Eugene Bragin

Ensembl’s 10th year

Ensembl (http://www.ensembl.org) integrates genomic information for a comprehensive set of chordate genomes with a particular focus on resources for human, mouse, rat, zebrafish and other high-value sequenced genomes. We provide complete gene annotations for all supported species in addition to specific resources that target genome variation, function and evolution. Ensembl data is accessible in a variety of formats including via our genome browser, API and BioMart. This year marks the tenth anniversary of Ensembl and in that time the project has grown with advances in genome technology. As of release 56 (September 2009), Ensembl supports 51 species including marmoset, pig, zebra finch, lizard, gorilla and wallaby, which were added in the past year. Major additions and improvements to Ensembl since our previous report include the incorporation of the human GRCh37 assembly, enhanced visualisation and data-mining options for the Ensembl regulatory features and continued development of our software infrastructure.

Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data

Summary Background Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. Methods The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. Findings Around 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. Interpretation Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene–phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. Funding Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.

DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation

The DECIPHER database (https://decipher.sanger.ac.uk/) is an accessible online repository of genetic variation with associated phenotypes that facilitates the identification and interpretation of pathogenic genetic variation in patients with rare disorders. Contributing to DECIPHER is an international consortium of >200 academic clinical centres of genetic medicine and ≥1600 clinical geneticists and diagnostic laboratory scientists. Information integrated from a variety of bioinformatics resources, coupled with visualization tools, provides a comprehensive set of tools to identify other patients with similar genotype–phenotype characteristics and highlights potentially pathogenic genes. In a significant development, we have extended DECIPHER from a database of just copy-number variants to allow upload, annotation and analysis of sequence variants such as single nucleotide variants (SNVs) and InDels. Other notable developments in DECIPHER include a purpose-built, customizable and interactive genome browser to aid combined visualization and interpretation of sequence and copy-number variation against informative datasets of pathogenic and population variation. We have also introduced several new features to our deposition and analysis interface. This article provides an update to the DECIPHER database, an earlier instance of which has been described elsewhere [Swaminathan et al. (2012) DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders. Hum. Mol. Genet., 21, R37–R44].

No expectation to share incidental findings in genomic research

Genomic sequencing studies can answer questions about the genetic contribution to complex medical disorders such as developmental disorders. Although fi ndings relating to the disorder of interest will be communicated to patients along with appropriate counselling, there is pressure on researchers to return secondary or incidental findings (ie, additional health-related data unrelated to the research question). But few studies have actually asked relevant stakeholders what their expectations are of researchers. Analysing and returning extensive data from genetic studies poses a particular dilemma simply because of the scale—with potentially hundreds of relevant variants that could be linked to future medical health. For many researchers, an exploration of such variants would have implications for time and resources that could compromise the ability to do research. Incidental findings could be uncovered by accident while exploring a pertinent finding, or might be revealed through a deliberate search for particular genes linked, for example, to serious, life-threatening treatable disorders. Whether to do such an opportunistic screen and what to do with incidental, health-related data, is subject to debate. With an online survey containing ten explanatory films, we gathered the attitudes of 6944 people from 75 different countries towards their expectations of genomic researchers with respect to sharing incidental fi ndings. These participants included four relevant stakeholder groups in sequencing research: members of the public (n=4961), genomic researchers (n=607), genetic health professionals (n=533), and other health professionals (eg, nurses, surgeons, paediatricians, and general physicians; n=843). We asked participants whether incidental findings from genome studies should be made available to research participants; and whether they expected researchers to deliberately do an opportunistic screen to look for incidental fi ndings of particular health relevance. 5628 of 6370 respondees thought that incidental findings should be made available to research participants (fi gure). However, despite such a strong interest in having access to data, only 1741 of 5653 participants expected genomic researchers to actively search for incidental fi ndings not relevant to their research. These results remained consistent even after adjustment for potential confounding eff ects. When asked, stakeholders do not expect researchers to search actively for incidental fi ndings in a research setting. The US Presidential Commission for the Study of Bioethical Issues also suggests that researchers do not have a duty to actively look for incidental fi ndings. Although researchers might choose to explore and share incidental fi ndings, within an appropriate ethics framework, our survey supports a policy that does not obligate researchers to search for and then communicate incidental findings to research participants.

Potential research participants support the return of raw sequence data

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 sequence 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.

Empirical research on the ethics of genomic research

© 2013 Wiley Periodicals, Inc.

Online questionnaire development: Using film to engage participants and then gather attitudes towards the sharing of genomic data

Highlights • We created a novel, online survey including 10 short films.• The extensive survey validation process involved 19 iterations before the final survey was ready.• Focussing on the survey design paid dividends in high response rate and low drop out rate.• Complex subject matter was no barrier to participant involvement.• Using a film-survey combination was a successful strategy in terms of recruitment.