Filters








1,826 Hits in 3.3 sec

Genomic variant sharing: a position statement

Caroline F. Wright, James S. Ware, Anneke M. Lucassen, Alison Hall, Anna Middleton, Nazneen Rahman, Sian Ellard, Helen V. Firth
2019 Wellcome Open Research  
Sharing de-identified genetic variant data via custom-built online repositories is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, population controls and correlation with clinical context and family history. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate
more » ... r missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of de-identified genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of genetic variants per individual, associated with limited clinical information, should become standard practice in genomic medicine. Information confirming or refuting the role of genetic variants in specific conditions is fundamental scientific knowledge from which everyone has a right to benefit, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for individual clinical interpretation, it may be more appropriate to use a controlled-access model for such data sharing, with the ultimate aim of making as much information available as possible with appropriate governance.
doi:10.12688/wellcomeopenres.15090.2 fatcat:dqqf3n3i2vbw7htkjbpg2qu67q

Genomic variant sharing: a position statement

Caroline F. Wright, James S. Ware, Anneke M. Lucassen, Alison Hall, Anna Middleton, Nazneen Rahman, Sian Ellard, Helen V. Firth
2019 Wellcome Open Research  
Sharing de-identified genetic variant data is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, as well as population controls. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of
more » ... aring individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of pseudonomised genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of individual genetic variants associated with limited clinical information should become standard practice in genomic medicine. Information robustly linking genetic variants with specific conditions is fundamental biological knowledge, not personal information, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for clinical interpretation, it may be more appropriate to use a controlled-access model for data sharing, with the ultimate aim of making as much information as open and de-identified as possible with appropriate consent.
doi:10.12688/wellcomeopenres.15090.1 pmid:31886409 pmcid:PMC6913213 fatcat:4zm7tkbgebao3bjts3ckhlxa7a

IMPROVE-DD: Integrating Multiple Phenotype Resources Optimises Variant Evaluation in genetically determined Developmental Disorders [article]

Stuart Aitken, Helen V Firth, Caroline F Wright, Matthew E Hurles, David R FitzPatrick, Colin A. Semple
2022 medRxiv   pre-print
SummaryDiagnosing rare developmental disorders using genome-wide sequencing data commonly necessitates review of multiple plausible candidate variants, often using ontologies of categorical clinical terms. We show that Integrating Multiple Phenotype Resources Optimises Variant Evaluation in Developmental Disorders (IMPROVE-DD) by incorporating additional classes of data commonly available to clinicians and recorded in health records. In doing so, we quantify the distinct contributions of
more » ... growth, and development in addition to Human Phenotype Ontology (HPO) terms, and demonstrate added value from these readily-available information sources. We use likelihood ratios for nominal and quantitative data and propose a novel classifier for HPO terms in this framework. This Bayesian framework results in more robust diagnoses. Using data systematically collected in the DDD study, we considered 77 genes with pathogenic/likely pathogenic variants in >10 probands. All genes showed at least a satisfactory prediction by ROC when testing on training data (AUC≥0.6), and HPO terms were the best individual predictor for the majority of genes, though a minority (13/77) of genes were better predicted by other phenotypic data types. Overall, classifiers based upon multiple integrated phenotypic data sources performed better than those based upon any individual source, and importantly, integrated models produced notably fewer false positives. Finally, we show that IMPROVE-DD models with good predictive performance on cross-validation can be constructed from relatively few cases. This suggests new strategies for candidate gene prioritisation, and highlights the value of systematic clinical data collection to support diagnostic programmes.
doi:10.1101/2022.05.20.22275135 fatcat:zpfoliuxzzcf3k6vll2fsa54xe

Returning genome sequences to research participants: Policy and practice

Caroline F. Wright, Anna Middleton, Jeffrey C. Barrett, Helen V. Firth, David R. FitzPatrick, Matthew Hurles, Michael Parker
2017 Wellcome Open Research  
Barrett 1, Helen V. Firth 1,2, David R.  ...  Lappalainen I, Almeida-King J, Kumanduri V, et al.: The European Genome- 6.  ... 
doi:10.12688/wellcomeopenres.10942.1 pmid:28317033 pmcid:PMC5351846 fatcat:3wc6ajhgc5bn5du77ubbjjp36u

Systematic assessment of outcomes following a genetic diagnosis identified through a large-scale research study into developmental disorders [article]

Harriet Copeland, Emma Kivuva, Helen V Firth, Caroline F Wright
2020 biorxiv/medrxiv   pre-print
Purpose The clinical and psychosocial outcomes associated with receiving a genetic diagnosis for developmental disorders are wide-ranging but under-studied. We sought to investigate outcomes from a subset of families who received a diagnosis through the Deciphering Developmental Disorders (DDD) study. Method Individuals recruited through the Peninsula Clinical Genetics Service who received a confirmed genetic diagnosis through the DDD study before August 2019 (n=112) were included in a clinical
more » ... audit. Families with no identified clinical outcomes (n=16) were invited to participate in semi-structured telephone interviews. Results Disease-specific treatment was identified for seven probands (6%), while 48 probands (43%) were referred for further investigations or screening and 60 probands (54%) were recruited to further research. Just five families (4%) opted for prenatal testing in a subsequent pregnancy, reflecting the relatively advanced maternal age in our cohort, and 42 families (38%) were given disease-specific information or signposting to patient-specific resources such as support groups. Six interviews were performed (response rate=47%) and thematic analysis identified four major themes: reaching a diagnosis, emotional impact, family implications and practical issues. Conclusions Our data demonstrate that receiving a genetic diagnosis has substantial positive medical and psychosocial outcomes for the majority of patients and their families.
doi:10.1101/2020.10.23.20213157 fatcat:7xsulni3lfg2zd2z44hxf77en4

De novo mutations in regulatory elements cause neurodevelopmental disorders [article]

Patrick J Short, Jeremy F McRae, Giuseppe Gallone, Alejandro Sifrim, Hyejung Won, Daniel H Geschwind, Caroline F Wright, Helen V Firth, David R FitzPatrick, Jeffrey C Barrett, Matthew E Hurles
2017 bioRxiv   pre-print
De novo mutations in hundreds of different genes collectively cause 25-42% of severe developmental disorders (DD). The cause in the remaining cases is largely unknown. The role of de novo mutations in regulatory elements affecting known DD-associated genes or other genes is essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 DD patients. Here we show that de novo mutations in highly conserved fetal-brain active elements are
more » ... nificantly and specifically enriched in neurodevelopmental disorders. We identified a significant two-fold enrichment of recurrently mutated elements. We estimate that, genome-wide, de novo mutations in fetal-brain active elements are likely to be causal for 1-3% of patients without a diagnostic coding variant and that only a small fraction (<2%) of de novo mutations in these elements are pathogenic. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasise the importance of combining functional and evolutionary evidence to delineate regulatory causes of genetic disorders.
doi:10.1101/112896 fatcat:jvukajgnszhb5huskswrlzu76e

Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study [article]

Ruth Y Eberhardt, Caroline F Wright, David R FitzPatrick, Matthew E Hurles, Helen V Firth
2022 medRxiv   pre-print
Purpose Structural mosaicism has been previously implicated in developmental disorders. We aim to identify rare mosaic chromosomal alterations (MCAs) in probands with severe undiagnosed developmental disorders. Methods We identified MCAs in SNP array data from 12,530 probands in the Deciphering Developmental Disorders (DDD) study using MoChA. Results We found 61 MCAs in 57 probands, many of these were tissue specific. In 23/26 (88.5%) cases for which the MCA was detected in saliva where blood
more » ... s also available for analysis, the MCA could not be detected in blood. The MCAs included 20 polysomies, comprising either one arm of a chromosome or a whole chromosome, for which we were able to show the timing of the error (25% mitosis, 40% meiosis I, 35% meiosis II). Only 2/57 (3.5%) of the probands in whom we found MCAs had another likely genetic diagnosis identified by whole exome sequencing, despite an overall diagnostic yield of ~40% across the cohort. Conclusion Our results show that identification of MCAs provides candidate diagnoses for previously undiagnosed patients with developmental disorders, potentially explaining ~0.45% of cases in the DDD study. Nearly 90% of these MCAs would have remained undetected by analysing DNA from blood and no other tissue.
doi:10.1101/2022.03.28.22273024 fatcat:orwe7rfxnzc5xaw7h6uknbieju

Exome-wide assessment of the functional impact and pathogenicity of multi-nucleotide mutations [article]

Joanna Kaplanis, Nadia Akawi, Giuseppe Gallone, Jeremy F McRae, Elena Prigmore, Caroline F Wright, David R Fitzpatrick, Helen V Firth, Jeffrey C Barrett, Matthew E Hurles
2018 bioRxiv   pre-print
However two-step missense MNVs 8 could also lead to an additional eleven amino acids that could not be achieved by 9 an SNV (F,S,C,I,T,K,S,V,A,E,G).  ...  V. Biankin, G. R. Bignell, N. Bolli, A. Borg, A. L. Borresen-Dale, S. Boyault, B. Puente, K. Raine, M. Ramakrishna, A. L. Richardson, J. Richter, P. Rosenstiel, M. Schlesner, T. N.  ... 
doi:10.1101/258723 fatcat:mspxiz5x7feiljzuyizx7hcqz4

Potential research participants support the return of raw sequence data

Anna Middleton, Caroline F Wright, Katherine I Morley, Eugene Bragin, Helen V Firth, Matthew E Hurles, Michael Parker
2015 Journal of Medical Genetics  
on behalf of the DDD study ▸ Additional material is published online only. To view please visit the journal online (http://dx. ABSTRACT Health-related results that are discovered in the process of genomic research should only be returned to research participants after being clinically validated and then delivered and followed up within a health service. Returning such results may be difficult for genomic researchers who are limited by resources or unable to access appropriate clinicians. Raw
more » ... uence data could, in theory, be returned instead. This might appear nonsensical as, on its own, it is a meaningless code with no clinical value. Yet, as and when direct to consumer genomics services become more widely available (and can be endorsed by independent health professionals and genomic researchers alike), the return of such data could become a realistic proposition. We explore attitudes from <7000 members of the public, genomic researchers, genetic health professionals and non-genetic health professionals and ask participants to suggest what they would do with a raw sequence, if offered it. Results show 62% participants were interested in using it to seek out their own clinical interpretation. Whilst we do not propose that raw sequence data should be returned at the moment, we suggest that should this become feasible in the future, participants of sequencing studies may possibly support this.
doi:10.1136/jmedgenet-2015-103119 pmid:25995218 pmcid:PMC4518751 fatcat:i3yooznaevdxfo64epfchi4piu

Novel compound heterozygous STN1 variants are associated with Coats Plus syndrome

Tanvi Acharya, Helen V. Firth, Shilpa Dugar, Tassos Grammatikopoulos, Luis Seabra, Angharad Walters, Yanick J. Crow, Alasdair P. J. Parker
2021 Molecular Genetics & Genomic Medicine  
(Asp299Argfs*58) in exons 7 and 9, respectively (Figure 2) --DECIPHER reference number 283482 (Firth et al., 2009; Figure 3 and 4). Parental testing confirmed that the variants were biallelic.  ...  AUTHOR CONTRIBUTION Helen V Firth, Luis Seabra and Yanick Crow conceived and planned the experiments, carried out Sanger Sequencing, analysed data and designed the figures.  ... 
doi:10.1002/mgg3.1708 pmid:34110109 pmcid:PMC8683631 fatcat:gqrkohugonc5bppwtbkrgnjdzu

De novo mutations in regulatory elements in neurodevelopmental disorders

Patrick J. Short, Jeremy F. McRae, Giuseppe Gallone, Alejandro Sifrim, Hyejung Won, Daniel H. Geschwind, Caroline F. Wright, Helen V. Firth, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles
2018 Nature  
V., Pennacchio, L. A. & Sunyaev, S. R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727-739 (2007). 38.  ... 
doi:10.1038/nature25983 pmid:29562236 pmcid:PMC5912909 fatcat:ifbjog5n5zex5c3uud4qoemhxa

Facilitating Collaboration in Rare Genetic Disorders Through Effective Matchmaking in DECIPHER

Eleni A. Chatzimichali, Simon Brent, Benjamin Hutton, Daniel Perrett, Caroline F. Wright, Andrew P. Bevan, Matthew E. Hurles, Helen V. Firth, Ganesh J. Swaminathan
2015 Human Mutation  
DECIPHER (https://decipher.sanger.ac.uk) is a web-based platform for secure deposition, analysis, and sharing of plausibly pathogenic genomic variants from well-phenotyped patients suffering from genetic disorders. DECIPHER aids clinical interpretation of these rare sequence and copy-number variants by providing tools for variant analysis and identification of other patients exhibiting similar genotype-phenotype characteristics. DE-CIPHER also provides mechanisms to encourage collaboration
more » ... a global community of clinical centers and researchers, as well as exchange of information between clinicians and researchers within a consortium, to accelerate discovery and diagnosis. DECIPHER has contributed to matchmaking efforts by enabling the global clinical genetics community to identify many previously undiagnosed syndromes and new disease genes, and has facilitated the publication of over 700 peer-reviewed scientific publications since 2004. At the time of writing, DECIPHER contains anonymized data from ß250 registered centers on more than 51,500 patients (ß18000 patients with consent for data sharing and ß25000 anonymized records shared privately). In this paper, we describe salient features of the platform, with special emphasis on the tools and processes that aid interpretation, sharing, and effective matchmaking with other data held in the database and that make DECIPHER an invaluable clinical and research resource. Hum Mutat 36:941-949, 2015. Published 2015 Wiley Periodicals, Inc. * *
doi:10.1002/humu.22842 pmid:26220709 pmcid:PMC4832335 fatcat:cftgjfynancvbnjjobgovyq3lq

InDelible: Detection and Evaluation of Clinically-relevant Structural Variation from Exome Sequencing [article]

Eugene J Gardner, Alejandro Sifrim, Sarah J Lindsay, Elena Prigmore, Dianna Rajan, Petr Danecek, Giuseppe Gallone, Ruth Y Eberhardt, Hilary C Martin, Caroline F Wright, David R FitzPatrick, Helen V Firth (+1 others)
2020 medRxiv   pre-print
Purpose Identifying structural variations (SVs) associated with developmental disorder (DD) patient phenotype missed by conventional approaches. Methods We have developed a novel SV discovery approach that mines split-read information, 'InDelible', and applied it to exome sequencing (ES) of 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study. Results Using InDelible we were able to find 59 previously undetected variants in genes previously
more » ... ciated with DD, of which 49.2% (29) had phenotypic features that accord with those of the patient in which they were found, and were deemed plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.0% (n = 29 variants). Of particular interest were seven confirmed de novo SVs in the gene MECP2; these variants represent 31.8% of all de novo protein truncating variants in MECP2 among DDD patients. Conclusion InDelible provides a rapid framework for the discovery of likely pathogenic SVs that are likely to be missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES.
doi:10.1101/2020.10.02.20194241 fatcat:jfyysluqrrbotmm42exyny5lci

VEP-G2P: A Tool for Efficient, Flexible and Scalable Diagnostic Filtering of Genomic Variants [article]

Anja Thormann, Mihail Halachev, William McLaren, David J Moore, Victoria Svinti, Archie Campbell, Shona M Kerr, Sarah Hunt, Malcolm G Dunlop, Matthew E Hurles, Caroline F Wright, Helen V Firth (+2 others)
2018 bioRxiv   pre-print
S e n s i t i v i t y a n d p r e c i s i o n o f i d e n t i f y i n g p r e v i o u s l y a s s i g n e d c a u s a t i v e v a r i a n t s i n D D D c o h o r t Using data from the first 4293 trio WES  ...  Furthermore, variants with Mapping quality (MQ) < 13 (95% confidence) in DDD G 2 P a n d V E P - G 2 P d e v e l o p m e n t Detailed descriptions of G2P and VEP-G2P development  ... 
doi:10.1101/416552 fatcat:jnw7kdkfbrhgpodijqyt22bvxe

Exome-wide assessment of the functional impact and pathogenicity of multinucleotide mutations

Joanna Kaplanis, Nadia Akawi, Giuseppe Gallone, Jeremy F. McRae, Elena Prigmore, Caroline F. Wright, David R. Fitzpatrick, Helen V. Firth, Jeffrey C. Barrett, Matthew E. Hurles
2019 Genome Research  
However, two-step missense MNVs could also lead to an additional 11 amino acids that could not be achieved by an SNV (F, S, C, I, T, K, S, V, A, E, G).  ... 
doi:10.1101/gr.239756.118 pmid:31227601 pmcid:PMC6633265 fatcat:prcotxgpdbe63cyiuozpqfixem
« Previous Showing results 1 — 15 out of 1,826 results