1. Consanguinity Developed by Dr. Judith Allanson, Ms. Shawna Morrison and Dr. June Carroll Last updated November 2015

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 consanguinity – Discuss and address patient concerns regarding consanguinity – Find high quality genomics educational resources appropriate for primary care

4. Case 1 You have a new patient to your practice, 32yo woman in good health She is a recent immigrant from Northern Africa and lives with her husband and their two sons ages 6 and 4, all are in good health She is about 9 weeks pregnant

5. Case 1 You are discussing conventional prenatal screening options (e.g. integrated prenatal screening) with her and she reveals that she and her husband are related by blood and asks if there are any tests available to better assess the couple’s chance of having a child with health concerns

6. P 6 4 32 35 ~9W Your patient’s familyHow are your patient and her husband related? 1A 3A 2B 1B 2A 1A and 1B are siblings (1 st degree relatives) 2A and 2B are first cousins (3 rd degree relatives) 3A and 2B are first cousins, once removed (4 th degree relatives) 1 1 2 3 1 2 3 4

7. Consanguinity Consanguinity is defined as a union between two individuals who are related as second cousins (5 th degree relatives) or closer One billion of the current global population live in communities with a preference for consanguineous union

8. 1a 1b 2a2b 2c 2d 1c 1d 3a 3b 4a 4b Double second cousins 1a 1b 2a2b 4b4a Second cousins 3a 3b

9. Consanguinity 20-50% of all unions in North Africa, Middle and West Asia, and South India (and immigrants from these communities) are consanguineous First cousin unions account for about 1/3 of all marriages Preference for a consanguineous union: – Cultural continuity – Family solidarity – Reduction of uncertainty associated with health and financial issues

10. What does consanguinity mean for my patient? The chance for adverse outcome in the offspring of a consanguineous union is not an absolute number but rather an estimate based on: – Family history – Degree of consanguinity – Background population risk The risk for a more closely related union is higher and for a more distantly related union is lower When there is no known genetic diagnosis in the family, first cousin unions are at a 1.7-2.8% additional risk above the general population risk of 2-3% to have offspring with a congenital anomaly (e.g. congenital heart defect)

11. Offspring, siblings, parents, grandparents, aunts, uncles, nieces, nephews, and first cousins of your patient, as appropriate (1 st, 2 nd, 3 rd degree relatives) Ethnicity of all grandparents Congenital anomalies Intellectual disability, learning disability, developmental delay or regression Inherited disorders (e.g. thalassemia) Early hearing and/or vision impairment Failure to thrive Unexplained neonatal or infant death Seizure disorder Undiagnosed severe conditions The first step and best tool for counselling a couple with consanguinity involves taking a detailed family history.

12. Online family history assistance www.geneticseducation.cawww.geneticseducation.ca > Point of Care tools > Family history > General family history tool PDF download (can be scanned into electronic medical record) General family history tool

13. Who should be offered referral for genetic consultation? Positive family history congenital anomalies, intellectual disability or suspected genetic condition Offer ethnicity-based screening and if both members of the couple are carriers of the same condition, or if both are carriers of a hemoglobinopathy

14. Back to case 1 You are discussing conventional prenatal screening options your patient who is about 9 weeks pregnant She has revealed that she and her husband are related by blood and asks if there are any tests available to better assess the couple’s chance of having a child with medical concerns

15. Case 1 Your patient and her husband are first cousins once removed You take a detailed family history and there are no reported significant health or developmental issues 1A 3A 2B 1B 2A You normalize for your patient that, in the absence of a genetic diagnosis in the family, all couples have a 2-3% risk of to have offspring with a congenital anomaly (e.g. congenital heart defect) For consanguineous couples, there is a small additional risk above the general population risk less than 2x for first cousins once removed as they are more distantly related that first cousins where the additional risk is 1.7-2.8% above the general population

16. Case 1 As with non-consanguineous couples, you offer your patient: – Conventional prenatal screening for fetal aneuploidy (trisomy 13, 18, 21) E.g. first trimester screening (FTS), integrated prenatal screening (IPS), serum integrated prenatal screening (SIPS) or quad screening – Second trimester ultrasound for dating, assessment of fetal anatomy As your patient and her husband are of North African ancestry you offer the couple hemoglobinopathy screening (thalassemia and sickle cell disease screening) – Recommended screening is both CBC, to assess the MCV and MCH, and hemoglobin electrophoresis or high performance liquid chromatography (HPLC)

17. Typical Prenatal Testing Algorithm Offer PN screening to all pregnant women 18-20 week fetal morphology scan FTS/IPS/SIPS/Quad NIPT for AMA and for women willing to pay Family history Ethnicity-based screening* If positive *for ethnicity-based screening, if both members of the couple are carriers of the same condition If negative or decline Refer to Genetics If indicated (e.g. fetal anomalies ) AMA = Advance Maternal Age, age 40y or older at estimated date of birth NIPT = non-invasive prenatal testing; FTS = first trimester screening ; IPS = integrated prenatal screening; serum integrated prenatal screening (SIPS)

18. Consanguinity Pearls Take a detailed family history to identify familial and/or ethnicity-specific disorders and screen accordingly In the absence of a positive family history, the risk for a first-cousin union to have a child with a congenital anomaly is about 4-6% (about 2x population risk) – The risk for a more closely related union is higher and for a more distantly related union is lower Refer or consult genetics when in doubt

19. Resources See www.geneticseducation.ca for more details and how to connect to your local genetics centrewww.geneticseducation.ca More information can be found the resources GECKO on the run and GECKO MessengerGECKO on the run GECKO Messenger To learn more about Canadian ethnicity-based carrier screening recommendations see the GECKO point of care toolthe GECKO point of care tool For a tool to assist in family history taking see the GECKO point of care toolsee the GECKO point of care tool