Genetics and Health Miriam G. Blitzer, PhD Professor, Department of Pediatrics Head, Division of Human Genetics University of Maryland School of Medicine September 10, 2008

What is the most important reason to think about human genetics? WE ARE!!! Your genes can be compared to your own personal ‘blueprint.’ Our genes hold the secrets to who we are, where we’re from and how we’re made.

Overview GENETICS 101 What are genes and DNA? What are genes and DNA? What is Genomic Medicine and why is it important to our health? What is Genomic Medicine and why is it important to our health? How do we inherit genetic disease? How do we inherit genetic disease? How can knowing our family history improve our health? How can knowing our family history improve our health?

DNA in Context (Not to scale!) The human body is made of millions of cells. Each contains identical copies of all of our genetic material.

DNA in Context (Not to scale!) The human body is made of millions of cells. Each contains identical copies of all of our genetic material.

DNA - deoxyribonucleic acid The molecule inside each cell that carries the genetic instructions for making living organisms – Instruction Manual The molecule inside each cell that carries the genetic instructions for making living organisms – Instruction Manual 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

Human sperm contains 23 chromosomes: numbers 1-22 plus either an X or a Y chromosome. A human egg contains 23 chromosomes: numbers 1-22 plus a single X chromosome. The union of sperm and egg creates a human embryo with 46 complete chromosomes. embryo l) m)

What’s a ____? Gene = segment of DNA coding a compound, (responsible for every body function) Gene = segment of DNA coding a compound, (responsible for every body function) Genome = all of the DNA in an organism Genome = all of the DNA in an organism Size of human genome: 3.4 billion base pairs Size of human genome: 3.4 billion base pairs Number of human genes: ~25,000 Number of human genes: ~25,000 Only about 5% of the human genome contains genes Only about 5% of the human genome contains genes

What is a Mutation?? Change in the DNA - Change in the DNA - Substitution of one base (“letter”) for another Substitution of one base (“letter”) for another Deletion or duplication of a piece of DNA sequence Deletion or duplication of a piece of DNA sequence Insertion of new DNA material Insertion of new DNA material COULD LEAD TO DISEASE, MILD VARIATION or NO CLINICAL FINDINGS AT ALL COULD LEAD TO DISEASE, MILD VARIATION or NO CLINICAL FINDINGS AT ALL MOST IMPORTANT – leads to variation -> make us individuals!

Impact of Genetic Disease Estimated that 3-7% of the population will be diagnosed with a recognized genetic disorder, NOT INCLUDING common disorders, such as cancer, diabetes, heart disease, and psychiatric disorders ~3% of newborns have a significant genetic disorder ~3% of newborns have 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.

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

> 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%)

Medical Genetics/Genomic Medicine Underlying basis for ALL conditions, including common/complex diseases – asthma, hypertension, diabetes, psychiatric disorders “Genomics – study not just of single genes, but of the functions and interactions of all the genes in the genome”

Family History Reflects the consequences of genetic background, 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.

PEDIGREE SYMBOLS 2 PROBAND AFFECTED DECEASED

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.

GrandfatherGrandmother FatherMother You Sister Brother NieceNephew AuntUncle Half-sister (same mother, different father) GrandfatherGrandmother Mexico Pregnancy Loss 8 weeks England and Germany Uncle Adopted First cousins Twins Non-identical months High blood pressure High cholesterol 60’s Colon cancer 70’s Breast cancer (diagnosed 68) 65 Heart attack ’s-40’s 3 2 First cousin Club foot

Single Gene Traits/Conditions Those traits that are determined by a change in one particular gene Those traits that are determined by a change in one particular gene Characterized by their transmission pattern in families Characterized by their transmission pattern in families Able to determine risks for specific family members if know how this is passed on in the family Able to determine risks for specific family members if know how this is passed on in the family

Autosomal Dominant Inheritance Vertical transmission (generation to generation) Vertical transmission (generation to generation) 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 pass on trait Unaffected individuals do not pass on trait Males and females both affected Males and females both affected

Autosomal Dominant Conditions Marfan Syndrome Marfan Syndrome Achondroplasia (common Dwarfism) Achondroplasia (common Dwarfism) 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)

Autosomal Recessive Inheritance: Carrier female, UNAFFECTEDCarrier male, UNAFFECTED AFFECTED CARRIER CARRIER NON-CARRIER NOT-AFFECTED 25% chance 50% chance 25% chance X

Autosomal Recessive Inheritance Trait typically seen in siblings but usually not in earlier generations (unaffected, carrier parents) Trait typically seen 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 Carriers of the mutant gene are normal but can pass the trait to offspring

Autosomal Recessive Conditions Sickle Cell disease Sickle Cell disease Cystic Fibrosis Cystic Fibrosis Tay-Sachs disease Tay-Sachs disease Phenylketonuria (PKU) Phenylketonuria (PKU) Thalassemias Thalassemias

X-linked Recessive Traits Duchenne muscular dystrophy Duchenne muscular dystrophy Hemophilia A Hemophilia A Color blindness Color blindness

Common Diseases With a Confirmed Genetic Component Hypertension Hypertension Diabetes Mellitus I & II Diabetes Mellitus I & II Alzheimer Disease Alzheimer Disease Cardiovascular disease Cardiovascular disease Cancer Cancer Osteoporosis Osteoporosis Psoriasis Psoriasis Glaucoma Age-related Hearing Loss Schizophrenia Bipolar Disease Depression

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 90-95% are “sporadic” 90-95% are “sporadic” No clear pattern in the family No clear pattern in the family “Later” age of onset “Later” age of onset

Sporadic Cancer Breast Ovarian dx. 76

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

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

“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

What is a Genetic Counselor? Master’s Level trained Health Professional Master’s Level trained Health Professional Work with the patient and family to : Work with the patient and family to : Understand the medical facts of the genetic condition Understand the medical facts of the genetic condition Learn more about genetics and risk of recurrence Learn more about genetics and risk of recurrence Understand the available options Understand the available options Help make decisions about those options Help make decisions about those options Provide emotional and psychosocial support Provide emotional and psychosocial support

Why focus on family history? 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

Most important genetic evaluation (test) FAMILY HISTORY FAMILY HISTORYwww.ashg.orgwww.hhs.gov/familyhistory/

Surgeon General’s American Family Health Initiative Thanksgiving – Family History Day Thanksgiving – Family History Day “… every time you get together with your family, you should have a conversation to learn more about who among your family and blood relatives suffered from what kinds of illnesses - and then write it down with the new tool or just on a piece of paper so you will remember to tell it to your doctor. You’ll be amazed at what you learn - and not just about disease.” “… every time you get together with your family, you should have a conversation to learn more about who among your family and blood relatives suffered from what kinds of illnesses - and then write it down with the new tool or just on a piece of paper so you will remember to tell it to your doctor. You’ll be amazed at what you learn - and not just about disease.” --Former U.S. Surgeon General Richard H. Carmona

U.S. Surgeon General’s Family History Initiative Web-based or paper copy

“ The most powerful ties are to the ones who gave us birth…….no matter how many years have passed, we remain connected.” Anthony Brandt a) b)