hvp5: meeting summary and thoughts - garry cutting

Meeting summary and thoughts

Garry Cutting, MDMcKusick Nathans Institute of Genetic Medicine

Johns Hopkins

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KudosScientific Programme CommitteeRichard G. H. Cotton (Melbourne, Australia)Raymond Dalgleish (Leicester, United Kingdom)Johan T. den Dunnen (Leiden, Netherlands)Marc Greenblatt (Burlington, VT, United States)Aida Falcon de Vargas (Caracas, Venezuela)Finlay Macrae (Melbourne, Australia)Martina Witsch-Baumgartner (Innsbruck, Austria)

Organising SecretariatRania Horaitis, ICOHeather Howard, ICOHelen Robinson , ICOTimothy Smith, ICOCasimiro Vizzini, UNESCO

And finish on time

Don’t be boring

Annotating variation in the human genome

• The challenge

• Potential solutions

The Cambridge Wine Blogger http://cambridgewineblogger.blogspot.com/2011/06/on-breadth-vs-depth-in-tasting.html

Stylianos Antonarakis, Session VIII

Rapid increase in the number of genes associated with mendelian phenotypes

Source: OMIMYears

Num

ber o

f gen

es

Number of variants reported per gene in the Leiden Open Variation Database (LOVD)

Variants from LOVD databases version 2.0-24 or higher and with properly configured reference sequences were used to extract the number of unique alleles reported per gene.  If a gene was present in multiple databases (duplicate instances), the raw data was parsed such that the highest number of variants per a given gene was reported. Data courtesy of Ivo F.A.C. Fokkema and Johan T. den Dunnen.

Figures courtesy of Melissa Lee Cutting GR AJHG 2014

• Increasing number of genes associated with mendelian disease

• Increasing number of variants per gene

Perfect Storm of Variants

Interpretive gap: Difference between rate of variant discovery and rate of

variant annotation

Variants identified Interpretive gap

Annotated

Cost of sequencing

Time

$$

Cutting GR AJHG 2014

Quantifying the interpretive gap

CFTR

137 for OMIM, 1301 for HGMD, 345 for LOVD

HBA1HBB

Gene matched counts of variants per gene, sorted by length

Christopher Cassa, Session X

Stylianos Antonarakis, Session VIII

Thomy de Ravel, Session II

Nik Nor Liza Nik Hassan, Session II

Raj Ramesar, Session III

Dwomoa Adu, Session III

Enock Matovu, Session III

Stylianos Antonarakis, Session VIII

Ted Kalbfleisch, Session IV

Moris Swertz, Session IV

Stylianos Antonarakis, Session VIII

Peter Taschner, Session V

Raymond Dalgleish, Session V

Ada Hamosh, Session V

Stylianos Antonarakis, Session VIII

Hoan Nyugen, Session VIII

Tuuli Lappalainen, Session VIII

Variant Annotation Projects

• INSiGHT: International Society for Gastrointestinal Hereditary Tumors – Mismatch repair genes (Thompson et al Nat Genet 2014)

• CFTR2: Clinical and Functional Translation of CFTR – CFTR (Sosnay et al Nat Genet 2013)

• ENIGMA :Evidence-based Network for the Interpretation of Germline Mutant Alleles– BRCA 1/2

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Maurizio Genuardi, Session IX

Finlay Macrae, Session IX

Christopher Cassa, Session X

Standards Development & Recommended Systems

• HGVS variation nomenclature• Mutalyzer • LOVD• VarioML • Variation Ontology (VariO)

• W01:Disclaimer Statements on G/DSDBs• WG02: Assigning Pathogenicity to a Genetic Variant• WG03 Minimal content for gene variant databases (LSDBS)• WG04 Minimum Content Requirements for HVP Country Nodes• WG05: Variant Database Quality Assessment• WG06: Disease &Phenotype Descriptions in Gene/Disease Specific

Databases

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Summary

Thank you for attending HVP5

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