19.07.18 Incidental findings

Question 1

What is an incidental finding (IFs)?

Answer 1

A finding that has the potential health or reproductive importance for an individual, discovered in the course of a particular study (research, clinical care or screening) but is beyond the aims of that study.

Question 2

What are the three categories of IFs

Answer 2

1) Actionable
2) clinically relevant but not actionable
3) Uncertain significance

Question 3

What is an actionable IF

Answer 3

An IF where a therapeutic or preventative measure exists that can significantly benefit the health of the individual with the IF.

Question 4

What is a clinically relevant but not actionable IF

Answer 4

Eg carrier status for an autosomal recessive condition

Question 5

What is an IF of uncertain significance

Answer 5

A finding that cannot be unequivocally classified as clinically significant or benign. Could be a novel variant, or one with reduced penetrance. Could be in a gene relevant to indication tested or an unrelated gene

Question 6

Considerations for reporting IFs

Answer 6

• Is it clinically relevant
• Is disease risk clearly proven
• Would reporting lead to better clinical outcomes
• Has patient given informed consent for this test
• Patient autonomy (is there an option for patient to opt-out of IF feedback)
• Would withholding lead to litigation
• Ethical to withhold?

Question 7

IFs in karyotyping

Answer 7

• chromosomal abnormalities detected which are not related to disorder in question
• e.g.Down syndrome/ trisomy testing because of maternal age, detects sex-linked aneuploidy (turners 45,x or Klinefelter 47,XXY). Would be reported
• e.g. normal variants such as inv(9) not reported as no clinical significance

Question 8

IFs in array CGH

Answer 8

• Potential to identify IFs due to higher resolution
• e.g. carrier status (CF) or susceptibility to late onset disorder/ increased risk of neoplasm (BRCA)
• Whole genome approach, hard to avoid these loci.
• Referring clinician must inform patient before ordering test.

Question 9

IFs in array CGH: reporting carrier status

Answer 9

• Outside scope of intended use, therefore not recommended.
• report should state that carrier status is not disclosed.
• Cases where reporting status maybe ok, when reproductive counselling available (for high carrier frequency diseases e.g. CF)

Question 10

IFs in array CGH: recessive disorders with clinical features relevant to patient

Answer 10

• Recommend further molecular testing.
• Mainly well described recessive disorders with clear clinical consequence.
• Report should state that not diagnostic of affected status unless a second variant found.

Question 11

IFs in array CGH: mutation status for adult onset/undiagnosed conditions

Answer 11

• Not related to reason for referral but may clearly be diagnostic of a presymptomatic/ clinically undetected condition (e.g. male infertility and deletions of AZF region on Y chromosome).
• Generally, reported as can facilitate early access to medical care.

Question 12

IFs in array CGH: Reporting CNVs associated with risk of neoplasia

Answer 12

• Deletions in known tumour suppressor genes should be reported.
• e.g. child with dysmorphic features and has a deletion containing FAP gene. Left untreated the child could develop bowel cancer in adulthood. Regular surveillance and prophylactic surgery will improve prognosis.

Question 13

Prenatal array CGH

Answer 13

• Primary clinical reasoning is to determine childhood disability due to a genetic disorder.
• no official guidelines currently.
• Generally, don’t disclose findings for adult-onset, where surveillance won’t affect outcome, they cannot consent themselves.
• Harder for genome wide testing. Context of entire family should be taken into account (maternally inherited neoplasia risk and surveillance is available). Withholding could cause harm.
• Traits- such as gender, not disease causing but could lead to termination for undesired gender (in some societies).
• Reporting IFs depends on pre-test counselling, lab policies, consent.

Question 14

-Examples of molecular IFs

Answer 14

• Klinefelters (XXY) in FRAX male testing. Reported as may explain reason for referral.
• Non-paternity. ~10% cases.
• ATM parental testing. Carriers are at an increased risk of cancer.

Question 15

ACMG 2016 update on reporting of IFs in clinical exomes and genomes

Answer 15

• List of constitutional variants that should be reported regardless of clinical indication.
• Responsibility of the ordering clinician to provide comprehensive pre and post-test counselling.
• However, patients should have the option to opt-out

Question 16

Three categories of IFs in research setting

Answer 16

• Strong net benefit (reveals condition likely to be life threatening, that can be avoided or ameliorated, can be used in reproductive decision making)
• Possible net benefit (as above but risk of serious condition that a research participant would deem important, when risk cannot be modified).
• Unlikely net benefit (conditions that are not of serious health or reproductive importance).

Question 17

What is a GWAS

Answer 17

Genome wide association study. A GWAS investigate the relationship between genomic and phenotypic variations.

Question 18

IFs in GWAS

Answer 18

• Serious treatable/ not- treatable
• Not serious
• Predisposition to serious future disease (preventable/not preventable)
• Intolerances to substances that could alter treatment (drug intolerances)
• Social (incest, non-paternity)

Question 19

Challenges of IFs in GWAS

Answer 19

• Variants identified in GWAS usually have limited/uncertain predictive value (e.g. penetrance, clinical significance)
• Variants found are not necessarily causal, follow up studies may be required
• Often carried out in non-accredited labs
• Hard to assess validity of associations as limited scope to replicate studies.
• Samples from around the world (treatable in Uk may not reflect in native country)
• Use of archived samples
• Future developments may identify clinically relevant findings, obligation to feedback?

Question 20

Pathway for managing feedback descision for incidental findings.

Answer 20

• Done at the outset of the project, should be considered by an ethics committee
• Consent form gives participants the option not to receive feedback
• Includes steps to verify the validity and clinical utility of IFs
• Who will give the feedback (a clinician is more appropriate)
• Whom feedback will be given

Question 21

Why are ethics committees important

Answer 21

• Provide guidance on the appropriateness of feeding back results
• Evaluate whether a condition is serious enough to justify re-contacting participants, is disease association reliable.

Question 22

Methods of minimising IFs

Answer 22

• Targeted approaches

- Looking at green genes (i.e. well established link with disease)