
- Published
- 2017
- Full Text
- View/download PDF
22. Genetic testing in the assessment of living related kidney donors at risk of autosomal dominant polycystic kidney disease.
- Author
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Simms RJ, Travis DL, Durkie M, Wilson G, Dalton A, and Ong AC
- Subjects
- Adolescent, Adult, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Polycystic Kidney, Autosomal Dominant etiology, TRPP Cation Channels genetics, Tomography, X-Ray Computed, Genetic Testing, Kidney Transplantation, Living Donors, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of renal failure. In most patients who develop end-stage renal disease, transplantation is the renal replacement modality of choice. For living related kidney donation (LRKD), the major challenge is to exclude the diagnosis of ADPKD in potential donors. Renal imaging may not exclude ADPKD particularly in younger donors and molecular genetic testing is advised. We report the largest series to date evaluating the role of genetic testing for ADPKD in LRKD assessment., Methods: A cohort of patients with ADPKD and potential LRKD were referred for genetic testing for ADPKD between April 2010 and October 2012. DNA sequencing of PKD1 and PKD2 was performed. Imaging investigations and transplant outcomes after genetic testing were collected., Results: Nineteen patients and 25 potential LRKD underwent genetic testing. Of potential LRKD, one tested positive for ADPKD and one with a diagnostic ultrasound tested negative. Despite negative genetic testing, two potential LRKD were considered unsuitable because of the detection of stage I ("simple") renal cysts on computed tomography. Four living related kidney transplants have occurred, and two are planned. Three patients subsequently refused the donation as the potential donor was a child., Conclusion: Predictive genetic testing can facilitate donor evaluation and augment living related kidney transplantation in ADPKD. Psychologic challenges associated with accepting an LRKD require careful consideration during recipient assessment. The acceptability of using a kidney with cysts from a mutation-negative donor should be evaluated by a multidisciplinary team.
- Published
- 2015
- Full Text
- View/download PDF
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