Direct to Consumer Test and Ancestry Testing - March 14, 2023

1. Direct to Consumer
Genetic Testing
& Ancestry Testing
Stephanie Sacharow, MD
March 14, 2023
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2. Learning Objectives
By the end of this session, attendees will be able to:
• Identify some benefits and risks of direct-to-
consumer genetic and ancestry testing.
• Understand the types of genetic testing offered
direct-to-consumer, to help in discussions with
patients.
• Articulate that mendelian gene findings should be
confirmed before acting upon this information, and
when to refer for evaluation by a Genetics provider.
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3. Richard’s story

5. What is Direct to Consumer (DTC) ancestry testing?
• Genetic Genealogy
– uses DNA test results in
combination with traditional
genealogical methods
– Aims to understand biological
relationships between or among
individuals
DTC company examples
– AncestryDNA from Ancestry
– Family Finder from Family Tree DNA
– 23andMe from 23andMe
– MyHeritage DNA from MyHeritage
– Living DNA from Living DNA
https://dna-explained.com/2012/07/21/ethnicity-finders/

6. Y-Chromosome DNA Testing
• Y chromosome passes from father
to son
• Reflects patrilineal line and may
follow surnames
https://www.dnafavorites.com/types-of-dna-testing.html

7. Mitochondrial DNA testing
• MtDNA passes from the mother to
sons and daughters
• Has a slower mutation rate so
matches may reflect female
common ancestors from thousands
of years ago
https://www.dnafavorites.com/types-of-dna-testing.html

8. Sample “relationship” ancestry report

9. Sample report -Ethnicity

10. Ancestry report sample
(23andME)

11. Public’s attitude toward Ancestry testing
(from focus groups)
• Perceived value
– Some saw as curiosity or entertainment
– Others perceived great value particularly if they were
adopted, had gaps in their family history or few living
relatives
• Concerns
– Intrusion into their lives of purported kin
– Control of data
– Secondary uses of data
– Possible law enforcement access
Direct-to-consumer genetic testing: Prospective users’ attitudes toward information about ancestry and biological relationships
| PLOS ONE

12. Unintended privacy effects of DNA
“relationship testing”
• Exposing family secrets
• Identifying “anonymous” sperm donors
• Solving “cold cases” from homicides
• DNA companies have reportedly shared data with the
FBI
– Pentagon leadership has encouraged military personnel not to
take 23andMe tests due to privacy concerns.
• Taking a test shares insights into their ancestors and
children
https://www.kqed.org/pop/104710/how-dna-tests-like-23andme-are-exposing-family-secrets

13. Family secrets
• Survey of people who used Genetic Relative Finder (GRF) with
DTC testing
– Most (82%) learned about a new genetic relative
• 3% learned a person believed to be a biological parents is not their
biological parent
• 5% found they had a half of full sibling
– Most adoptees knew about their adoption
• ~half of donor-conceived learned about their conception from GRF
service
– Those who discovered a new biological parents, child, or sibling
who reached out to the family member almost always received a
response
– Generally there was low regret, but those who discovered a
parent is not biological and donor-conceived had the highest
decisional regret and net-negative consequences
https://www.cell.com/ajhg/pdf/S0002-9297(22)00013-1.pdf

14. Direct to Consumer Genomic Testing

15. What is Direct to Consumer (DTC)
Genomic Testing?
• Traditional genetic testing is ordered by medical
providers (MD, DO, or NP) or genetic counselors
– Genetic testing traditionally looks for mendelian
disease
– Based on clinical features and family history
– Requires discussion and informed consent
• DTC testing can be ordered by consumers
– Risk scores for multifactorial disease
– Asymptomatic individuals
– Often no discussion prior to consent, may not be
well informed
– May be recreational “Spit parties”

16. History of DTC Testing
• DTC testing started with 23andME in the mid 2000’s
• Originally they gave multifactorial risk scores and
trait scores
– Added cancer risks
• Decade-long battle with FDA
• FDA removed from the market…
– On the grounds of public protection from “abusive
marketing” and “exaggerated claims” regarding health
risks, and lack of clinical validity
• 2017 FDA authorized 23andME DTC test
– Included genotyping for a limited set of genetic
diseases
– Testing of genetic health risks
• Since 2017, rapid expansion in the market

17. DTC Genomic testing marketing
• Marketed directly to customers
– Television
– Internet
– Telemarketing
• Purchase online or in stores
– Does NOT require a health care provider or
genetic counselor
• Varies between companies
– Cancer predisposition genes
– Carrier Screening
– Multifactorial risk assessment
– Genetic traits (eye color, ear wax quality)
– Ancestry information

18. Genetics DTC Testing Result Types

19. Traits
• Ability to Match Musical
Pitch
• Asparagus Odor Detection
• Back Hair & Bald Spot
Bitter Taste
• Bunions
• Cheek Dimples
• Cilantro Taste Aversion
• Cleft Chin
• Dandruff
• Earlobe Type
• Early Hair Loss
• Earwax Type
• Eye Color
• Fear of Heights
• Fear of Public Speaking
• Finger Length Ratio
• Flat Feet
• Freckles
• Hair Photobleaching
(lightening from sun)
• Hair Texture
• Hair Thickness
• Ice Cream Flavor Preference
• Light or Dark Hair
• Misophonia (hatred of the
sound of chewing)
• Mosquito Bite Frequency
• Motion Sickness
• Newborn Hair
• Photic Sneeze Reflex
• Red Hair
• Skin Pigmentation
• Stretch Marks
• Sweet vs. Salty
• Toe Length Ratio
• Unibrow
• Wake-Up Time
• Widow's Peak

21. Multifactorial (Complex) Disease Risk
• Multifactorial definition: disorders and
genetic traits that occur and are determined
by the interaction of environmental factors
and multiple genes
– Non-Mendelian
• Examples: blood pressure, obesity, asthma,
coronary artery disease, schizophrenia,
Alzheimer’s
• Interpretation is complex and not a part of
general clinical genetics practice

23. Pharmacogenetics
(Pharmacogenomics)
• How a person's genes affect how he or she responds
to medications
– Goal is to help doctors select the drugs and doses best
suited for each person

24. DTC Mendelian Disease Testing
(only select variants – not full sequencing)
Mendelian diseases
• Caused by germline mutations
• Follow the patterns described by Mendel
(Autosomal Dominant, Autosomal Recessive, X-linked)
Examples:
• Age-Related Macular Degeneration - 2 variants in the ARMS2 and CFH genes; relevant for European descent
• BRCA1/BRCA2 (Selected Variants) - 3 variants in the BRCA1 and BRCA2 genes; relevant for Ashkenazi
Jewish descent
• Chronic Kidney Disease (APOL1-Related) -2 variants in the APOL1 gene; relevant for African descent
• Familial Hypercholesterolemia -24 variants in the LDLR and APOB genes; relevant for European, Lebanese,
Old Order Amish descent
• G6PD Deficiency – 2 variants in the G6PD gene; relevant for African, Southern European, Kurdish Jewish,
Middle Eastern, Central Asian, South Asian descent
• Hereditary Hemochromatosis (HFE-Related) - 2 variants in the HFE gene; relevant for European descent
• Hereditary Thrombophilia - 2 variants in the F2 and F5 genes; relevant for European descent
• Late-Onset Alzheimer's Disease - 1 variant in the APOE gene; variant found and studied in many ethnicities
• MUTYH-Associated Polyposis - 2 variants in the MUTYH gene; relevant for Northern European descent
• Parkinson's Disease - 2 variants in the LRRK2 and GBA genes; relevant for European, Ashkenazi Jewish,
North African Berber descent

25. Testing methods
• DTC testing for complex disease is based on SNP-chip
genotyping, not DNA sequencing
– Involves thousands of probes on a slide that
hybridized to patient DNA
• Can look at variants for common disorders
• May be inaccurate for rare pathogenic variants
• 40-96% false positive rate
• Not confirmed with Sanger sequencing
– Some DTC companies were granted FDA clearance to report
diagnostic genetic variants for Mendelian disorders
• Example: BRCA1/2 results, pharmacogenetic results, carrier
screening
– Individuals can request raw genetic data, have analyzed by a
third party
Outpatient Primary Care Genetic Testing Primer: What to Order and Testing Considerations - PubMed (nih.gov)

26. Results of DTC testing vs
Genetic Testing Laboratory
• Third party analyses vary widely in classification
– The same variant may be classified as pathogenic, benign,
uncertain, based on their own definitions
• Misclassification can lead to multiple ED visits, subspecialty
workup, extensive imaging, and even surgery
• Emotional, social and financial burden of misclassification
• ACMG and Association for Molecular Pathology
– Strict variant classification standards
– Defined criteria for variant classification
– Result interpretation by a board-certified clinical molecular
geneticist or molecular genetics pathologist
– Internal validation or secondary testing method for
confirmation

27. Case Examples

28. CASE 1 - Predictive value is low when there is no family
history of disease
• Jake bought a DTC genetic test online
while researching his family history.
• He enjoyed learning about his ancestry
so decided to pay for an optional health
report.
• He was very upset to find that: “you
have one variant detected in the
LRRK2 gene. People with this variant
have an increased risk of developing
Parkinson’s disease.” Jake had no family
history of Parkinson’s disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829432/?report=printable

29. CASE 1 - Predictive value is low when there is
no family history of disease
• If a “disease-causing” or “disease-predisposing” genetic variant is
found in a person with no medical or family history of the
corresponding disease, the variant is less likely to lead to disease in
that person
– unmeasurable protective genetic (or other) factors
• Most people with apparent “positive” results will not go on to develop
the related condition
– The predictive meaning of a “disease-causing variant” is often much reduced when
found outside the context of a family history of the relevant disease
• False positives are common, especially where third party
interpretation services are used
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829432/?report=printable

30. • Molly was given a DTC ancestry test for Christmas.
She sent her raw genetic data to an online
interpretation service.
• This reported that she had a disease-causing
BRCA1 variant (increasing her risk of breast and
ovarian cancer).
• Molly did not have a strong family history of breast
or ovarian cancer. She asked her PCP to refer her to
a breast surgeon.
– She met the surgeon, who booked a date for her
surgery. Her PCP also referred her to a clinical
genetics service.
– A genetics clinician ordered testing to confirm that the
BRCA1 variant was really present in Molly’s DNA—it
wasn’t.
– The online interpretation service had reported a false
positive result. Molly’s operation was cancelled but she
still felt anxious about her cancer risk.
CASE 2 – False positive result
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829432/?report=printable

31. False positives
• False positive results can arise for a number of reasons
• The quality control for DTC genetic tests is variable
• Some tests may be more vulnerable to issues like sample
“miscalls”
• Databases used to interpret the data may not be up to date
• May classify variants incorrectly based on outdated evidence
• The SNP-chip genotyping method that most DTC genetic
tests use is unreliable at testing for very rare disease-
causing genetic variants
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829432/?report=printable

32. CASE 3 – False negative result
• Lily had treatment for breast cancer in her
40s, and her mother died of ovarian cancer in
her 50s.
• Lily bought a DTC test that included a BRCA
screen.
• She was delighted by the result: no variants
were found in BRCA1 or BRCA2.
• Lily’s PCP explained that many DTC BRCA
screens only screen for a small proportion of
the possible variants in these genes, and
referred her to clinical genetics in view of her
family history.
– Clinical genetic testing found that Lily had a
BRCA1 variant that conferred a high lifetime
risk of cancer.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829432/?report=printable

33. ACMG Position Statement
2016
● A knowledgeable professional should be involved in the process of ordering a
genetic test with medical implications
● Laboratory results should be interpreted and delivered by a board-certified
genetics professional
● A genetics professional should be available to help the consumer determine, for
example, whether a genetic test should be performed and how to interpret test
results in light of personal and family history
● The scientific evidence base describing the validity and utility of a genetic test
should be clearly stated
● The consumer should be fully informed regarding what the test can and cannot say
about his or her health
– Many direct-to-consumer genetic tests do not give a definitive answer regarding
whether an individual will develop a given condition

34. Prenatal DTC Testing
ACMG Position Statement 2021
• DTC testing for multi/polygenic diseases is
particularly troubling
– Especially when applied as a prenatal test to
mitigate genetic risk through selective embryo
termination
– A definitive and specific genetic diagnosis cannot
be made, only risk inferred.
• Prenatal testing for disorders with multigenic
or polygenic inheritance is not yet
appropriate for clinical use and should not
be offered as direct-to-consumer testing.

35. Privacy Problems with DTC testing
• When consumers opt into "research," many are providing third-
party access not only to their DNA but also to other types of
data the company has about you, which can include
information about your relatives
• Problems include:
– expansive permissions granted to companies regarding DNA
(and non-DNA) data when consumers opt in to research
– overcollection of non-DNA data
– oversharing of non-DNA data
https://www.consumerreports.org/dna-test-kits/privacy-and-direct-
to-consumer-genetic-testing-dna-test-kits-a1187212155/

36. Are DTC companies selling genetic data?
• 23andME original business concept
1. To sell DNA kits that would be of interest
2. To become very affordable
3. Tailor drugs to different genetic profiles
• Consent
– If checked allows various uses of the DNA,
including for profit
– 8.8 million of ~11 million consented (per
reference)
• The company is selling the data for use in
drug development
– 5 billion net worth
https://www.bloomberg.com/news/features/2021-11-04/23andme-to-use-dna-tests-to-make-cancer-drugs

37. Genetics Information
Non-Discrimination Act (GINA)
• Routine part of pre-test counseling in clinical practice
• GINA prevents employers and health insurance
companies from discrimination based on genetic
information
– Does NOT apply to disability insurance, life insurance, or
long-term care insurance
• These insurances can use medical information including genetic
information for underwriting, pricing, and other aspects of
insurance products
– GINA does NOT apply to certain federal programs and
groups
• U.S. Military, Department of Veteran affairs, or Indian Health
Service

38. Things you might discuss with a patient who is
considering a DTC genetic test
 Why do you want the test?
 Imagine receiving a result you are concerned about.
 Have you read all the information and small print about the test?
 Could your decision to have a test affect your family?
 Are you happy with what the DTC company might do with your
data?
 Do they understand the limitation of the genetic testing and
need to confirm a potentially actionable result?
https://pged.org/direct-to-consumer-genetic-testing/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829432/?report=printable

39. Thank you!