1. Expanded carrier screening
Developed by Ms. Shawna Morrison, Dr. Judith Allanson and Dr. June Carroll
Last updated June 2017

2. Disclaimer
This presentation is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein.

3. Objectives Following this session the learner will be able to:
Refer to their local genetics centre and/or order genetic testing appropriately regarding reproductive genetic carrier screening
Discuss with patients expanded carrier screening, beyond family history and ethnicity
Find high quality genomics educational resources appropriate for primary care

4. Case 1: my sister said… A healthy non-consanguineous couple
Both are 33 years old
Your patient is of French Canadian and Northern European ancestry
Her partner is of German and English ancestry
There is no significant family history for either member of the couple
Planning to start their family

5. Case 1: my sister said…
Your patient’s sister is 2 years older and also recently married
She lives in Boston, MA and was offered a family planning carrier screening panel which was partly covered by her health insurance
Your patient would also like to have this panel and understands that she would have to pay for the test herself
She needs you to order the test
Physician signature here____________
She has brought all the completed paperwork to you

6. Case 2: family history A healthy non-consanguineous couple
Male is 42 years of age; Female is 36 years of age
Male is of Ashkenazi Jewish ancestry
Female is of Irish and Scottish ancestry
Female’s father has late onset Pompe disease
Autosomal recessive
Glycogen storage disease
Presentation is dependant upon residual enzyme function
Without treatment by enzyme replacement therapy (ERT), IOPD commonly results in death by age two years from progressive left ventricular outflow obstruction and respiratory insufficie
Late onset:
proximal muscle weakness
respiratory insufficiency
no cardiomyopathy
Infantile onset (<4months of age):
generalized muscle weakness
respiratory distress
hypertrophic cardiomyopathy

7. Case 3: consanguinity A newly Canadian patient presents pregnant24 27
Take a standard 3-generation family history
Everyone is alive, well and healthy
Couple reveals they are consanguineous (their parents are brother and sister) making them first cousins
First cousins share about 12% (1/8) of their genes

8. Case 3: consanguinity Targeted prenatal/preconception history 24 27 P
~9W 24 27
> Point of Care tools > Reproductive Genetic Carrier Screening

9. Case 3: consanguinity d.13m d.18m d.12m 24 27
Symptoms of affected children:
Very irritable around 6 months of age
Loss of milestones
Seizures
Rigid/restricted muscles
Vision loss
Grandparents are also consanguineous (uncle and niece) meaning there is a higher degree of relatedness and so more genes are shared
~9W P

10. Why offer traditional reproductive carrier screening?
To facilitate informed reproductive decision making by identifying those couples at risk of having an affected child with an (autosomal or X-linked) recessive disorder

11. How is traditional reproductive carrier screening offered?
Screening is ideally offered to all individuals considering a pregnancy (pre-conception) and to women presenting at their first prenatal visit, regardless of gestational age
Allows for the greatest number of options with more time to make an informed decision
Adoption
Egg or Sperm donor
Assisted reproductive technology (i.e. in vitro fertilization with preimplantation genetic diagnosis (IVF with PGD))
Prenatal diagnosis with the option of termination
Consideration of a different reproductive partner
Limitation of family size or not have children 
Wilson 2016 JOGC

12. How is traditional reproductive carrier screening offered?
Screening is ideally offered to all individuals considering a pregnancy (pre-conception) and to women presenting at their first prenatal visit, regardless of gestational age
Allows for the greatest number of options with more time to make an informed decision
Discussion about the value and risk of carrier screening
Wilson 2016 JOGC

13. How is traditional reproductive carrier screening offered?
Screening is ideally offered to all individuals considering a pregnancy (pre-conception) and to women presenting at their first prenatal visit, regardless of gestational age
Offered following guidelines which are based on family history and ethnicity
Family history-based risk assessment is still the gold standard in initial assessment for heritable conditions
Wilson 2016 JOGC

14. What are the Canadian recommendations for reproductive carrier screening?
Geneticseducation.ca > Point of Care Tools > Reproductive genetic carrier screening in Canada

15. What are the Canadian recommendations for reproductive carrier screening?
Geneticseducation.ca > Point of Care Tools > Reproductive genetic carrier screening in Canada

16. Five facts about expanded carrier screening
1. Screening beyond guidelines, family history and ethnicity
Allows testing of all individuals regardless of family history, ethnicity or geographic origin

17. Five facts about expanded carrier screening
1. Screening beyond guidelines, family history and ethnicity
2. Increased detection of carriers of serious inherited disorders
A large study (n=23,453) found that about 24% of individuals were identified as a carrier of at least one of 108 disorders (Lazarin 2013 Genet in Med)
Negative
Negative
Possibility to ‘avoid’ more affected pregnancies
Theoretically will detect more at risk couples that with guideline only carrier testing
More positive results means more counselling issues
Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening. JAMA. 2016;316(7):
Negative
Positive

18. Five facts about expanded carrier screening
1. Screening beyond guidelines, family history and ethnicity
2. Increased detection of carriers of serious inherited disorders
3. Technology is rapidly advancing and the costs are decreasing
Decreasing cost = increasing demand, on top of marketing targeting family planners
~995$/person

19. Five facts about expanded carrier screening
1. Screening beyond guidelines, family history and ethnicity
2. Increased detection of carriers of serious inherited disorders
3. Technology is rapidly advancing and the costs are decreasing
4. There are several limitations and so pre- and post-counselling is important but not always available
Indications for genetics referral
Available genetic services
Accessing formal genetic counselling
Bottleneck image:

20. Five facts about expanded carrier screening
1. Screening beyond guidelines, family history and ethnicity
2. Increased detection of carriers of serious inherited disorders
3. Technology is rapidly advancing and the costs are decreasing
4. There are several limitations and so pre- and post-counselling is important but not always available
Discrepant results between laboratories
Variant classification differs
Reporting differs – some report VUS some only likely pathogenic
Differences in re-contacting when variants re-classified
Likely benign
Likely pathogenic
VUS

21. Five facts about expanded carrier screening
1. Screening beyond guidelines, family history and ethnicity
2. Increased detection of carriers of serious inherited disorders
3. Technology is rapidly advancing and the costs are decreasing
4. There are several limitations and so pre- and post-counselling is important but not always available
Can’t eliminate all risk even with negative test results
Not all conditions, even all recommended via guideline and if indicated by family history are included
Risk assessment assumes correct paternity

22. Five facts about expanded carrier screening
1. Screening beyond guidelines, family history and ethnicity
2. Increased detection of carriers of serious inherited disorders
3. Technology is rapidly advancing and the costs are decreasing
4. There are several limitations and so pre- and post-counselling is important but not always available
5. Is generally not considered standard of care
Provincial funding has been requested and approved in certain cases
Is generally a self-pay service

23. Five facts about expanded carrier screening
1. Screening beyond guidelines, family history and ethnicity
2. Increased detection of carriers of serious inherited disorders
3. Technology is rapidly advancing and the costs are decreasing
4. There are several limitations and so pre- and post-counselling is important but not always available
5. Is generally not considered standard of care
Panels do not typically distinguish between serious and mild, or early-onset and late-onset conditions
Unclear clinical utility and relevance in reproductive planning

24. Geneticseducation.ca > Point of Care Tools > Expanded Carrier Screening

25. Geneticseducation.ca > Point of Care Tools > Expanded Carrier Screening

26. Geneticseducation.ca > Point of Care Tools > Expanded Carrier Screening

27. Low risk to have child affected with condition on panel
Negative
Reassurance.
Low risk to have child affected with condition on panel
Does not eliminate risk
Consider:
Family history
Ethnicity

28. Usually no screening or medical management recommendations
Positive
Patient is a carrier
Patient has one or more gene mutations which may have health implications e.g. familial hypercholesterolemia, hereditary hemochromatosis
Usually no screening or medical management recommendations
Consider offering same panel to the partner
Refer to Genetics if both members are carriers of the same recessive condition
Offer referral to an appropriate specialist (e.g. geneticist, lipid specialist, hematologist)
Encourage patient to share results with family members

29. Most companies do not report VUS for carrier screening
Variant
Negative
Positive
Most companies do not report VUS for carrier screening
Benign and likely benign generally not reported
Consider:
The gene
The disorder
The literature
Specialist consultation (via company?)

30. Sample report
Sample report from Counsyl

31. Sample report

32. Sample report

33. Sample report

34. Sample report

35. Case 1: my sister said… Would you arrange testing? A) Yes B) No
A healthy non-consanguineous couple
Neither are of an ‘at-risk’ ethnicity
No reported significant family history
Physician signature here____________
Would you arrange testing?
A) Yes
B) No

36. Case 2: family history
Are they good candidates for expanded carrier screening?
Yes No
Maybe
Ashkenazi Jewish 42 36
Female’s father has late onset Pompe disease
Female is obligate carrier of AR disease
Healthy
Non consanguineous couple
Male is of Ashkenazi Jewish ancestry

37. Are they good candidates for expanded carrier screening?
Case 2: family history
Are they good candidates for expanded carrier screening?
Yes No
Maybe 36 42
Ashkenazi Jewish
Yes!
Because female is obligate carrier, to assess couple’s risk of having an affected child, carrier testing of male partner is needed
AJ panels test 3 or more genes
ECS can screen for 4+ disorders at one time (for less cost and less time)
Healthy
Non consanguineous couple
Offer referral to genetics for family history and AJ carrier screening

38. Are they good candidates for expanded carrier screening?
Case 3: consanguinity
d.13m
d.18m
d.12m 24 27
Are they good candidates for expanded carrier screening?
Yes No
Maybe
Symptoms of affected children:
Very irritable around 6 months of age
Loss of milestones
Seizures
Rigid/restricted muscles
Vision loss
Double loop of consanguinity means higher degree of relatedness and more genes are shared
~9W P

39. Are they good candidates for expanded carrier screening?
Case 3: consanguinity
Are they good candidates for expanded carrier screening?
Yes No
Maybe
Maybe!
Familial disorder does look AR
ECS panels do screen for many AR disorders, but not all
 Residual risk unknown
Offer referral to genetics
Family records, pictures, previous testing/assessment
Other testing may be considered

40. Expanded carrier screening may be appropriate for:
Individuals who [have limited family history and] would make reproductive choices based on the results
Couples who would be offered carrier screening for several recessive disorders on a panel based on family history, ethnicity or other
May be more cost and time effective
Consanguineous couples, especially those who have a family history of an undiagnosed recessive disorder
Results may not confirm or rule out a diagnosis, but may provide reassurance or additional information