Medical Genetics. Impact of Genetic Disease Estimated that 3-7% of the general population will be diagnosed with a recognized genetic disorder, NOT INCLUDING.

Medical GeneticsMedical Genetics

Impact of Genetic DiseaseImpact of Genetic Disease

Estimated that 3-7% of the general population Estimated that 3-7% of the general population will be diagnosed with a recognized genetic will be diagnosed with a recognized genetic disorder, NOT INCLUDING common disorders, disorder, NOT INCLUDING common disorders, such as cancer, diabetes, heart disease and such as cancer, diabetes, heart disease and psychiatric disorderspsychiatric disorders ~3% of pregnancies are of a child with a significant ~3% of pregnancies are of a child with a significant

genetic disordergenetic disorder Genetic disorders account for 10% of pediatric Genetic disorders account for 10% of pediatric

admissions in the U.S.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. 9 of the CDC’s 10 Leading Causes of U.S. Deaths Have Genetic ComponentsDeaths 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%)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 GeneticsMedical Genetics

Any application of genetic principlesto medical practice.

“Genetics – study of individual genes and their effects”

Includes studies of inheritance, mappingdisease genes, diagnosis and treatment,and genetic counseling.

Genomic MedicineGenomic Medicine

Study of conditions that are partly caused or Study of conditions that are partly caused or prevented by mutation(s) in gene(s)prevented by mutation(s) in gene(s)

““GenomicsGenomics – study not just of single genes, but of the – study not just of single genes, but of the

functions and interactions of all the genes in the functions and interactions of all the genes in the genome”genome”

Mechanism for common/complex diseases – asthma, Mechanism for common/complex diseases – asthma, hypertension, diabetes, psychiatric disordershypertension, diabetes, psychiatric disorders

Why Do Health Professionals Need to Prepare Why Do Health Professionals Need to Prepare for Genomic Medicine?for Genomic Medicine?

Need to learn to “think genetically” - to:Need to learn to “think genetically” - to: realize when genetic factors play a rolerealize when genetic factors play a role effectively use family hx & genetic testseffectively use family hx & genetic tests be able to explain genetics conceptsbe able to explain genetics concepts deal with “risk” & genetic predispositiondeal with “risk” & genetic predisposition realize personal and societal impact of genetic realize personal and societal impact of genetic

informationinformation protect genetic privacyprotect genetic privacy use genetics to individualize patient careuse genetics to individualize patient care use genetics to preserve healthuse genetics to preserve health

Types Of Genetic DiseaseTypes Of Genetic Disease

Single gene disordersSingle gene disorders

Chromosomal disordersChromosomal disorders

Multifactorial/Polygenic disordersMultifactorial/Polygenic disorders Complex/Common diseasesComplex/Common diseases

DNA - DNA - deoxyribonucleic aciddeoxyribonucleic acid

The molecule inside each cell that carries the The molecule inside each cell that carries the genetic instructions for making living organisms.genetic instructions for making living organisms.

Double-stranded - made up of four building Double-stranded - made up of four building blocks called nucleotide blocks called nucleotide basesbases: A, T, C, G: A, T, C, G

The human genome has 3 billion pairs of bases. The human genome has 3 billion pairs of bases.

DNA in ContextDNA in Context

(Not to scale!)

Human Chromosome FactsHuman Chromosome Facts

# of chromosomes per somatic cell: 22 pairs + 1 pair # of chromosomes per somatic cell: 22 pairs + 1 pair sex-determining chromosomes = sex-determining chromosomes = 4646

# of chromosomes per gamete (egg/sperm): # of chromosomes per gamete (egg/sperm): 2323 One chromosome of each pair donated from each One chromosome of each pair donated from each

parent’s egg or spermparent’s egg or sperm Sex chromosomes: Sex chromosomes: XYXY for males; for males; XXXX for females for females Largest chromosome #1 = ~263 million base pairs (bp)Largest chromosome #1 = ~263 million base pairs (bp) Smallest chromosome Y = ~59 million bpSmallest chromosome Y = ~59 million bp

What’s a ___?What’s a ___?

GeneGene = = The functional and physical unit of heredity The functional and physical unit of heredity passed from parent to offspringpassed from parent to offspring

ChromosomeChromosome = Threadlike structures on which the = Threadlike structures on which the genes reside and are organizedgenes reside and are organized

LocusLocus = Position of a gene on a chromosome = Position of a gene on a chromosome

Mutation = Mutation = A change in the DNA sequence A change in the DNA sequence (permanent, heritable) (permanent, heritable)

What’s a ___?What’s a ___?

GenomeGenome = all of the DNA in an organism or cell = all of the DNA in an organism or cell

Size of human genome: Size of human genome: 3.4 billion base pairs3.4 billion base pairs Number of human genes: Number of human genes: ~30,000~30,000 Genes vary in length and can cover thousands of basesGenes vary in length and can cover thousands of bases

average size: ~3,000 bpaverage size: ~3,000 bp

Only about 5% of the human genome contains genesOnly about 5% of the human genome contains genes Action of much of the genome is unknownAction of much of the genome is unknown

Family HistoryFamily 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

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 familymembers, but do know the number of boys andthe number of girls, you can do this:

•If you do not know the number of boysand the number of girls, use diamond with number inside it (if total is known) or “?”.

Example: This shows that there are 8 children.

5 3Example: This shows that there

are 5 boys and 3 girls.

This line is used to show parents who are divorced/not together

SB

SB standsfor stillbirth.Include number of weeks, if known.

Single Gene Traits/DisordersSingle Gene Traits/Disorders

Those traits that are determined by one Those traits that are determined by one particular geneparticular gene Characterized by their transmission pattern in families Characterized by their transmission pattern in families

– – PEDIGREE ANALYSISPEDIGREE ANALYSIS Able to determine risks for particular family members Able to determine risks for particular family members

if know mode of inheritanceif know mode of inheritance

Common Genetic TermsCommon Genetic Terms

GenotypeGenotype: An individual’s genetic makeup - : An individual’s genetic makeup - forms of a forms of a particular gene at a given locusparticular gene at a given locus

PhenotypePhenotype: The observable expression of a : The observable expression of a genotype genotype

HomozygousHomozygous: Identical forms of a particular gene: Identical forms of a particular gene

HeterozygousHeterozygous: Different forms of a gene– CARRIER if one : Different forms of a gene– CARRIER if one normal and one abnormalnormal and one abnormal

Common Genetic TermsCommon Genetic Terms

DominantDominant: Condition phenotypically expressed : Condition phenotypically expressed in someone carrying one copy of a mutant genein someone carrying one copy of a mutant gene

RecessiveRecessive: Condition phenotypically expressed : Condition phenotypically expressed only in someone with two copies of the mutant only in someone with two copies of the mutant genegene

AUTOSOMAL DOMINANT INHERITANCE

Autosomal Dominant InheritanceAutosomal Dominant Inheritance

Vertical transmissionVertical transmission

On average, 50% of offspring of affected parent On average, 50% of offspring of affected parent

will be affectedwill be affected

Unaffected individuals do not transmit traitUnaffected individuals do not transmit trait

Males and females equally affectedMales and females equally affected

Autosomal Dominant ConditionsAutosomal Dominant Conditions

Marfan SyndromeMarfan Syndrome AchondroplasiaAchondroplasia Familial (early-onset) Alzheimer Disease Familial (early-onset) Alzheimer Disease Huntington DiseaseHuntington Disease Familial HypercholesterolemiaFamilial Hypercholesterolemia Familial Breast Cancer (BRCA1 or Familial Breast Cancer (BRCA1 or

BRCA2 mutations)BRCA2 mutations)

Autosomal Recessive InheritanceAutosomal Recessive Inheritance

Autosomal Recessive InheritanceAutosomal Recessive Inheritance

Horizontal transmission; disease in siblings but usually Horizontal transmission; disease in siblings but usually not in earlier generations (unaffected, carrier parents)not in earlier generations (unaffected, carrier parents)

On average, 25% recurrence riskOn average, 25% recurrence risk

Males and females equally affectedMales and females equally affected

Increased consanguinity (relatedness) seenIncreased consanguinity (relatedness) seen

Autosomal Recessive ConditionsAutosomal Recessive Conditions

Sickle cell disease Sickle cell disease Cystic fibrosisCystic fibrosis Tay-Sachs diseaseTay-Sachs disease Hemochromatosis Hemochromatosis PhenylketonuriaPhenylketonuria ThalassemiasThalassemias

X-linked Recessive InheritanceX-linked Recessive Inheritance

X-linked Recessive InheritanceX-linked Recessive Inheritance

Incidence of trait is much higher in males than femalesIncidence of trait is much higher in males than females No father-to-son transmissionNo father-to-son transmission 100% of daughters of affected males are (unaffected) 100% of daughters of affected males are (unaffected)

carriers carriers 50% of sons of carrier females are affected and 50% of 50% of sons of carrier females are affected and 50% of

daughters are carriersdaughters are carriers Trait may be transmitted through series of carrier Trait may be transmitted through series of carrier

femalesfemales

X-linked Recessive DisordersX-linked Recessive Disorders

Duchenne muscular dystrophyDuchenne muscular dystrophy Hemophilia AHemophilia A Color blindnessColor blindness Glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase

(G6PD) deficiency(G6PD) deficiency

Is Cancer Inherited?Is Cancer Inherited?

Most cancers are NOT inheritedMost cancers are NOT inherited Not due to a predisposing factor that is passed Not due to a predisposing factor that is passed

down from parent to childdown from parent to child 95-90% are “sporadic”95-90% are “sporadic” No clear pattern in the familyNo clear pattern in the family ““Later” age of onsetLater” age of onset

Sporadic CancerSporadic Cancer

Breast

Ovarian

dx. 76

Hereditary CancerHereditary Cancer

5-10% of all cancers5-10% of all cancers Multiple relatives Multiple relatives

affectedaffected Early onset Early onset Multiple cases of Multiple cases of

cancer in same relativecancer in same relative ““Rare” cancersRare” cancers

Hereditary CancerHereditary Cancer

dx. 55

Breast

Ovarian

dx. 42dx. 61

dx. 44

dx. 38

dx. 76

““Red Flags”Red Flags”

Multiple cases of breast cancer in the same Multiple cases of breast cancer in the same genetic lineage, particularly at a young agegenetic lineage, particularly at a young age

Presence of breast and ovarian cancer on the Presence of breast and ovarian cancer on the same side of the familysame side of the family

Early age at diagnosis (particularly breast Early age at diagnosis (particularly breast cancers)cancers)

Male breast cancerMale breast cancer Bilateral breast cancerBilateral breast cancer

'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.”

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

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”

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