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

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.

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

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

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

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

Case 3: consanguinity A newly Canadian patient presents pregnant 24 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

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

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

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

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

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

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

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

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

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

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):734-742. Negative Positive

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

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: https://www.google.ca/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjvk83UovXTAhVF8RQKHeo3B6cQjRwIBw&url=https%3A%2F%2Fwww.khanacademy.org%2Fscience%2Fbiology%2Fher%2Fheredity-and-genetics%2Fv%2Fgenetic-drift-bottleneck-effect-and-founder-effect&psig=AFQjCNEWbhWdfRBsTFxPPs1WQhKftx_XCg&ust=1495053559163593

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

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

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

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

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

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

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

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

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

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?)

Sample report Sample report from Counsyl http://www.lifelabsgenetics.com/wp-content/uploads/2015/04/Sample-Report-Individual-Carrier.pdf

Sample report

Sample report

Sample report

Sample report

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

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

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

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

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

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