Understanding Human Variation
Since the completion of the sequencing of the human genome, genomics has become relevant not only to clinical genetics but also to public health genetics and healthcare. An explosion of genetic testing has revealed copy number variants of unknown clinical significance. The understanding, interpretation and application of this knowledge have challenged those working in human genetics. This workshop aims to outline our current understanding of human variation and the means of managing new data from multiple sources by harnessing bioinformatics and international collaboration.
The HGSA Education Committee
The Human Genetic Society of Australasia (HGSA) is the peak body for clinical geneticists, genetic counsellors, laboratory and research scientists, and other professionals engaged in human genetics. The Education Committee aims to keep abreast of trends in genetic education and training, nationally and internationally, and aims to advance education about human genetics to professionals and to the wider community. The focus has been the development of recommendations for core competencies in human genetics for new medical graduates and assembly of educational resources for those involved in curriculum development to facilitate their implementation.
The Australian Node of the Human Variome Project
The Australian Node of the Human Variome Project was initiated at a meeting in Melbourne 24th November, 2008 where the problems of collecting genetic information were addressed and a consortium was formed. Subsequently funding was secured via the Federal Government NeAT scheme to develop Software and Data support systems to collect and share genetic data to assist clinicians and researchers working in the field. This funding gave a dramatic boost to the work and many have been working over the past year to develop and integrate this new system. Currently there is a trial in laboratories underway and we are pleased to have this opportunity to share these outcomes with you. The Human Variome Project will be extending this collection to further genes and are looking to collaborate with any hospital or laboratory within Australia to achieve the best outcomes for patients. When established this system is intended to be transferred to other countries.
Program09:0009:30Registration and coffee09:3009:45Speaker I : Agnes Bankier - Welcome. Developing genetic literacy for health professionals09:4510:15Speaker 2 : Richard Cotton - Philosophy of the Human Variome Project International: harnessing databases and sharing knowledge10:1510:45Speaker 3: Howard Slater - Understanding copy number variants in molecular cytogenetics (SNP microarray)10:4511:15Speaker 4: Paul James - Interpreting missense variation: integrated models and their applications to common disorders11:1511:40Morning Tea11:4012:10Speaker 5: Amanda Spurdle - Understanding unclassified variants in cancer12:1012:40Speaker 6: Andy Faucett – Explaining variants to clients12:4013:10Speaker 7: Alan Lo - The Australian Node Project, The Australian Node database in practice – achievements to date and the importance of submitting to database13:1014:15Buffet lunch and hands-on learning14:15 Meeting EndsReport
“Understanding Human Variation”, a satellite meeting convened by the Education Committee of the Human Genetic Society of Australasia (HGSA) together with the Human Variome Project, addressed current understanding, interpretation and application of human variation and the means of managing new data from multiple sources by harnessing bioinformatics and international collaboration. Forty delegates from a range of disciplines attended the meeting.
Professor Agnes Bankier spoke to the importance of genetic education for medical graduates to ensure that they had the knowledge and skills to utilise this emerging knowledge for the benefit of their patients. The HGSA has developed recommendation for core competencies in human genetics for new medical graduates and web-based educational resources for their instruction. These are available on the HGSA website and may be useful for the international community as a guide.
Associate Professor Howard Slater explained copy number variants in molecular cytogenetics, which now incorporate SNP microarray technology. Whilst new phenotypes have emerged, of the CNVs detected, 28% are of uncertain and 39% of unknown clinical significance, a challenge to the laboratory scientists and clinical colleagues.
Associate Professor Paul James outlined integrated models for interpreting missense variation and their application to common disorders. The evolution of models for assessing evidence for pathogenicity from various sources has been integrated for assessing variants in the breast cancer genes and this model has now been applied to interpretation of variants in LQT “sudden death” genes. There is ongoing challenge for clinicians to further evaluate laboratory results that guide clinical practice.
Dr Amanda Spurdle outlined how the likely clinical significance of variants is assessed in cancer genetics using a multifactorial model that incorporates bioinformatically predicted protein effects, and also demonstrated the potential to include bioinformatic prediction of splicing aberrations in future models. Unclassified variants comprise a significant proportion of gene testing results in family cancer clinics and are classified into 5 categories based on quantitative or qualitative classification schemes: pathogenic, likely pathogenic, uncertain, likely not pathogenic and not pathogenic. These classes have been linked to general clinical management guidelines (Kohonen-Corish et al. 2010; Plon et al. 2008).
Professor Andrew Faucett shared his experience of genetic counselling, emphasising the importance of discussing concepts rather than detail and preparing the client for uncertainty of the gene testing results before testing and the possibility that these results may be re-interpreted in the future.
Professor Richard Cotton outlined the Philosophy of the Human Variome Project which is an international effort he established, to link locus specific databases with the aim of sharing knowledge for research and ultimately for better clinical outcomes for all. This aim is being addressed through HVP Country Nodes, as outlined by Timothy Smith. The Australian Node Project, as outlined by Alan Lo, will provide a proof of principle. When established this system is intended to be transferred to other countries. The pilot project is InSiGHT which aims to register all variants in genes that cause bowel cancer starting with MMR genes, linking with related databases internationally. Some of the challenges and barriers of data curation and data sharing were discussed.
Participants had the opportunity for some hands-on experience with the available databases.
- Kohonen-Corish, M. R., Al-Aama, J. Y., Auerbach, A. D., Axton, M., Barash, C. I., Bernstein, I. et al. (2010). How to catch all those mutations---the report of the third Human Variome Project Meeting, UNESCO Paris, May 2010. Human Mutation, 31(12), 1374-1381.
- Plon, S. E., Eccles, D. M., Easton, D., Foulkes, W. D., Genuardi, M., Greenblatt, M. S. et al. (2008). Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Human Mutation, 29(11), 1282-1291.