Genetic Counselors’ Perspective on Constitutional Genomic Testing

Curtis R. Coughlin II, MS, MBe, CGC

Assistant Professor of Pediatrics

Associate Faculty, Center for Bioethics and Humanities

University of Colorado School of Medicine

• A mother was born at 35 weeks to a 16 year old G1P0→1 mother

• The patient was noted to have neonatal onset seizures and transposition of the great arteries

• The neonatology fellow ordered a chromosomal microarray

• Absence of heterozygosity was detected in several chromosomes involving ≥11% of the genome

• A 4.8 Mb copy number loss was identified at Xq22.1

• chrX:100,689,116-105,523,589; hg19

• A patient with similar CNV and intellectual disabilities reported in DECIPEHR

• CNV encompassed GLA (Fabry disease)

Secondary Findings

• “Whether to divulge results like these [incidental findings], and how, is arguably the most pressing issue in genetics today”

• Jennifer Couzin-Frankel, Science, 2011

• “Ethically speaking, [return of incidental findings] is the most difficult one [ethical dilemma] I’ve ever dealt with in my entire career”

• Wayne Grody, President ACMG, Science, 2013

Shuster, Lancet, 2007 Feb 10;369:526-9.

“These technologies prompt constant revisions of our health... …that will probably cause more, rather than fewer, abortions of healthy babies.”

Misattributed paternity: The original secondary finding

• Survey of 677 genetic providers

• Case study of false paternity (misattributed paternity) • 96%: maternal confidentiality overrode disclosure of paternity

• 81%: report results to mother in private

• 13%: tell both partners they are genetically responsible

• 2%: ascribe child’s disorder to a new mutation

Hereditary breast and ovarian cancer Li-Fraumeni syndrome Peutz-Jeghers syndrome

Lynch syndrome Familial adenomatous polyposis MYH-associated polyposis

Von Hippel-Lindau syndrome Multiple endocrine neoplasia type I Multiple endocrine neoplasia type 2

Familial medullary thyroid cancer PTEN hamartoma tumor syndrome Retinoblastoma

Hereditary paragangliomapheochromocytoma syndrome

Tuberous sclerosis complex WT1-related Wilms tumor

Neurofibromatosis type 2 Ehlers-Danlos syndrome, Vascular type

Marfan, Loeys-Dietz and familial thoracic aortic aneurysms and dissections

Hypertrophic and dilated cardiomyopathy Catecholaminergic polymorphic ventricular tachycardia

Arrhythmogenic right-ventricular cardiomyopathy

Romano-Ward long QT syndrome and Burgada syndrome

Familial hypercholesterolemia Malignant hyperthermia susceptibility

Kiltzman et al, JAMA 2013 Jul 310(4):369-70.

“At state are fundamental differences in ethical views and interpretations – concerning the

ethical responsibilities of clinicians and laboratories, and of

paternalism in the name of beneficence vs autonomy”

Disclosure of secondary results: A possible burden?

• Paternalism: • Concern that patients may feel

that clinicians are ‘inflicting results’ as opposed to ‘offering results’

• Autonomy• Genetics has a long history of

supporting voluntary consent (autonomy) prior to genetic testing/results

• Beneficence• Does benefit of knowing the

result outweigh the patient’s autonomy?

Dimmock, Science, 2013

“…[patients] have stated if you force us to have secondary results

we won’t have our genome sequenced.”

Incidental Findings

Genetic testing that utilizes a broad scope technology such as array-based testing or genomic sequencing may produce findings of likely medical significance unrelated to the reasons for testing. When these incidental findings relate to a serious, well-characterized medical risk with implications for clinical care, laboratories should identify and disclose them as routine part of return of results, absent a compelling and case-specific reason to do otherwise. The National Society of Genetic Counselors

(NSGC) strongly advises that a plan for return of results be formulated in advance of testing, and that the process of pre-test counseling establish clear expectations for what categories of results will and will not be returned. Healthcare providers ordering untargeted clinical genomic testing should consider the need for a specialty referral network and should ensure that their patients have access to a medical professional with specific expertise in genetics, such as a genetic counselor, throughout the testing and return of results process.

Educational Materials

Short (<2 min) conversation with clinician

Materials could be on paper, interactive, online, etc

Materials provided would be written:

• In lay language

• At an appropriate reading level

• In a language that the patient is comfortable reading

Targeted Discussion

Conversation with clinician (<15 min)

Brief discussion of condition of concern

Brief discussion of key elements of genetic testing

Educational materials provided

Traditional Genetic Counseling

In depth discussion with clinician with genetics expertise (>30 min)

Information gathering for detailed risk assessment (e.g., family history)

Detailed discussion of condition of concern

Detailed discussion of genetic testing

Educational materials provided

Test result

Significant potential for near-term mortality?

Clinician with appropriate genetics expertise provides

detailed discussion of results, management plan, and implications for family(modeled after traditional

genetic counseling)

Clinician provides result online or by phone with

personalized education and follow up plan

Per clinician tooland patient desires

Condition associated with increased risk of adverse psychological

impact?

Is this a typically adult-onset condition in someone under age

18?

No

No

No

Yes

Yes

Yes

Pathogenic Variant/ Likely Pathogenic Variant

No Variant Detected/Variant Likely Benign/Variant of Uncertain Significance

Clinician provides educational materials;

clinician remains available to answer patient’s

questions

Per clinician tool and patient desires

Are quality educational materials available?

Yes

No

Test has limited sensitivity

No

Yes

Clinician with appropriate genetics expertise provides

detailed discussion of results, management plan, and implications for family(modeled after traditional

genetic counseling)

Clinician provides result online or by phone with personalized education

and follow up plan

Clinician provides educational materials;

clinician remains available to answer patient’s

questions

• Confirmatory testing for known clinical diagnosis

OR• Patient is well educated about

conditionOR

• Clinician comfortable with communicating results and managing condition/providing appropriate referrals for management

• NOTE: In order to decrease level of communication to educational materials, there must be quality educational materials available

Results DisclosureRecommended Level of Communication

• Ordering clinician wants genetics input on communicating results and/or managing condition

OR• Patient has an increased baseline level

of anxiety/depression/other psychological dx

OR• Patient has contextual issues that

suggest a risk for adverse response (e.g., significant family history factors)

OR• Patient is asymptomatic/pre-

symptomaticOR

• Testing revealed a new diagnosisOR

• Clinician still has strong suspicion of diagnosis even with negative result

Reasons to increase the level of communication

Reasons to decrease the level of communication

What could have been done?

• Pre-test education is paramount• Laboratory policies

• Best practices (ClinGen)

• Education of colleagues

• Return of results plan• Return of results is often nuanced

• No one “best” person to return results to every patient

• Family centered care requires a team approach

Patient

Clinician

Genetics Expert

Trusted Health

Provider

Laboratory

Thank you for your attention