Informed Consent; What can I tell the doctor? & Incidental Findings; What can I tell the patient?
Informed Consent; What can I tell the doctor? & Incidental Findings; What can I tell the patient? Dorien Lugtenberg Clinical laboratory geneticist (i....
Informed Consent; What can I tell the doctor? & Incidental Findings; What can I tell the patient? Dorien Lugtenberg Clinical laboratory geneticist (i.t.) Genome diagnostics laboratory Radboudumc Nijmegen
Exome sequencing
Exome sequencing
Why diagnostic exome sequencing for (highly) heterogeneous disorders?
Limitations of current genetic tests: not available for all disease genes, time consuming and expensive testing one gene at a time one
Exome sequencing vs targeted sequencing
Exome • Generic test for all diseases • less updating required • (many) new discoveries • more samples = more controls • chance for unsolicited findings
Targeted • develop per disease • needs to be updated regularly • no new discoveries • less samples = less controls • no unsolicited findings
Take best of both worlds, sequence the exome, analyse a gene panel Blind ness
Deaf ness
Move ment
Renal
Disorder gene panels (www.genomediagnosticsnijmegen.nl) Bli ndne ss
Neurologic
D e a f n e s s
M ov e m en t
Ciliopathy
Intellectual disability
Craniofacial
Movement (ataxia, HSP, etc)
Hereditary cancer
Muscle
Hypogonadotrophic hypogonadism
Epilepsy
Metabolic
HMSN (neuropathy)
Mitochondrial
Sensory
Primary immunodeficiency Vision
Renal
Hearing Multiple congenital anomalies
re n al
Looking beyond the gene panel also gives information about other diseases Incidental/accidental/unsolicited findings
Unsolicited findings are not new
• imaging techniques reveal cancer • linkage analysis reveals non-paternity • genome wide CNV detection reveals deletion with cancer gene
Final workflow Informed consent procedure
DNA
Exome sequencing Counselling by clinical geneticist Analysis of genes in package
yes
no
Report
Confirmation of diagnose?
Patient referral
“Whole” exome analysis De novo analysis
Report
(Candidate) gene
Genome diagnostics Clinicians Scientists
Unsolicited findings
Discussion in Bi Bi-weekly meeting
Report
Incidental finding committee
Procedure informed consent
Pre-test counselling procedure (1) • Written information leaflet
Pre-test counselling procedure (2)
• Oral counselling by clinical geneticist • Cause of the disease • Possible cause of the disease • No significant findings
• Unsolicited findings
Pre-test counselling procedure (3)
• Signing of the informed consent by the patient and/or the legal representative
Informed consent procedure September 2011 – September 2013 All individuals should sign the informed consent form All individuals must agree with the entire procedure; package and open exome
Unsolicited findings will be assessed by an independent committee of experts
All individuals must agree to be informed about relevant unsolicited findings
Reactions of patients/parents
Intellectual Disability Many parents interested
Waiting list Desperate in order to find the cause of the ID in their child Reproductive issues
Reactions of patients/parents Gene package groups
“ We just really want to know the genetic cause and the recurrence risk. “
“Great, after this test you can tell me everything about me! “
“ Completely ridiculous this unsolicited finding committee. I just want to know everything little thing you detect in his DNA. ”
Bli ndne ss
D e a f n e s s
M ov e m en t
re n al
Reactions of patients/parents Gene package groups
Bli ndne ss
D e a f n e s s
“ I thought it was for scientific purposes. For me personally, there is actually no urgent question of finding the genetic cause of my handicap. ”
“ I am way too scared for an incidental finding. I am just sure you will find a genetic form of cancer. ”
“ We will wait a few more years; perhaps the procedure will change over time and we can have an opt out for incidental findings in our daughter. “
M ov e m en t
re n al
Informed consent procedure October 2013 All individuals should sign the informed consent form Individuals have the option for analysis of package only, or continue with open exome
Unsolicited findings will be assessed by an independent committee of experts
All individuals must agree to be informed about relevant unsolicited findings
Who decides what is medically relevant for the patient?
treatable
In a 5-year-old boy the test for genetic causes of his ataxia shows that he has a mutation causing Long QT syndrome, a cardiac disease in which ventricular arrhythmia may result in recurrent syncopes, seizure, or sudden death. The ventricular arrhythmia could be prevented by medication or implantation of a defibrillator.
Adopted from Couzin-Frankel (2011) Science 331:662
actionable
A woman with retinitis pigmentosa is tested to find the genetic cause of her blindness. The test shows that she carries a mutation in BRCA1. The mutation raises the risk of breast and ovarian cancer and can be passed to any children she may have.
Adopted from Couzin-Frankel (2011) Science 331:662
untreatable
A young woman with deafness receives a positive report from exome sequencing. The lab also found that she carries APOE4, which raises her risk of Alzheimer’s. The disease remains unpreventable, though some measures may delay it.
Adopted from Couzin-Frankel (2011) Science 331:662
Committee unsolicited findings
• Clinical genetic laboratory specialist
• Clinical geneticist • Bioethicist • Lawyer • Social worker • Medical specialist
¾ Decision on whether or not the referring clinician will be informed
Unsolicited findings; informing the patient • Clinician receives a letter including information on the unsolicited finding(s)
• Committee Unsolicited Findings provides advice on further investigation(s) • See the patient at the out-patient clinic, possibly together with second medical specialist with expert knowledge on particular disease • Further investigation, i.e. referral to cardiologist, imaging techniques, segregation analysis in family
• Provide psychological support if necessary
What should be reported to the patient?
Berg (2011) Genetics in Medicine 13:499
Unsolicited findings in diagnostic exome sequencing • Expected: ~1% (Green et al; ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing) • In practice: 8 (out of ~500): • 3 real loss of function oncogenic
• 2 missense cardio (likely pathogenic) • XYY • 2 VUS • Not reported: late onset neurologic disease, VUS in cardiac disease
Case
• Male ID patient (2004) • No de novo changes explaining the ID • de novo missense change in RB1 • Classification: VUS!
• Presumed deleterious when detected in affected child (A. vd Hout, pers comm)
Berg (2011) Genetics in Medicine 13:499
Decision of expert committee Considerations
• RB1 variant not identified previously (literature and personal communication) • Variant of unknown significance Outcome Advice to inform the parents • Risk for RB is very small considering the age of the patient • Small risk for osteosarcoma at adolescent age • Quick recognition of prognostic value (actionable)
Only a yes/no option for disclosure of unsolicited findings might be too easy………….
Nijmegen now
Wish national ethics committees Informed consent
NO unsolicited findings
Maximal choice for patient, based on Bredenoord et al (2011) Human mutation 32: 861-867
Choices (Bredenoord et al.)
1. Standard default package Life-saving data and data of immediate clinical utility that entail a significant health problem 2. Extra package 1 Data of potential or moderate clinical utility 3. Extra package 2 Data of reproductive significance (including information for woman at risk of being in early menopause) 4. Extra package 3 Data of personal or recreational significance ¾ Opt out for default package / Opt in for extra packages ¾ Take into account the possibilities of the laboratory/health care system
Right not to know • Patient has a right not to be informed about unsolicited findings
Duty to inform; conflict of interest • The doctor has the duty to inform a patient about medically relevant findings • Can parents decide for their children?
Unsolicited findings Positive • genetic predisposition to disease that can be treated/prevented • carrier of recessive condition; reproductive choices • health risk that can be decreased by change in life style
Negative • uncertainty regarding the manifestation of the disease • patient may feel sick, but does not yet suffer from the disease • problems with health insurance/employers/ mortgage • increased concern for children or other family members
Implementation in diagnostics
• Ethics discussion appeared to be very important • Patients need to be aware of the possible risks • Take into account the “right not to know” and the “duty to inform” • Ask advice of ethics committee
Concluding remarks • Whole exome sequencing provides a high chance of finding the underlying genetic cause in heterogeneous diseases • Implementation of whole exome sequencing requires a multidisciplinary approach, in the pre- and post testing phase • Unsolicited findings may have positive or negative consequences; important to anticipate
• Adequate pre-test counselling is essential, especially in children
