114 results found
Cookson W, Nastase A, Mandal A, et al., 2021, Integrated genomics point to immune vulnerabilities in pleural mesothelioma, Scientific Reports, ISSN: 2045-2322
Guimier A, Achleitner MT, de Bellaing AM, et al., 2021, PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families, Genetics in Medicine, Pages: 1-11, ISSN: 1098-3600
PurposeBiallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants.MethodsSynthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized.ResultsAmong the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity.ConclusionWe expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.
Shoemark A, Rubbo B, Legendre M, et al., 2021, Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia, EUROPEAN RESPIRATORY JOURNAL, Vol: 58, ISSN: 0903-1936
Sepahzad A, Morris-Rosendahl D, Davies J, 2021, Cystic fibrosis lung disease modifiers and their relevance in the new era of precision medicine, Genes, Vol: 12, ISSN: 2073-4425
Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.
Fleming AG, Brett L, Wilkinson S, et al., 2020, Non-segregation of truncating TTN variants in families with dilated cardiomyopathy (DCM), Publisher: SPRINGERNATURE, Pages: 268-268, ISSN: 1018-4813
Domingo-Sabugo C, Starren E, Mandal A, et al., 2020, Distinct Landscapes of Genomic Alterations between Lung Carcinoids and Non-Small Cell Lung Cancers, Publisher: SPRINGERNATURE, Pages: 528-528, ISSN: 1018-4813
Vijayasingam A, Frost E, Wilkins J, et al., 2020, Tablet and web-based audiometry to screen for hearing loss in adults with cystic fibrosis, Thorax, Vol: 75, Pages: 632-639, ISSN: 0040-6376
INTRODUCTION: Individuals with chronic lung disease (eg, cystic fibrosis (CF)) often receive antimicrobial therapy including aminoglycosides resulting in ototoxicity. Extended high-frequency audiometry has increased sensitivity for ototoxicity detection, but diagnostic audiometry in a sound-booth is costly, time-consuming and requires a trained audiologist. This cross-sectional study analysed tablet-based audiometry (Shoebox MD) performed by non-audiologists in an outpatient setting, alongside home web-based audiometry (3D Tune-In) to screen for hearing loss in adults with CF. METHODS: Hearing was analysed in 126 CF adults using validated questionnaires, a web self-hearing test (0.5 to 4 kHz), tablet (0.25 to 12 kHz) and sound-booth audiometry (0.25 to 12 kHz). A threshold of ≥25 dB hearing loss at ≥1 audiometric frequency was considered abnormal. Demographics and mitochondrial DNA sequencing were used to analyse risk factors, and accuracy and usability of hearing tests determined. RESULTS: Prevalence of hearing loss within any frequency band tested was 48%. Multivariate analysis showed age (OR 1.127; (95% CI: 1.07 to 1.18; p value<0.0001) per year older) and total intravenous antibiotic days over 10 years (OR 1.006; (95% CI: 1.002 to 1.010; p value=0.004) per further intravenous day) were significantly associated with increased risk of hearing loss. Tablet audiometry had good usability, was 93% sensitive, 88% specific with 94% negative predictive value to screen for hearing loss compared with web self-test audiometry and questionnaires which had poor sensitivity (17% and 13%, respectively). Intraclass correlation (ICC) of tablet versus sound-booth audiometry showed high correlation (ICC >0.9) at all frequencies ≥4 kHz. CONCLUSIONS: Adults with CF have a high prevalence of drug-related hearing loss and tablet-based audiometry can be a practical, accurate screening tool within integrated ototoxicity monitoring programmes for early detection.
Morris-Rosendahl DJ, Edwards M, McDonnell MJ, et al., 2020, Whole-gene sequencing of CFTR reveals a high prevalence of the intronic variant c.3874-4522A>G in cystic fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1438-1441, ISSN: 1073-449X
Fassad MR, Patel MP, Shoemark A, et al., 2020, Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort, JOURNAL OF MEDICAL GENETICS, Vol: 57, Pages: 322-330, ISSN: 0022-2593
Olubando D, Hopton C, Eden J, et al., 2020, Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships, JOURNAL OF HUMAN GENETICS, Vol: 65, Pages: 531-539, ISSN: 1434-5161
Morris-Rosendahl DJ, Crocq M-A, 2020, Neurodevelopmental disorders-the history and future of a diagnostic concept, DIALOGUES IN CLINICAL NEUROSCIENCE, Vol: 22, Pages: 65-72, ISSN: 1294-8322
Rubbo B, Shoemark A, Legendre M, et al., 2020, Topological Data Analysis Coupled with Machine Learning Reveals New Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Yazdani MF, Morris-Rosendahl D, Chen L, et al., 2020, Images of the month 1: Cough before the storm: A case of pulmonary alveolar microlithiasis, Clinical Medicine, Vol: 20, Pages: 110-111, ISSN: 1470-2118
Shovlin CL, Morris-Rosendahl DJ, Copeland F, et al., 2019, DELIVERING THE 100,000 GENOMES PROJECT TO ESTABLISH THE FUNCTIONAL ROLE OF DNA SEQUENCE VARIANTS IN RESPIRATORY RARE DISEASES, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A44-A45, ISSN: 0040-6376
Wallmeier J, Frank D, Shoemark A, et al., 2019, De novo mutations in FOXJ1 result in a motile ciliopathy with hydrocephalus and randomization of left/right body asymmetry, American Journal of Human Genetics, Vol: 105, Pages: 1030-1039, ISSN: 0002-9297
Wilkinson SL, Edwards M, John S, et al., 2019, Complex indel variant calling in a repetitive genomic region, 52nd Conference of the European-Society-of-Human-Genetics (ESHG), Publisher: NATURE PUBLISHING GROUP, Pages: 1255-1256, ISSN: 1018-4813
Hoang L, Domingo-Sabugo C, Starren E, et al., 2019, Integrative Omics Analysis Reveals Important Roles of Adenosine Diphosphate in Haemostasis and Platelet Activation in NSCLC, Publisher: ELSEVIER SCIENCE INC, Pages: S419-S419, ISSN: 1556-0864
Mandal A, Nastase A, Lu SK, et al., 2019, Analysis of Immune Phenotype Composition in Malignant Pleural Mesothelioma (MPM) Using Bulk RNA Sequencing, Publisher: ELSEVIER SCIENCE INC, Pages: S345-S346, ISSN: 1556-0864
Domingo-Sabugo C, Starren E, Mandal A, et al., 2019, Comprehensive Molecular Profiling and Comparison of Common and Rarer Subtypes of Lung Cancer, Publisher: ELSEVIER SCIENCE INC, Pages: S686-S686, ISSN: 1556-0864
Nastase A, Mandal A, Lu SK, et al., 2019, Low Number of Mutations and Frequent Co-Deletions of CDKN2A and IFN Type I Characterize Malignant Pleural Mesothelioma, Publisher: ELSEVIER SCIENCE INC, Pages: S345-S345, ISSN: 1556-0864
Edwards M, Wilkinson S, van den Broek F, et al., 2019, Sudden cardiac death caused by bi-allelic variants in the PPA2 gene, 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Publisher: NATURE PUBLISHING GROUP, Pages: 161-161, ISSN: 1018-4813
Wilkinson S, Hodgson U, Honti F, et al., 2019, The application of targeted sequencing and whole exome analysis to identify disease-causing variants in familial pulmonary fibrosis, 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Publisher: NATURE PUBLISHING GROUP, Pages: 83-84, ISSN: 1018-4813
Vijayasingam A, Frost E, Wilkins J, et al., 2019, S140 Interim results from a prospective study of tablet and web-based audiometry to detect ototoxicity in adults with cystic fibrosis (vol 73, pg A87, 2018), THORAX, Vol: 74, Pages: 723-723, ISSN: 0040-6376
Budaj I, Gupta P, Saggar A, et al., 2019, IMAGING CARDIOVASCULAR FEATURES OF A FAMILY WITH TYPE 4 LOEYS-DIETZ SYNDROME, Annual Spring Meeting of the British-Society-of-Cardiovascular-Imaging/British-Society-of-Cardiac-Computed-Tomography (BSCI/BSCCT), Publisher: BMJ PUBLISHING GROUP, Pages: A1-A1, ISSN: 1355-6037
Vijayasingam A, Shah A, Simmonds NJ, et al., 2018, INTERIM RESULTS FROM A PROSPECTIVE STUDY OF TABLET AND WEB-BASED AUDIOMETRY TO DETECT OTOTOXICITY IN ADULTS WITH CYSTIC FIBROSIS, THORAX, Vol: 73, Pages: A87-A88, ISSN: 0040-6376
Brett L, Wilkinson SL, Monk T, et al., 2018, Mosaicism in inherited cardiac conditions detected by targeted NGS analysis, 50th European-Society-of-Human-Genetics (ESHG) Conference, Publisher: NATURE PUBLISHING GROUP, Pages: 274-275, ISSN: 1018-4813
Honti F, Beaman G, Edwards M, et al., 2018, Copy number variants account for at least 2% of non-syndromic cardiomyopathies, 50th European-Society-of-Human-Genetics (ESHG) Conference, Publisher: NATURE PUBLISHING GROUP, Pages: 105-105, ISSN: 1018-4813
Hoehe MR, Morris-Rosendahl DJ, 2018, The role of genetics and genomics in clinical psychiatry, Dialogues in Clinical Neuroscience, Vol: 20, Pages: 169-177, ISSN: 1294-8322
The enormous successes in the genetics and genomics of many diseases have provided the basis for the advancement of precision medicine. Thus, the detection of genetic variants associated with neuropsychiatric disorders, as well as treatment outcome, has raised growing expectations that these findings could soon be translated into the clinic to improve diagnosis, the prediction of disease risk and individual response to drug therapy. In this article, we will provide an introduction to the search for genes involved in psychiatric illness and summarize the present findings in major psychiatric disorders. We will review the genetic variants in genes encoding drug metabolizing enzymes and specific drug targets which were found to be associated with variable drug response and severe side effects. We will evaluate the clinical translatability of these findings, whether there is currently any role for genetic testing and in this context, make valuable sources of information available to the clinician seeking guidance and advice in this rapidly developing field of psychiatric genetics.
Whiffin N, walsh R, Govind R, et al., 2018, CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation, Genetics in Medicine, Vol: 20, Pages: 1246-1254, ISSN: 1098-3600
PurposeInternationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier (http://www.cardioclassifier.org), a semiautomated decision-support tool for inherited cardiac conditions (ICCs).MethodsCardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules.ResultsWe benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher’s P = 1.1 × 10−18), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data.ConclusionCardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines.
Mandal A, Gennatas S, Liu K, et al., 2018, Copy number variations in malignant pleural mesothelioma reveal novel regions of genomic imbalances, Publisher: ELSEVIER IRELAND LTD, Pages: S27-S27, ISSN: 0169-5002
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