1. Introduction to Inheritance Sara Levene Registered Genetic Counsellor London IDEAS Genetic Knowledge Park

3. Mendelian Genetics

4. Genetic conditions are not very common

5. Inheritance Patterns  Autosomal dominant (AD)  Autosomal recessive (AR)  X-Linked (X-L)

6. Dominant Inheritance 

8. Common Autosomal Dominant Disorders  Huntington Disease  Marfan syndrome  Myotonic dystrophy  Neurofibromatosis  Breast / ovarian cancer susceptibility (BRCA1/2)  Familial Adenomatous polyposis  Hereditary Non-Polyposis Colorectal cancer (HNPCC)

9. Recessive Inheritance Affected individualCarrierNon carrierCarrier

10. Recessive Inheritance

11. Common Autosomal Recessive Disorders  Cystic Fibrosis  Sickle cell anaemia  Thalassaemia  Tay Sachs disease  Spinal muscular atrophy  PKU  Haemachromatosis

12. X-Linked Inheritance Affected boy Carrier girl Non carrier boy Non carrier girl  

13. X-Linked Inheritance

14. Common X-Linked Disorders  Duchenne muscular dystrophy  Becker muscular dystrophy  Haemophilia  Fragile X syndrome

15. Multifactorial Inheritance

16.  Familial clustering (does not conform to patterns of Mendelian inheritance).  Recurrence risks ~2–4% (compared to higher risks in Mendelian disorders)  Caused by interaction of genetic and environmental factors  None of these factors are well understood!

17. Multifactorial Inheritance: Congenital malformations  Cleft lip/palate  Congenital dislocation of the hip  Congenital heart defects  Neural tube defects  Pyloric stenosis  Talipes

18. Multifactorial Inheritance: Acquired diseases of childhood and adult life  Asthma  Autism  Diabetes mellitus  Epilepsy  Glaucoma  Hypertension  Inflammatory bowel disease (Crohn disease/ulcerative colitis)  Ischaemic heart disease  Ischaemic stroke  Manic depression  Multiple sclerosis  Parkinson disease  Psoriasis  Rheumatoid arthritis  Schizophrenia

19. Theory of Polygenic inheritance (Continuous inheritance)  Many genes at different loci, with each gene exerting a small additive effect  Effects of the genes are cumulative i.e. no one gene is dominant or recessive  Applies to characteristics that show normal distribution in the population e.g. height, IQ (bell curve)  ? Application of this model to discontinuous multifactorial disorders (affected/not affected)

20. Liability / Threshold Model  ‘Bad’ genes + adverse environmental factors = liability to disorder  Liability = continuous variable (normal distribution)  Above threshold abnormal phenotype expressed.  General population – beyond the threshold is the population incidence  Relatives of cases – beyond the threshold is the familial incidence  Recurrence risk depends on number of affected relatives and closeness to index case