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Medical Genetics 101

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Head, Division of Human Genetics. University of Maryland School of Medicine ... able to explain genetics concepts. deal with 'risk' ... Human Chromosome Facts ... – PowerPoint PPT presentation

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Title: Medical Genetics 101


1
Medical Genetics 101
  • Miriam G. Blitzer, PhD
  • Professor, Department of Pediatrics and
    Obstetrics, Gynecology Reproductive Sciences
  • Head, Division of Human Genetics
  • University of Maryland School of Medicine

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
  • 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 CDCs 10 Leading Causes of U.S.
Deaths Have Genetic Components
  • 1. Heart disease (31.0 of deaths in 98)
  • 2. Cancer (23.2)
  • 3. Stroke (6.8)
  • 4. COPD (4.8)
  • 5. Injury (4.2)
  • 6. Pneumonia/Influenza (3.9)
  • 7. Diabetes (2.8)
  • 8. Suicide (1.3)
  • 9. Kidney 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)
  • 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

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

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

9
DNA - deoxyribonucleic acid
  • 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
  • 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 gamete (egg/sperm) 23
  • One chromosome of each pair donated from each
    parents egg or sperm
  • Sex chromosomes XY for males XX for females
  • Largest chromosome 1 263 million base pairs
    (bp)
  • Smallest chromosome Y 59 million bp

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

13
Whats a ___?
  • Genome all of the DNA in an organism or cell
  • Size of human genome 3.4 billion base pairs
  • Number of human genes 30,000
  • Genes vary in length and can cover thousands of
    bases
  • average size 3,000 bp
  • Only about 5 of the human genome contains genes
  • 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
This line is used to show parents who are
divorced/not together
Adopted
  • 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 ?.

The diagonal line is used to show that the
person has died.
Pregnancy loss. Include number of weeks, if
known.
Example This shows that there are 5 boys and 3
girls.
3
5
SB stands for stillbirth. Include number of
weeks, if known.
SB
8
Example This shows that there are 8 children.
16
Single Gene Traits/Disorders
  • Those traits that are determined by one
    particular gene
  • Characterized by their transmission pattern in
    families PEDIGREE ANALYSIS
  • Able to determine risks for particular family
    members if know mode of inheritance

17
Common Genetic Terms
  • Genotype An individuals genetic makeup -
    forms of a particular gene at a given locus
  • Phenotype The observable expression of a
    genotype
  • Homozygous Identical forms of a particular gene
  • 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
  • Recessive Condition phenotypically expressed
    only in someone with two copies of the mutant
    gene

19
AUTOSOMAL DOMINANT INHERITANCE
20
Autosomal Dominant Inheritance
  • Vertical transmission
  • On average, 50 of offspring of affected parent
    will be affected
  • Unaffected individuals do not transmit trait
  • Males and females equally affected

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

22
Autosomal Recessive Inheritance
23
Autosomal Recessive Inheritance
  • Horizontal transmission disease in siblings but
    usually not in earlier generations (unaffected,
    carrier parents)
  • On average, 25 recurrence risk
  • Males and females equally affected
  • Increased consanguinity (relatedness) seen

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

25
X-linked Recessive Inheritance
26
X-linked Recessive Inheritance
  • Incidence of trait is much higher in males than
    females
  • No father-to-son transmission
  • 100 of daughters of affected males are
    (unaffected) carriers
  • 50 of sons of carrier females are affected and
    50 of daughters are carriers
  • Trait may be transmitted through series of
    carrier females

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

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

29
Sporadic Cancer
dx. 76
Breast
Ovarian
30
Hereditary Cancer
  • 5-10 of all cancers
  • Multiple relatives affected
  • Early onset
  • Multiple cases of cancer in same relative
  • Rare cancers

31
Hereditary Cancer
dx. 42 dx. 61
dx. 55
dx. 44
dx. 76
Breast
Ovarian
dx. 38
32
Red Flags
  • 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
  • Early age at diagnosis (particularly breast
    cancers)
  • Male 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 40s - 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
Family history a genomic tool
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.
36
Family history is an independent risk factor for
most chronic diseases of public health
significance
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