Acmg secondary findings open forum 3 28-12 final
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ACMG Open Forum Introduc3on to Preliminary Report from Secondary Findings in Clinical Sequencing Workgroup Mike Watson
March 28, 2012
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Open Forum Agenda • Introduc)on
– Michael Watson
• Preliminary Report of the Secondary Findings in Clinical Sequencing Workgroup – Robert Green
• Audience Response Ques)ons – Leslie Biesecker
• Open Microphone Discussion – Michael Watson and Workgroup Members Panel
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Current College Ac3vi3es on Clinical Sequencing
• Task Force on WGS/WES – Co-‐Chaired by Sherri Bale, PhD and David Miller, MD – Informed ACMG Board of work for commiNees to pursue
• Posi)on statement on clinical use of WGS/WES – High level statement from ACMG Board of Directors – Dis3nguishes diagnos3c component from the screening component
• Clinical Laboratory Standards for Next Genera)on Sequencing – Laboratory Quality Assurance CommiNee workgroup – Co-‐Chaired by Heidi Rehm, PhD and Pinar Bayrak-‐Toydemir, MD, PhD
• Secondary Findings in Clinical Sequencing Workgroup – This ad hoc workgroup formed by the ACMG Board to develop guidelines – Work of many ACMG CommiNees are dependent on addressing issues around
the return of secondary results
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Secondary Findings in Clinical Sequencing Workgroup
• Robert Green, MD, MPH (Co-‐Chair) Brigham & Women’s; Harvard • Leslie Biesecker, MD (Co-‐Chair) NHGRI/NIH • Jonathan Berg, MD, PhD Univ. of North Carolina • Wayne Grody, MD, PhD Univ. Calif. Los Angeles • Bruce Korf, MD, PhD Univ. Alabama Birmingham • Amy McGuire, JD, PhD Baylor • Christa Mar3n, PhD Emory Univ. • Robert Nussbaum, MD Univ. Calif. San Francisco • Julianne O’Daniel, MS Illumina • Kelly Ormond, MS Stanford Univ. • Heidi Rehm, PhD Brigham & Women’s; Harvard • Marc Williams, MD Geisinger Health System • Sarah Kalia, ScM Brigham & Women’s; (ex officio) • Michael Watson, MS, PhD ACMG Staff (ex-‐officio)
(poten0al COI were reviewed by ACMG Board prior to approval)
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Previous Workgroup Strategy and Timeline
• Workgroup chairs appointed November, 2011.
• Charge to workgroup ar3culated by workgroup chairs and ACMG Board of Directors in November/December, 2011.
• Workgroup members appointed and approved by ACMG Board of Directors in January, 2012.
• Workgroup meets weekly January-‐March, 2012.
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Upcoming Workgroup Strategy and Timeline
• Workgroup seeks feedback from membership March-‐April, 2012.
• Based upon feedback, workgroup will revise approach and seek addi3onal expert input April-‐May, 2012.
• Workgroup recommenda3ons will be presented to ACMG Board of Directors May, 2012.
• Workgroup recommenda3ons will be submiNed for publica3on as ACMG Guideline June, 2012.
Concepts and ideas under considera)on by the workgroup do not yet represent ACMG policy.
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ACMG Open Forum Preliminary Report from Secondary Findings in Clinical Sequencing Workgroup Robert Green
March 28, 2012
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Thank You
Cassa, Savage, Taylor, McGuire, Green, Mandl: Genome Research, 2011.
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Also see Clinical PlaAorm Presenta0on 2 CharloDe Conv Center Ballroom A-‐D Friday 4:30 pm, Abstract #28
Published online March 15, 2012
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Charge to the Workgroup
1. What principles should guide search and repor3ng of secondary findings from WES/WGS?
2. Should there be a list of genes or variants
sought, interpreted and reported on every pa3ent undergoing WES/WGS?
3. If so, what should be on that list?
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An3cipated Ques3ons
1. Why the accelerated 3metable? 2. Who are these guidelines wriNen for?
3. Will these guidelines be “evidence based”?
4. Is the exper3se of the workgroup members sufficient? 5. What is the medical model for secondary findings?
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What did we NOT address? • Sequencing as screening. • Dis3nguishing guidelines for adults vs children. • Tes3ng mul3ple family members.
• Considering ethnicity. • Obtaining preferences from pa3ents.
• Reanalysis of sequence over 3me.
• Integra3on of report or sequence with medical records.
• Educa3on or qualifica3ons of ordering clinician. • Patent, IP, insurance or reimbursement issues.
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Charge to the Workgroup
1. What principles should guide search and repor3ng of secondary findings from WES/WGS?
2. Should there be a list of genes or variants
sought, interpreted and reported on every pa3ent undergoing WES/WGS?
3. If so, what should be on that list?
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Principles: initial decisions…
• Guidelines to apply to molecular laboratories.
• Leave educa3on, counseling, preference seing and other contextualiza3on to ordering clinicians.
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Principles: creating a list…
• Generate a specific list.
• Generate a minimum list of variants/condi3ons that laboratories should look for and return, recognizing that laboratories may wish to provide more.
• Revise the list at least annually.
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Principles: laboratory transparency…
• Laboratories genera3ng WES/WGS should have a clear policy regarding analysis and return of secondary findings.
• This policy should be stated clearly on laboratory website, requisi3on form, consent, and/or results report.
• Report should include level of coverage and/or confidence for all genes included on the report.
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Charge to the Workgroup
1. What principles should guide search and repor3ng of secondary findings from WES/WGS?
2. Should there be a list of genes or variants
sought and interpreted on every pa3ent undergoing WES/WGS?
3. If so, what should be on that list?
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Principles: creating a minimum list…
• High penetrance • Pa3ents may be asymptoma3c for a long period of 3me
• Interven3on clearly demonstrated to be efficacious
• High posi3ve predic3ve value • Not otherwise detected by newborn screening
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Principles: variant categories…
• Variants in ACMG interpre3ve categories 1 or 2 are included on this minimum list – Category 1: Variant previously reported and a recognized cause of the disorder
– Category 2: Variant previously unreported and of the type which is expected to cause the disorder
Richards et al, ACMG recommenda3ons for standards for interpreta3on and repor3ng of sequence varia3ons. Genet Med 2008.
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Were AR and X-‐linked disorders considered?
• Homozygotes/compound heterozygotes or hemizygotes were considered separately for inclusion on the minimum list.
• Carriers were considered for inclusion only if a carrier phenotype has been described – Examples of carrier states included on minimum list: Fabry, Gaucher, LCHAD
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Were NBS condi3ons considered?
• Minimum list focuses on condi3ons not detected rou3nely on newborn screening panels.
• Some labs may choose to report all metabolic disorders.
Ra3onale: Clinical sequencing is not an acceptable subs3tute for NBS.
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Were PGx variants considered?
• Factors to consider: – Poten3al for huge cost savings – Limited disadvantages to returning, despite low penetrance
à Included (based on Pharm GKB/CPIC)
• However, need to determine whether WES or WGS can accurately detect HLA subtypes – Abacavir, Carbamazepine – Workgroup will seek addi3onal exper3se
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Examples included on minimum list…
• Inherited cancer syndromes and Marfan syndrome – If a secondary finding, pa3ent is unaware of risk and would not otherwise be screened
– Poten3al for severe ini3al presenta3on
• Familial hypercholesterolemia – Poten3al for severe ini3al presenta3on – Treatments available & effec3ve
• Fabry – Most cases have late onset – ERT more effec3ve if started earlier
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Examples not included on minimum list…
• Neurological/Neuromuscular disorders – No interven3on – Limited ability to detect repeat expansions
• Mitochondrial disorders – Extremely variable presenta3on
• Inherited thrombophilia variants – Low PPV
• APOE – Low penetrance – No interven3on
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Examples that were challenging…
• Hypertrophic cardiomyopathy – Long asymptoma3c period – Poten3al for severe ini3al presenta3on – Low PPV for some variants and unclear penetrance – Knowledge carries high burden à Included
• Bio3nidase deficiency – Simple treatment – Unclear meaning in an asymptoma3c pa3ent à Not included
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Limita3ons of these dran guidelines…
• Current technological capabili3es of WES/WGS.
• Point muta3ons and in/dels, not CNVs. • Decision to return variants for certain condi3ons may depend on age of pa3ent (especially children < age 2).
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Charge to the Workgroup
1. What principles should guide search and repor3ng of secondary findings from WES/WGS?
2. Should there be a list of genes or variants
sought and interpreted on every pa3ent undergoing WES/WGS?
3. If so, what should be on that list?
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ACMG Open Forum Audience Response Ques3ons Related to the Secondary Findings in Clinical Sequencing Workgroup Leslie Biesecker
March 28, 2012