ACMG  Open  Forum    Introduc3on  to  Preliminary  Report  from  Secondary  Findings  in  Clinical  Sequencing  Workgroup    Mike  Watson  

March  28,  2012  

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  

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        

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)    

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.  

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.  

ACMG  Open  Forum    Preliminary  Report  from  Secondary  Findings  in  Clinical  Sequencing  Workgroup    Robert  Green  

March  28,  2012  

Thank You

Cassa,  Savage,  Taylor,  McGuire,  Green,  Mandl:  Genome  Research,  2011.    

Also  see  Clinical  PlaAorm  Presenta0on  2  CharloDe  Conv  Center  Ballroom  A-­‐D  Friday  4:30  pm,  Abstract  #28  

Published  online  March  15,  2012  

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?  

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?  

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.  

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?  

Principles: initial decisions…

• Guidelines  to  apply  to  molecular  laboratories.  

 

•  Leave  educa3on,  counseling,  preference  seing  and  other  contextualiza3on  to  ordering  clinicians.  

 

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.  

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.  

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?  

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  

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.  

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  

 

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.    

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  

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  

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  

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  

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).  

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?  

ACMG  Open  Forum    Audience  Response  Ques3ons  Related  to  the  Secondary  Findings  in  Clinical  Sequencing  Workgroup    Leslie  Biesecker    

March  28,  2012