Scholarly Works - Medical Genetics


Recent Submissions

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  • ItemPublished versionOpen Access
    Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
    (Elsevier BV, 2018-07-05) Whitworth, James; Smith, Philip S; Martin, Jose-Ezequiel; West, Hannah; Luchetti, Andrea; Rodger, Faye; Clark, Graeme; Carss, Keren; Stephens, Jonathan; Stirrups, Kathleen; Penkett, Chris; Mapeta, Rutendo; Ashford, Sofie; Megy, Karyn; Shakeel, Hassan; Ahmed, Munaza; Adlard, Julian; Barwell, Julian; Brewer, Carole; Casey, Ruth T; Armstrong, Ruth; Cole, Trevor; Evans, Dafydd Gareth; Fostira, Florentia; Greenhalgh, Lynn; Hanson, Helen; Henderson, Alex; Hoffman, Jonathan; Izatt, Louise; Kumar, Ajith; Kwong, Ava; Lalloo, Fiona; Ong, Kai Ren; Paterson, Joan; Park, Soo-Mi; Chen-Shtoyerman, Rakefet; Searle, Claire; Side, Lucy; Skytte, Anne-Bine; Snape, Katie; Woodward, Emma R; NIHR BioResource Rare Diseases Consortium; Tischkowitz, Marc D; Maher, Eamonn R; Whitworth, James [0000-0002-3682-2298]; Smith, Philip [0000-0002-9306-1747]; Maher, Eamonn [0000-0002-6226-6918]
    Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.
  • ItemPublished versionOpen Access
    APOBEC3A/B deletion polymorphism and cancer risk.
    (Oxford University Press, 2018-02-09) Gansmo, Liv B; Romundstad, Paal; Hveem, Kristian; Vatten, Lars; Nik-Zainal, Serena; Lønning, Per Eystein; Knappskog, Stian; Nik-Zainal Abidin, Serena [0000-0001-5054-1727]
    Activity of the apolipoprotein B mRNA editing enzyme, catalytic-polypeptide-like (APOBEC) enzymes has been linked to specific mutational processes in human cancer genomes. A germline APOBEC3A/B deletion polymorphism is associated with APOBEC-dependent mutational signatures, and the deletion allele has been reported to confer an elevated risk of some cancers in Asian populations, while the results in European populations, so far, have been conflicting. We genotyped the APOBEC3A/B deletion polymorphism in a large population-based sample consisting of 11 106 Caucasian (Norwegian) individuals, including 7279 incident cancer cases (1769 breast, 1360 lung, 1585 colon, and 2565 prostate cancer) and a control group of 3827 matched individuals without cancer (1918 females and 1909 males) from the same population. Overall, the APOBEC3A/B deletion polymorphism was not associated with risk of any of the four cancer types. However, in subgroup analyses stratified by age, we found that the deletion allele was associated with increased risk for lung cancer among individuals <50 years of age (OR 2.17, CI 1.19-3.97), and that the association was gradually reduced with increasing age (P = 0.01). A similar but weaker pattern was observed for prostate cancer. In support of these findings, the APOBEC3A/B deletion was associated with young age at diagnosis among the cancer cases for both cancer forms (lung cancer: P = 0.02; dominant model and prostate cancer: P = 0.03; recessive model). No such associations were observed for breast or colon cancer.
  • ItemPublished versionOpen Access
    Wars2 is a determinant of angiogenesis.
    (Springer Science and Business Media LLC, 2016-07-08) Wang, Mao; Sips, Patrick; Khin, Ester; Rotival, Maxime; Sun, Ximing; Ahmed, Rizwan; Widjaja, Anissa Anindya; Schafer, Sebastian; Yusoff, Permeen; Choksi, Pervinder Kaur; Ko, Nicole Shi Jie; Singh, Manvendra K; Epstein, David; Guan, Yuguang; Houštěk, Josef; Mracek, Tomas; Nuskova, Hana; Mikell, Brittney; Tan, Jessie; Pesce, Francesco; Kolar, Frantisek; Bottolo, Leonardo; Mancini, Massimiliano; Hubner, Norbert; Pravenec, Michal; Petretto, Enrico; MacRae, Calum; Cook, Stuart A; Sips, Patrick [0000-0001-9241-5980]; Pesce, Francesco [0000-0002-2882-4226]; Bottolo, Leonardo [0000-0002-6381-2327]
    Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo. Here we exploit this relationship and show that CF in the rat is influenced by a locus on rat chromosome 2 that is also associated with cardiac capillary density. Mitochondrial tryptophanyl-tRNA synthetase (Wars2), encoding an L53F protein variant within the ATP-binding motif, is prioritized as the candidate at the locus by integrating genomic data sets. WARS2(L53F) has low enzyme activity and inhibition of WARS2 in endothelial cells reduces angiogenesis. In the zebrafish, inhibition of wars2 results in trunk vessel deficiencies, disordered endocardial-myocardial contact and impaired heart function. Inhibition of Wars2 in the rat causes cardiac angiogenesis defects and diminished cardiac capillary density. Our data demonstrate a pro-angiogenic function for Wars2 both within and outside the heart that may have translational relevance given the association of WARS2 with common human diseases.
  • ItemAccepted versionOpen Access
    Expression QTLs Mapping and Analysis: A Bayesian Perspective.
    (Springer New York, 2017) Imprialou, Martha; Petretto, Enrico; Bottolo, Leonardo; Bottolo, Leonardo [0000-0002-6381-2327]
    The aim of expression Quantitative Trait Locus (eQTL) mapping is the identification of DNA sequence variants that explain variation in gene expression. Given the recent yield of trait-associated genetic variants identified by large-scale genome-wide association analyses (GWAS), eQTL mapping has become a useful tool to understand the functional context where these variants operate and eventually narrow down functional gene targets for disease. Despite its extensive application to complex (polygenic) traits and disease, the majority of eQTL studies still rely on univariate data modeling strategies, i.e., testing for association of all transcript-marker pairs. However these "one at-a-time" strategies are (1) unable to control the number of false-positives when an intricate Linkage Disequilibrium structure is present and (2) are often underpowered to detect the full spectrum of trans-acting regulatory effects. Here we present our viewpoint on the most recent advances on eQTL mapping approaches, with a focus on Bayesian methodology. We review the advantages of the Bayesian approach over frequentist methods and provide an empirical example of polygenic eQTL mapping to illustrate the different properties of frequentist and Bayesian methods. Finally, we discuss how multivariate eQTL mapping approaches have distinctive features with respect to detection of polygenic effects, accuracy, and interpretability of the results.
  • ItemOpen Access
    Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management.
    (Springer Science and Business Media LLC, 2018-12) Maher, Eamonn R; Maher, Eamonn R [0000-0002-6226-6918]
    PURPOSE: Genetic factors have been implicated in the pathogenesis of renal cell carcinoma (RCC), with around 3% of cases having a family history. A greater knowledge of the genetics of inherited RCC has the potential to translate into novel therapeutic targets for sporadic RCC. METHODS: A literature review was performed summarising the current knowledge on hereditary RCC diagnosis, surveillance and management. RESULTS: Familial RCC is usually inherited in an autosomal dominant manner, although inherited RCC may present without a relevant family history. A number of familial RCC syndromes have been identified. Familial non-syndromic RCC is suspected when ≥ 2 relatives are affected in the absence of syndromic features, although clear diagnostic criteria are lacking. Young age at onset and bilateral/multicentric tumours are recognised characteristics which should prompt molecular genetic analysis. Surveillance in individuals at risk of inherited RCC aims to prevent morbidity and mortality via early detection of tumours. Though screening and management guidelines for some inherited RCC syndromes (e.g. von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis) are well defined for rare cause of inherited RCC (e.g. germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities. CONCLUSION: Increasing knowledge of the natural history and genetic basis has led to characterisation and tailored management of hereditary RCC syndromes. International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis, surveillance protocols and management of these rare conditions.
  • ItemPublished versionOpen Access
    APOE and ACE polymorphisms and dementia risk in the older population over prolonged follow-up: 10 years of incidence in the MRC CFA Study.
    (Oxford University Press (OUP), 2010-01) Keage, HAD; Matthews, FE; Yip, A; Gao, L; McCracken, C; McKeith, IG; Rubinsztein, DC; Brayne, C; MRC Cognitive Function and Ageing Study; Matthews, Fiona [0000-0002-1728-2388]; Gao, Lu [0000-0003-3353-1855]; Rubinsztein, David [0000-0001-5002-5263]; Brayne, Carol [0000-0001-5307-663X]
    BACKGROUND: dementia risk conferred by apolipoprotein-E (APOE) and angiotensin-1-converting enzyme (ACE) polymorphisms have been reported for the MRC Cognitive Function and Ageing Study (CFAS) at 6-year follow-up. We concentrate on incident dementia risk over 10 years. METHODS: participants come from MRC CFAS, a multi-centre longitudinal population-based study of ageing in England and Wales. Three follow-up waves of data collection were used: 2, 6 and 10 years. Logistic regressions were undertaken to investigate associations between APOE (n = 955) and ACE (n = 856) alleles/genotypes and incident dementia. Two types of control groups were used: non-demented and highly functioning non-demented. Results were back-weighted. RESULTS: compared to APOE epsilon3, epsilon2 conferred protection of odds ratio (OR) = 0.3 (95% confidence interval, CI = 0.1-0.6) and epsilon4 risk of OR = 2.9 (95% CI = 1.7-4.9) for incident dementia. Compared to epsilon3/epsilon3, the epsilon3/epsilon4 and epsilon4/epsilon4 genotypes conferred risks of OR = 3.6 (95% CI = 1.8-7.3) and OR = 7.9 (95% CI = 1.6-39.2), respectively. The epsilon3/epsilon2 genotype protected against dementia (OR = 0.2, 95% CI = 0.1-0.7), and epsilon2/epsilon2 had a similar protective effect but with wide CIs (OR = 0.3, 95% CI = 0.1-1.7). Restricting the control group accentuated these differentials. The effects of ACE alleles/genotypes on incident dementia risk were small. CONCLUSIONS: APOE but not ACE is associated with late-onset incident dementia in the population. Using longer term follow-up with proper adjustment for attrition and incident cases increases estimates of risk.
  • ItemPublished versionOpen Access
    Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.
    (Springer Science and Business Media LLC, 2018-04) Brioude, Frédéric; Kalish, Jennifer M; Mussa, Alessandro; Foster, Alison C; Bliek, Jet; Ferrero, Giovanni Battista; Boonen, Susanne E; Cole, Trevor; Baker, Robert; Bertoletti, Monica; Cocchi, Guido; Coze, Carole; De Pellegrin, Maurizio; Hussain, Khalid; Ibrahim, Abdulla; Kilby, Mark D; Krajewska-Walasek, Malgorzata; Kratz, Christian P; Ladusans, Edmund J; Lapunzina, Pablo; Le Bouc, Yves; Maas, Saskia M; Macdonald, Fiona; Õunap, Katrin; Peruzzi, Licia; Rossignol, Sylvie; Russo, Silvia; Shipster, Caroleen; Skórka, Agata; Tatton-Brown, Katrina; Tenorio, Jair; Tortora, Chiara; Grønskov, Karen; Netchine, Irène; Hennekam, Raoul C; Prawitt, Dirk; Tümer, Zeynep; Eggermann, Thomas; Mackay, Deborah JG; Riccio, Andrea; Maher, Eamonn R; Maher, Eamonn [0000-0002-6226-6918]
    Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
  • ItemAccepted versionOpen Access
    Penetrance estimates for BRCA1, BRCA2 (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?
    (BMJ, 2018-07) Evans, D Gareth; Woodward, Emma; Harkness, Elaine F; Howell, Anthony; Plaskocinska, Inga; Maher, Eamonn R; Tischkowitz, Marc D; Lalloo, Fiona; Evans, D Gareth [0000-0002-8482-5784]; Maher, Eamonn R [0000-0002-6226-6918]
    PURPOSE: The identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive. METHODS: We assessed the penetrance of BRCA1, BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1/BRCA2. RESULTS: Using results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1, 60% (95% CI 49% to 71%) for BRCA2, 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2. There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1. CONCLUSION: We describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases.
  • ItemAccepted versionOpen Access
    Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases.
    (Elsevier BV, 2019-02) Ejlerskov, Patrick; Ashkenazi, Avraham; Rubinsztein, David C; Rubinsztein, David [0000-0001-5002-5263]
    Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins that are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy-independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such diseases. Here we review studies in vertebrate models using genetic manipulations of core autophagy genes and describe how these improve pathology and neurodegeneration, supporting the validity of autophagy upregulation as a target for certain neurodegenerative diseases.
  • ItemPublished versionOpen Access
    The use of panel testing in familial breast and ovarian cancer.
    (Royal College of Physicians, 2017-12) Prapa, Matina; Solomons, Joyce; Tischkowitz, Marc; Tischkowitz, Marc [0000-0002-7880-0628]
    Advances in sequencing technology have led to the introduction of panel testing in hereditary breast and ovarian cancer. While direct-to-consumer testing services have become widely available, the clinical validity of many of the genes on panel tests remains contentious and risk management guidelines are often lacking. This article gives an overview of advantages with panel testing as well as important challenges, including clinical translation of test results.
  • ItemAccepted versionOpen Access
    Functionally Conserved Noncoding Regulators of Cardiomyocyte Proliferation and Regeneration in Mouse and Human
    (American Heart Association, 2018-02) Adamowicz, Martyna; Morgan, Claire C; Haubner, Bernhard J; Noseda, Michela; Collins, Melissa J; Paiva, Marta Abreu; Srivastava, Prashant K; Gellert, Pascal; Razzaghi, Bonnie; O'Gara, Peter; Raina, Priyanka; Game, Laurence; Bottolo, Leonardo; Schneider, Michael D; Harding, Sian E; Penninger, Josef; Aitman, Timothy J; Bottolo, Leonardo [0000-0002-6381-2327]
    BACKGROUND: The adult mammalian heart has little regenerative capacity after myocardial infarction (MI), whereas neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI. METHODS AND RESULTS: Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA (miRNA) expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and noncoding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two-thirds of each of the messenger RNAs, long noncoding RNAs, and miRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these miRNAs, miR-144-3p, miR-195a-5p, miR- 451a, and miR-6240 showed evidence of functional conservation in human cardiomyocytes. CONCLUSIONS: The sets of messenger RNAs, miRNAs, and long noncoding RNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.
  • ItemPublished versionOpen Access
    Clinical implications of germline mutations in breast cancer genes: RECQL.
    (Springer Science and Business Media LLC, 2019-04) Bowden, A Ramsay; Tischkowitz, Marc; Bowden, Anne [0000-0003-1138-4452]; Tischkowitz, Marc [0000-0002-7880-0628]
    BACKGROUND: The identification of new hereditary breast cancer genes is an area of highly active research. In 2015, two independent studies provided initial evidence for a novel breast cancer susceptibility gene, RECQL, a DNA helicase which plays an important role in the DNA damage response. Several subsequent studies in independent patient cohorts have provided further data on RECQL variant frequency in additional populations, some of which have brought in to question the increased breast cancer risk associated with RECQL mutations. RESULTS: The initial reports present findings from whole exome sequencing of high-risk familial breast cancer cases in the French-Canadian, Polish and Han Chinese populations and estimate the carrier frequency of pathogenic RECQL mutations in high-risk breast cancer patients who have previously tested negative for BRCA1 and BRCA2 mutations to be approximately 1-2%. Proposed founder mutations were identified in French-Canadian and Polish populations. Functional studies support loss of function of the helicase activity of RECQL for some of the reported pathogenic mutations. An additional study in a cohort of Southern Chinese high-risk breast cancer patients estimated the frequency of pathogenic RECQL mutations to be 0.54%. A possible Chinese founder mutation was identified, but only a small number of controls were sequenced. Subsequent case-control studies screening for the Polish founder mutation in patients from Germany and Belarus did not find any evidence for increased breast cancer risk for this variant. An Australian case-control study also failed to identify an increased risk of breast cancer associated with RECQL loss of function variants. CONCLUSIONS: RECQL plays an important role in DNA repair, and is a plausible candidate breast cancer susceptibility gene. Initial studies showed evidence of an association between variants in this gene and an increased breast cancer risk in three separate populations, and identified founder mutations with significantly increased odds ratios. However, several subsequent studies have failed to support the association. With the limited and conflicting evidence available, there remains debate as to whether there is an increased breast cancer risk in individuals carrying RECQL loss of function variants. Further studies are required to better quantify the risks associated with RECQL variants and the current evidence base is not sufficient to justify routine inclusion of RECQL on breast cancer gene panels in clinical use. Management of patients in whom RECQL variants have been identified should be based on clinician assessment, in the context of the family history. Further studies are required to better quantify the risks to RECQL mutation carriers and may also guide management and potential therapeutic targeting for patients.
  • ItemAccepted versionOpen Access
    p.Val804Met, the Most Frequent Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid Cancer.
    (The Endocrine Society, 2018-11-01) Loveday, Chey; Josephs, Katherine; Chubb, Daniel; Gunning, Adam; Izatt, Louise; Tischkowitz, Marc; Ellard, Sian; Turnbull, Clare; Tischkowitz, Marc [0000-0002-7880-0628]
    CONTEXT: To date, penetrance figures for medullary thyroid cancer (MTC) for variants in rearranged during transfection (RET) have been estimated from families ascertained because of the presence of MTC. OBJECTIVE: To gain estimates of penetrance, unbiased by ascertainment, we analyzed 61 RET mutations assigned as disease causing by the American Thyroid Association (ATA) in population whole-exome sequencing data. DESIGN: For the 61 RET mutations, we used analyses of the observed allele frequencies in ∼51,000 individuals from the Exome Aggregation Consortium (ExAC) database that were not contributed via The Cancer Genome Atlas (TCGA; non-TCGA ExAC), assuming lifetime penetrance for MTC of 90%, 50%, and unbounded. SETTING: Population-based. RESULTS: Ten of 61 ATA disease-causing RET mutations were present in the non-TCGA ExAC population with observed frequency consistent with penetrance for MTC of >90%. For p.Val804Met, the lifetime penetrance for MTC, estimated from the allele frequency observed, was 4% [95% confidence interval (CI), 0.9% to 8%]. CONCLUSIONS: Based on penetrance analysis in carrier relatives of p.Val804Met-positive cases of MTC, p.Val804Met is currently understood to have high-lifetime penetrance for MTC (87% by age 70), albeit of later onset of MTC than other RET mutations. Given our unbiased estimate of penetrance for RET p.Val804Met of 4% (95% CI, 0.9% to 8%), the current recommendation by the ATA of prophylactic thyroidectomy as standard for all RET mutation carriers is likely inappropriate.
  • ItemPublished versionOpen Access
    pedigreejs: a web-based graphical pedigree editor.
    (Oxford University Press (OUP), 2018-03-15) Carver, Tim; Cunningham, Alex P; Babb de Villiers, Chantal; Lee, Andrew; Hartley, Simon; Tischkowitz, Marc; Walter, Fiona M; Easton, Douglas F; Antoniou, Antonis C; Cunningham, Alex [0000-0002-3737-9611]; Babb, Chantal Louiza [0000-0003-1334-1819]; Lee, Andrew [0000-0003-0677-0252]; Tischkowitz, Marc [0000-0002-7880-0628]; Walter, Fiona [0000-0002-7191-6476]; Easton, Douglas [0000-0003-2444-3247]; Antoniou, Antonis [0000-0001-9223-3116]
    MOTIVATION: The collection, management and visualization of clinical pedigree (family history) data is a core activity in clinical genetics centres. However, clinical pedigree datasets can be difficult to manage, as they are time consuming to capture, and can be difficult to build, manipulate and visualize graphically. Several standalone graphical pedigree editors and drawing applications exist but there are no freely available lightweight graphical pedigree editors that can be easily configured and incorporated into web applications. RESULTS: We developed 'pedigreejs', an interactive graphical pedigree editor written in JavaScript, which uses standard pedigree nomenclature. Pedigreejs provides an easily configurable, extensible and lightweight pedigree editor. It makes use of an open-source Javascript library to define a hierarchical layout and to produce images in scalable vector graphics (SVG) format that can be viewed and edited in web browsers. AVAILABILITY AND IMPLEMENTATION: The software is freely available under GPL licence ( CONTACT: SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
  • ItemPublished versionOpen Access
    The RAB11A-Positive Compartment Is a Primary Platform for Autophagosome Assembly Mediated by WIPI2 Recognition of PI3P-RAB11A.
    (Elsevier BV, 2018-04-09) Puri, Claudia; Vicinanza, Mariella; Ashkenazi, Avraham; Gratian, Matthew J; Zhang, Qifeng; Bento, Carla F; Renna, Maurizio; Menzies, Fiona M; Rubinsztein, David C; Rubinsztein, David [0000-0001-5002-5263]
    Autophagy is a critical pathway that degrades intracytoplasmic contents by engulfing them in double-membraned autophagosomes that are conjugated with LC3 family members. These membranes are specified by phosphatidylinositol 3-phosphate (PI3P), which recruits WIPI2, which, in turn, recruits ATG16L1 to specify the sites of LC3-conjugation. Conventionally, phosphatidylinositides act in concert with other proteins in targeting effectors to specific membranes. Here we describe that WIPI2 localizes to autophagic precursor membranes by binding RAB11A, a protein that specifies recycling endosomes, and that PI3P is formed on RAB11A-positive membranes upon starvation. Loss of RAB11A impairs the recruitment and assembly of the autophagic machinery. RAB11A-positive membranes are a primary direct platform for canonical autophagosome formation that enables autophagy of the transferrin receptor and damaged mitochondria. While this compartment may receive membrane inputs from other sources to enable autophagosome biogenesis, RAB11A-positive membranes appear to be a compartment from which autophagosomes evolve.
  • ItemPublished versionOpen Access
    Consensus for genes to be included on cancer panel tests offered by UK genetics services: guidelines of the UK Cancer Genetics Group.
    (BMJ, 2018-06) Taylor, Amy; Brady, Angela F; Frayling, Ian M; Hanson, Helen; Tischkowitz, Marc; Turnbull, Clare; Side, Lucy; UK Cancer Genetics Group (UK-CGG); Taylor, Amy [0000-0001-9811-330X]
    Genetic testing for hereditary cancer predisposition has evolved rapidly in recent years with the discovery of new genes, but there is much debate over the clinical utility of testing genes for which there are currently limited data regarding the degree of associated cancer risk. To address the discrepancies that have arisen in the provision of these tests across the UK, the UK Cancer Genetics Group facilitated a 1-day workshop with representation from the majority of National Health Service (NHS) clinical genetics services. Using a preworkshop survey followed by focused discussion of genes without prior majority agreement for inclusion, we achieved consensus for panels of cancer genes with sufficient evidence for clinical utility, to be adopted by all NHS genetics services. To support consistency in the delivery of these tests and advice given to families across the country, we also developed management proposals for individuals who are found to have pathogenic mutations in these genes. However, we fully acknowledge that the decision regarding what test is most appropriate for an individual family rests with the clinician, and will depend on factors including specific phenotypic features and the family structure.
  • ItemPublished versionOpen Access
    A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model.
    (2018-02-13) McEwan, Phil; Bennett Wilton, Hayley; Ong, Albert CM; Ørskov, Bjarne; Sandford, Richard; Scolari, Francesco; Cabrera, Maria-Cristina V; Walz, Gerd; O'Reilly, Karl; Robinson, Paul; Ong, Albert CM [0000-0002-7211-5400]; Sandford, Richard [0000-0002-7437-0560]
  • ItemAccepted versionOpen Access
    Whole exome sequencing study to detect germline pathogenic variants in PALB2 and other cancer-predisposing genes in CDH1 mutation negative diffuse gastric cancer families.
    Tischkowitz, MDK; Tischkowitz, Marc [0000-0002-7880-0628]
    Background: Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer (HDGC) syndrome. The risk assessment and management of HDGC families that do not carry a CDH1 variant is limited. It is therefore difficult for such families to make informed choices about surveillance and risk reducing surgery. This study aimed to identify new candidate genes for HDGC predisposition in families with no detected pathogenic CDH1 variants (CDH1-NPV). Methods: Whole exome sequencing (WES) was performed on DNA extracted from blood obtained as part of the Familial Gastric Cancer Study. Analysis was performed across 39 individuals (28 affected and 11 unaffected) from 22 CDH1-NPV families that fulfil the international criteria for HDGC. Genes with loss-of-function variants were prioritised using gene interaction analysis to identify clusters of genes that could be involved in HDGC predisposition. Findings: Protein-affecting germline variants were identified in known cancer predisposition genes or lesser studied DNA repair genes in six HDGC families. A frameshift deletion within PALB2 was found in a family with a history of gastric and breast cancer. Two MSH2 variants were identified, one frameshift insertion and one previously described start loss, in unrelated affected individuals. One family was identified with a unique combination of variants in DNA repair genes ATR and NBN. A missense variant and a splice acceptor variant were seen in two unrelated families in DNA repair gene RECQL5. Interpretation: This study supports the role of known cancer predisposition gene PALB2 in the HDGC syndrome. It also puts forward new candidates in relation to HDGC risk within CDH1-NPV families. Funding: This work has been funded and supported by the UK Medical Research Council (MRC)/Sackler programme, the European Union Seventh Framework Program (2007–2013)/European Research Council (310018), the National Institute for Health Research Cambridge Biomedical Research Centre and the Experimental Cancer Medicine Centre and Cancer Research UK.
  • ItemAccepted versionOpen Access
    RIPK1 promotes inflammation and β-amyloid accumulation in Alzheimer's disease.
    (Proceedings of the National Academy of Sciences, 2017-10-10) Rubinsztein, David C; Rubinsztein, David [0000-0001-5002-5263]
    Alzheimer’s disease (AD), the leading cause of dementia, is a major cause of death and a significant economic burden. In 2016, ∼700,000 Americans aged 65 and over died of AD, and the total health and social care payments for AD in the United States alone exceeded $230 billion (1). Currently, there are no validated disease-modifying therapies that slow the progression of human AD.
  • ItemAccepted versionOpen Access
    Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.
    (Oxford University Press (OUP), 2018-07-01) Nahorski, Michael S; Maddirevula, Sateesh; Ishimura, Ryosuke; Alsahli, Saud; Brady, Angela F; Begemann, Anaïs; Mizushima, Tsunehiro; Guzmán-Vega, Francisco J; Obata, Miki; Ichimura, Yoshinobu; Alsaif, Hessa S; Anazi, Shams; Ibrahim, Niema; Abdulwahab, Firdous; Hashem, Mais; Monies, Dorota; Abouelhoda, Mohamed; Meyer, Brian F; Alfadhel, Majid; Eyaid, Wafa; Zweier, Markus; Steindl, Katharina; Rauch, Anita; Arold, Stefan T; Woods, C Geoffrey; Komatsu, Masaaki; Alkuraya, Fowzan S; Woods, Geoff [0000-0002-8077-2101]
    The post-translational modification of proteins through the addition of UFM1, also known as ufmylation, plays a critical developmental role as revealed by studies in animal models. The recent finding that biallelic mutations in UBA5 (the E1-like enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation in human brain development. More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation. This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins. Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.