1. Medical Genetics

2. Impact of Genetic Disease Estimated that 3-7% of the general population will be diagnosed with a recognized genetic disorder, NOT INCLUDING common disorders, such as cancer, diabetes, heart disease and psychiatric disorders ~3% of pregnancies are of a child with a significant genetic disorder ~3% of pregnancies are of a child with a significant genetic disorder Genetic disorders account for 10% of pediatric admissions in the U.S. Genetic disorders account for 10% of pediatric admissions in the U.S.

3. ALL DISEASE (WITH THE POSSIBLE EXCEPTION OF TRAUMA) IS GENETIC!

4. > 9 of the CDC’s 10 Leading Causes of U.S. Deaths Have Genetic Components 1. Heart disease (31.0% of deaths in ‘98) 1. Heart disease (31.0% of deaths in ‘98) 2. Cancer (23.2%) 2. Cancer (23.2%) 3. Stroke (6.8%) 3. Stroke (6.8%) 4. COPD (4.8%) 4. COPD (4.8%) ? 5. Injury (4.2%) 6. Pneumonia/Influenza (3.9%) 6. Pneumonia/Influenza (3.9%) 7. Diabetes (2.8%) 7. Diabetes (2.8%) 8. Suicide (1.3%) 8. Suicide (1.3%) 9. Kidney disease (1.1%) 9. Kidney disease (1.1%) 10. Chronic liver disease (1.1%) 10. Chronic liver disease (1.1%)

5. Medical Genetics Any application of genetic principles to medical practice. “Genetics – study of individual genes and their effects” Includes studies of inheritance, mapping disease genes, diagnosis and treatment, and genetic counseling.

6. Genomic Medicine Study of conditions that are partly caused or prevented by mutation(s) in gene(s) Study of conditions that are partly caused or prevented by mutation(s) in gene(s) “Genomics – study not just of single genes, but of the functions and interactions of all the genes in the genome” “Genomics – study not just of single genes, but of the functions and interactions of all the genes in the genome” Mechanism for common/complex diseases – asthma, hypertension, diabetes, psychiatric disorders Mechanism for common/complex diseases – asthma, hypertension, diabetes, psychiatric disorders

7. Why Do Health Professionals Need to Prepare for Genomic Medicine? Need to learn to “think genetically” - to: Need to learn to “think genetically” - to: realize when genetic factors play a role realize when genetic factors play a role effectively use family hx & genetic tests effectively use family hx & genetic tests be able to explain genetics concepts be able to explain genetics concepts deal with “risk” & genetic predisposition deal with “risk” & genetic predisposition realize personal and societal impact of genetic information realize personal and societal impact of genetic information protect genetic privacy protect genetic privacy use genetics to individualize patient care use genetics to individualize patient care use genetics to preserve health use genetics to preserve health

8. Types Of Genetic Disease Single gene disorders Single gene disorders Chromosomal disorders Chromosomal disorders Multifactorial/Polygenic disorders Multifactorial/Polygenic disorders Complex/Common diseases Complex/Common diseases

9. DNA - deoxyribonucleic acid The molecule inside each cell that carries the genetic instructions for making living organisms. The molecule inside each cell that carries the genetic instructions for making living organisms. Double-stranded - made up of four building blocks called nucleotide bases: A, T, C, G Double-stranded - made up of four building blocks called nucleotide bases: A, T, C, G The human genome has 3 billion pairs of bases. The human genome has 3 billion pairs of bases.

10. DNA in Context (Not to scale!)

11. Human Chromosome Facts # of chromosomes per somatic cell: 22 pairs + 1 pair sex-determining chromosomes = 46 # of chromosomes per somatic cell: 22 pairs + 1 pair sex-determining chromosomes = 46 # of chromosomes per gamete (egg/sperm): 23 # of chromosomes per gamete (egg/sperm): 23 One chromosome of each pair donated from each parent’s egg or sperm One chromosome of each pair donated from each parent’s egg or sperm Sex chromosomes: XY for males; XX for females Sex chromosomes: XY for males; XX for females Largest chromosome #1 = ~263 million base pairs (bp) Largest chromosome #1 = ~263 million base pairs (bp) Smallest chromosome Y = ~59 million bp Smallest chromosome Y = ~59 million bp

12. What’s a ___? Gene = The functional and physical unit of heredity passed from parent to offspring Gene = The functional and physical unit of heredity passed from parent to offspring Chromosome = Threadlike structures on which the genes reside and are organized Chromosome = Threadlike structures on which the genes reside and are organized Locus = Position of a gene on a chromosome Locus = Position of a gene on a chromosome Mutation = A change in the DNA sequence (permanent, heritable) Mutation = A change in the DNA sequence (permanent, heritable)

13. What’s a ___? Genome = all of the DNA in an organism or cell Genome = all of the DNA in an organism or cell Size of human genome: 3.4 billion base pairs Size of human genome: 3.4 billion base pairs Number of human genes: ~30,000 Number of human genes: ~30,000 Genes vary in length and can cover thousands of bases Genes vary in length and can cover thousands of bases average size: ~3,000 bp average size: ~3,000 bp Only about 5% of the human genome contains genes Only about 5% of the human genome contains genes Action of much of the genome is unknown Action of much of the genome is unknown

14. Family History Reflects the consequences of genetic susceptibilities, shared environment and common behaviors Allows us to identify potentially inherited disorders in families Is an independent risk factor for most chronic diseases of public health significance

15. Male / boy Female / girl Pregnancy loss. Include number of weeks, if known. The diagonal line is used to show that the person has died. Adopted 8 What if there is limited information about family members? If you do not know names and ages of family members, but do know the number of boys and the number of girls, you can do this: If you do not know the number of boys and the number of girls, use diamond with number inside it (if total is known) or “?”. Example: This shows that there are 8 children. 5 3 Example: This shows that there are 5 boys and 3 girls. This line is used to show parents who are divorced/not together SB SB stands for stillbirth. Include number of weeks, if known.

16. Single Gene Traits/Disorders Those traits that are determined by one particular gene Those traits that are determined by one particular gene Characterized by their transmission pattern in families – PEDIGREE ANALYSIS Characterized by their transmission pattern in families – PEDIGREE ANALYSIS Able to determine risks for particular family members if know mode of inheritance Able to determine risks for particular family members if know mode of inheritance

17. Common Genetic Terms Genotype: An individual’s genetic makeup - forms of a particular gene at a given locus Genotype: An individual’s genetic makeup - forms of a particular gene at a given locus Phenotype: The observable expression of a genotype Phenotype: The observable expression of a genotype Homozygous: Identical forms of a particular gene Homozygous: Identical forms of a particular gene Heterozygous: Different forms of a gene– CARRIER if one normal and one abnormal Heterozygous: Different forms of a gene– CARRIER if one normal and one abnormal

18. Common Genetic Terms Dominant: Condition phenotypically expressed in someone carrying one copy of a mutant gene Dominant: Condition phenotypically expressed in someone carrying one copy of a mutant gene Recessive: Condition phenotypically expressed only in someone with two copies of the mutant gene Recessive: Condition phenotypically expressed only in someone with two copies of the mutant gene

19. AUTOSOMAL DOMINANT INHERITANCE

20. Autosomal Dominant Inheritance Vertical transmission Vertical transmission On average, 50% of offspring of affected parent will be affected On average, 50% of offspring of affected parent will be affected Unaffected individuals do not transmit trait Unaffected individuals do not transmit trait Males and females equally affected Males and females equally affected

21. Autosomal Dominant Conditions Marfan Syndrome Marfan Syndrome Achondroplasia Achondroplasia Familial (early-onset) Alzheimer Disease Familial (early-onset) Alzheimer Disease Huntington Disease Huntington Disease Familial Hypercholesterolemia Familial Hypercholesterolemia Familial Breast Cancer (BRCA1 or BRCA2 mutations) Familial Breast Cancer (BRCA1 or BRCA2 mutations)

22. Autosomal Recessive Inheritance

23. Horizontal transmission; disease in siblings but usually not in earlier generations (unaffected, carrier parents) Horizontal transmission; disease in siblings but usually not in earlier generations (unaffected, carrier parents) On average, 25% recurrence risk On average, 25% recurrence risk Males and females equally affected Males and females equally affected Increased consanguinity (relatedness) seen Increased consanguinity (relatedness) seen

24. Autosomal Recessive Conditions Sickle cell disease Sickle cell disease Cystic fibrosis Cystic fibrosis Tay-Sachs disease Tay-Sachs disease Hemochromatosis Hemochromatosis Phenylketonuria Phenylketonuria Thalassemias Thalassemias

25. X-linked Recessive Inheritance

26. Incidence of trait is much higher in males than females Incidence of trait is much higher in males than females No father-to-son transmission No father-to-son transmission 100% of daughters of affected males are (unaffected) carriers 100% of daughters of affected males are (unaffected) carriers 50% of sons of carrier females are affected and 50% of daughters are carriers 50% of sons of carrier females are affected and 50% of daughters are carriers Trait may be transmitted through series of carrier females Trait may be transmitted through series of carrier females

27. X-linked Recessive Disorders Duchenne muscular dystrophy Duchenne muscular dystrophy Hemophilia A Hemophilia A Color blindness Color blindness Glucose-6-phosphate dehydrogenase (G6PD) deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency

28. Is Cancer Inherited? Most cancers are NOT inherited Most cancers are NOT inherited Not due to a predisposing factor that is passed down from parent to child Not due to a predisposing factor that is passed down from parent to child 95-90% are “sporadic” 95-90% are “sporadic” No clear pattern in the family No clear pattern in the family “Later” age of onset “Later” age of onset

29. Sporadic Cancer Breast Ovarian dx. 76

30. Hereditary Cancer 5-10% of all cancers 5-10% of all cancers Multiple relatives affected Multiple relatives affected Early onset Early onset Multiple cases of cancer in same relative Multiple cases of cancer in same relative “Rare” cancers “Rare” cancers

31. Hereditary Cancer dx. 55 Breast Ovarian dx. 42 dx. 61 dx. 44 dx. 38 dx. 76

32. “Red Flags” Multiple cases of breast cancer in the same genetic lineage, particularly at a young age Multiple cases of breast cancer in the same genetic lineage, particularly at a young age Presence of breast and ovarian cancer on the same side of the family Presence of breast and ovarian cancer on the same side of the family Early age at diagnosis (particularly breast cancers) Early age at diagnosis (particularly breast cancers) Male breast cancer Male breast cancer Bilateral breast cancer Bilateral breast cancer

33. 'This is happening every day' ( CNNSI Online-June 24, 2002) “Kile's father's death from cardiovascular disease in his 40’s - should have been a red flag signaling that the pitcher had an increased risk of the same fate.” “Patients with a strong family history should get rigorous routine checkups including cholesterol screening, exercise stress tests or heart imaging tests.”

34. Why focus on family history? News stories about sudden cardiac death FH is underutilized in preventive medicine Geneticists use of pedigrees FH is risk factor for many common diseases Current strategies not working (diet, exercise, smoking) Jim Fixx 1932 - 1984

35. Most common diseases result from interactions of multiple genes with multiple environmental factors in complex patterns that - despite progress in sequencing the human genome – are unlikley to be fully understood in the near future. In the meantime, family medical history represents a “genomic tool” that can capture the interactions of genetic susceptibility, shared environment and common behaviors in relation to disease risk. Family history – a “genomic tool”

36. Family history is an independent risk factor for most chronic diseases of public health significance