This document discusses genetic counseling and provides information on: 1. Genetic counseling involves evaluating family history, testing, and establishing diagnoses to educate individuals on genetic diseases and inheritance risks. 2. Calculating risks involves determining modes of inheritance and using statistical methods like Mendelian laws and Bayes' theorem. 3. Special considerations include reduced penetrance, delayed onset, phenocopies, pleiotropy, and special populations/relationships.

1. Genetic Counseling Weiying Jiang Department of Medical Genetics P253

2. Genetic counseling should be provided by a medical specialist who has been trained in genetic counseling.

3. Definition of Genetic counseling An educational counseling process for individuals and families who have a genetic disease or who are at risk for such a disease.

4. The medical diagnosis and its implications in terms of prognosis and treatment. The mode of inheritance of the disorder and the risk of developing and transmitting it. The choice or option available for dealing with the risk. Genetic counseling: What should we do?

5. Evaluation of the family history Discussion of the importance of testing other family members who are at risk for or to be a carrier. Genetic counseling: What should we do?

6. Taking a history Examination Investigation laboratory tests Establishing the diagnosis

7. Taking a history Family history Personal medical history

8. Genetic counseling: physical examination

9. Neonatal screening Genetic counseling: laboratory tests Prenatal diagnosis: Cytogenetics, biochemistry, DNA, and/or other testing;

10. Genetic counseling: Genetic heterogeneity A similar phenotype being caused by more than one genetic mechanism. Most commonly used for a similar phenotype being caused by mutations in different genes. Allelic heterogeneity refers to different mutations in the same gene.

11. Genetic counseling: Genetic heterogeneity Hearing loss Non-special mental retardation

12. How to do genetic counseling? A standard prenatal screening test showed the alpha fetoprotein increased.

13. The mother has had two or more miscarriages or babies that died in infancy

15. Down’ syndrome Down’ syndrome

19. 1 ． Genotype - Known ： estimating the probability of recurrence risk by Mendelian law AD ， AR ， XD ， XR 2. Genotype - Unknown ： estimating the probability of recurrence risk by Bayes law Genetic counseling: Calculating and presenting the risk (P330)

20. AD Known-Genotype 1/2

21. carrier = (2/4)/(1/4+2/4)=2/3 AR ¼ patient ； ¼ normal ； ½ carrier Normal phenotype

22. AR 2/3 1/3 2/3 1/2 1/4

23. XD

24. XD 1/2 1/2

25. XR

26. Genetic counseling: Calculating and presenting the risk (P330) Please pay attention to the followings: Delayed age of onset Reduced penetrance Expressivity Phenocopy Pleiotropy

27. Genetic counseling: Calculating and presenting the risk (Reduced penetrance) (p332) 1/2 1/2(1-P) Joint 1/2(1-P) ∻1/2(1-P)+1/2 =(1-p) ∻(2-p) posterior 1 1-P Not affected Conditional 1/2 1/2 Prior Ⅱ⒈ is not heterozygous Ⅱ⒈ is heterozygous Probability Table 22.2 Bayesian calculation for Ⅱ⒈in Fig.22.2

28. Genetic counseling: Calculating and presenting the risk (Delayed age of onset) (p332) 1/4∻(1/4+1/2) =1/3 posterior 1/2 1/4 Joint 1 1/2 Unaffected at age 50 years Conditional 1/2 1/2 Prior Ⅱ⒈ is not heterozygous Ⅱ⒈ is heterozygous Probability Table 22.3 Bayesian calculation for Ⅱ⒈in Fig.22.4

29. DMD- Heterozygote CK: µ Mol/L Numbers of the heterozygote

30. Genetic counseling: Calculating and presenting the risk (X-linkage recessive inheritance) p336 1/2 1/48 Joint 1/48∻(1/48+1/2) =1/25 posterior 1 1/3 Normal creatine kinase 1 1/8 Three healthy sons Conditional 1/2 1/2 Prior Ⅱ⒉ is not a carrier Ⅱ⒉ is a carrier Probability Table 22.5 Bayesian calculation for Ⅱ⒉in Fig.22.1

31. Phenocopy: 1.An environmental condition that imitates (copies) one produced by a gene. 2. The person who has an environmentally-produced condition that mimics one produced by a gene. Genetic counseling: Calculating and presenting the risk (P330) Noise

32. Definition of pleiotropy: The phenomenon whereby a single mutation affects several apparently unrelated aspects of the phenotype . Genetic counseling: Calculating and presenting the risk (P330)

33. Genetic counseling: Quantification (p255) 1 in 4 An odds ratio of 3 to 1 against

34. Genetic counseling: Quantification (p255) Tail (50% chance) Head (50% chance)

35. Genetic counseling: Qualification (p255) Normal Abnormal

36. Genetic counseling: Discussing the option Establishing the diagnosis Discussing the risk of occurrence and reoccurrence Counselor provide all information

37. Genetic counseling: Discussing the option Making informed decision by consultants

38. Total probability= 1/64+ 1/64=32 Genetic counseling: Special problems Consanguinity: 1/2 1/4 1/8 1/2 1/4 1/8 1/64

39. Genetic counseling: Special problems Incest Brother –Sister parent– child Marriage between first degree relatives is forbidden

40. Genetic counseling: Special problems Adoption

41. Genetic counseling: Special problems Disputed paternity

42. Thank you!