1. The Diagnostic Laboratory ……the ideal system……

2. Molecular Genetics Diagnostic Laboratory Exciting area of medical pathology Need to continually up-date methods and technology used in diagnosis Need to continually up-date methods and technology used in diagnosis Impacts on accuracy and efficiency Impacts on accuracy and efficiency A drive to continually expand services into new diseases, new applications and extension of services A drive to continually expand services into new diseases, new applications and extension of services Funding implications Funding implications Continuing education and training of staff essential Continuing education and training of staff essential Providing information for use in clinical management, laboratory must operate within a highly regulated pathology arena. Providing information for use in clinical management, laboratory must operate within a highly regulated pathology arena.

3. Regulations….. Assurance of quality Assurance of quality laboratory operations laboratory operations laboratory results laboratory results highly trained staff highly trained staff Required at International Level Required at International Level Newly released OECD Guidelines for Quality Assurance in Molecular Genetic Testing Newly released OECD Guidelines for Quality Assurance in Molecular Genetic Testing

4. Activities in a Diagnostic Laboratory Test Assay Test patients Interpret Results Report to clinic Accessible Databases

5. In-House Laboratory Data Collection of large amount of sequence data on many genes Collection of large amount of sequence data on many genes Used to interpret mutation data within own cohort of patients Used to interpret mutation data within own cohort of patients This data is not available to external quality assessment or peer review This data is not available to external quality assessment or peer review

6. Human Variome Project Aim: collect and make available genetic variants and their effects to move ahead in a coordinated manner Aim: collect and make available genetic variants and their effects to move ahead in a coordinated manner Change procedures in Diagnostic Laboratories to report large body of sequence data to central repository Change procedures in Diagnostic Laboratories to report large body of sequence data to central repository

7. Activities in a Diagnostic Laboratory HUMAN VARIOME DATABASE Accessible Databases Test Assay Test patients Interpret Results Report to clinic

8. WHY? External quality assurance External quality assurance Increase data integrity of accessible databases Increase data integrity of accessible databases New research Areas New research Areas

9. External QA Newly released OECD Guidelines for Quality Assurance in Molecular Genetic Testing emphasize that participation in external QA essential part of ensuring quality Newly released OECD Guidelines for Quality Assurance in Molecular Genetic Testing emphasize that participation in external QA essential part of ensuring quality External QA is usually achieved through participation in Proficiency Testing Programs, which assess a snap-shot of laboratory processes External QA is usually achieved through participation in Proficiency Testing Programs, which assess a snap-shot of laboratory processes Process of submitting mutation data and interpretation outcomes to a central repository would create another form of external QA occurring in a continuous manner Process of submitting mutation data and interpretation outcomes to a central repository would create another form of external QA occurring in a continuous manner

10. Impact on the integrity and depth of the accessible data Difficult to get absolute proof of pathogenicity Difficult to get absolute proof of pathogenicity mutations tracking with disease [family studies; control studies] mutations tracking with disease [family studies; control studies] cause functional effect cause functional effect in highly conserved region in highly conserved region If rare mutation, cant exclude other gene changes/effects If rare mutation, cant exclude other gene changes/effects If mutation seen in a wide range of gene backgrounds causes the same disease phenotype, then greater proof of pathogenicity If mutation seen in a wide range of gene backgrounds causes the same disease phenotype, then greater proof of pathogenicity Submission of mutation data to central repository enables collection of data from wide range of gene backgrounds, and therefore would facilitate proof of pathogenicity or non-pathogenicity Submission of mutation data to central repository enables collection of data from wide range of gene backgrounds, and therefore would facilitate proof of pathogenicity or non-pathogenicity

11. New Research Areas More tools to explore More tools to explore genetic network genetic network genetic links genetic links data mining data mining

12. How could data be submitted? A quick and efficient process is crucial A quick and efficient process is crucial Links in mutation analysis software Links in mutation analysis software Links in search engines for information about specific sequence change Links in search engines for information about specific sequence change Submission of data could be a key to allow assess to interpretation/classification data present in central repository Submission of data could be a key to allow assess to interpretation/classification data present in central repository

13. Outcome HUMAN VARIOME DATABASE Accessible Databases Test Assay Test patients Interpret Results Report to clinic Quality Assurance of in-house data Access to wider breadth of data Increasing data Integrity, increasing Research capabilities