Uf Cop Pbd Genetics

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There are over ------ genetic diseases known today.

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8000

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The life years lost from birth defects due to genetic causes is ---times that from cancer and --- times that of heart disease

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3.5 times that from cancer
6.5 times that of heart disease

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Define Pharmacogenomics—

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the study of how inherited genetic differences in humans influence

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Define Dominant traits:

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allele whose effects are observable. Can be expressed if homozygote or heterozygote state.

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To be co-dominant...

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both allele members of a gene pair are expressed in the heterozygote

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Define Recessive trait:

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requires homozygote condition of genes to be present – allele whose effect are hidden.

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Define Homozygote gene:

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required for recessive allele to be expressed. Both alleles (one for each loci) are identical.

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Defiine Heterozygote gene:

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Different allele at each locus of gene. One allele dominant over the other.

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Define Hemizygote:

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males are hemizygote for genes on the X chromosome i.e. not homozygote or heterozygote. Have no corresponding loci.

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Define Penetrance:

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(statistical term) – refers to the percentage of individuals with a specific genotype who also exhibit the expected phenotype.

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Define Karyotype:

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identification of individual chromosomes prepared by slides during metaphase.

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Diseases caused by cytogenetic defects results in

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A change in number or structure of chromosomes.

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Frequency of cytogenetic defects: (conceptions and live births)

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1 of 12 conceptions (8%)
1 of every 150 live births (0.7%)

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----% of all spontaneous abortions have a chromosomal abnormality

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50%

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True/False Cytogenetic diseases are usually not inherited?

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True

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Define an aneuploid cell:

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Somatic cells that do not contain a multiple of 23 chromosomes

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Define trisomy:

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3 copies of 1 chromosome

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Define monosome:

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Only 1 copy – not compatible with life (if autosome)

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aneuploidy is a result of ________________ (which can occur in mitosis or meiosis

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Nondisjunction

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Diagnosis of cytogenetic disease are...

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initially made by physical signs associated with the phenotype

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How do you confirm diagnosis of cytogenetic diseases?

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Karyotype

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True/False
Cytogenic abnormalities of sex chromosomes are LESS common than autosomal abnormalities

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False, MORE common.

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Example of Autosomal deletion (of part of chromosome)-Disease State:

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Cri-du-chat syndrome (5p-)

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Cri-du-chat syndrome (5p-) Characteristics (3)

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-1/50,000 births

50% with cardiovascular abnormalities

Mental (mean IQ~20) and growth retardation

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Deletion of sex chromosome Disease State Example:

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Turner's syndrome (45, XO) - no homologous X or Y

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Turner's syndrome (45, XO) - Characteristics (6)

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-1/2500 life births(99% aborted)
Phenotypic female
Sterile
Short stature
Webbed neck
35% cardiovascular abnormalities

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Would Turner's Syndrome always be recognizable at birth?

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Not Necessarily-More so at puberty.

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In Turner's Syndrome it Appears transcription level on remaining x chromosome is......

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upregulated

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True/False In Turner's Syndrome individuals have male pattern for x-linked disorders

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True.

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Individuals who have Turner's Syndrome are more susceptible to other conditions, such as

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metabolic syndrome, hypertension, CAD, osteoporosis.

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True/False Sex chromosome additions are more severe than autosomal additions

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False. Less.

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Example of Sex Chromosome Addition (Disease State):

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Klinefelter’s syndrome (47, XXY)

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Klinefelter’s syndrome (47, XXY) Characteristics: (8)

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1/500-700 newborn males
Phenotypic male
Sterile- small testicles
Sparse body hair
Gynecomastia
abdominal adipostiy
Tall
2/3 may never be diagnosed

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Other health issues more common in these individuals who have Klinefelter’s syndrome:

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Osteoporosis
- Varicose Veins
- Autoimmune diseases
-ncreased risk for breast cancers and cancers that affect bone, bone marrow and lymph nodes.

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Example of an Autosomal addition (Disease State):

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Trisomy 21 - Down's syndrome - most common live birth (47XY+21)

See Power Point for Numerous Characterisitcs.

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3% of Trisomy 21 cases are due to

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translocation – may be inherited

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97% of Trisomy 21 cases are due to

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Nondisjunction

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1-3% of Trisomy Cases are mosaic meaning :

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symptoms are less severe

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True/False Risk of trisomy increases with advancing age

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True -Although 73% of Down's syndrome infants born to women below 35 years of age.

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There are over -----Diseases Caused by Single Gene Defects known:

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3000

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Diseases Caused by Single Gene Defects account for ---% of live births

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1-3%

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True/False- You can diagnosis diseases caused by single gene defects with a karyotype

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False-Because individuals have all of their chromosomes -there is only a difference in how the phenotypes are being expressed.

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Autosomal dominant characteristics (4)

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1.If 100% penetrance, always expressed in phenotype
- No carriers

2.Relatively mild.

3. Many cases may have a delay in onset

4.Usually involves some structural gene.

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Most Common of all Mendelian disorders

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Familial hypercholesterolemia -chromosome 19

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Familial hypercholesterolemia Charcteristics (4)

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Frequency of heterozygotes is 1:5000 in general population
Lack of LDL surface receptor
Environment plays significant role
Increased synthesis of LDL
Elevated plasma cholesterol

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Familial hypercholesterolemia Elevated Plasma Cholesterol Levels for Heterozygote

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2-3 fold higher than normal (300-400 mg/dl)

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Familial hypercholesterolemia Elevated Plasma Cholesterol Levels for homozygote and usual cause of death?

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Can be 5 times normal level (600-1200 mg/dl)
-Usually die from CAD as teen

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True/False Familial hypercholesterolemia-is not a disease candidate for gene therapy?

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False-It is a candidate.

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True/False Familial hypercholesterolemia is a Co-Dominant Disease?

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True-Different Degrees of expression depending if your heterozygous/homozygous.

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Autosomal Recessive Genes result when there are

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inborn errors of metabolism

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In Autosomal Recessive Gene Disorders the gene either

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does not function or produce a crippled form of protein (enzyme)

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True/False with Autosomal Recessive Gene Disorders the trait does not usually affect parent

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True.

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With Autosomal Recessive Gene Disorders Siblings have _____% chance of being affected if 2 carriers mate, _____% will be carriers (Aa x Aa) –

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1. 25% chance
2. 50% will be carriers

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Primary example of Autosomal Recessive Disorder:

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PKU - Phenylketonuria

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PKU - Phenylketonuria results from a problem on chromosome---

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12

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Frequency of PKU - Phenylketonuria

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1/15,000 births

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PKU - Phenylketonuria Characteristics:(3)

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• phenylalanine hydroxylase deficiency get accumulation of phenyalanine– CNS damage

Ist biochemical cause for mental retardation

98% mental retardation if not treated

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Treatment for Phenylketonuria

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Alter diet to reduce amount of phenyalanine.

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True/False Phenylketonuria is a candidate for gene thereapy?

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True

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most common lethal single autosomal - recessive defect in North America

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Cystic Fibrosis - (chromosome 7)

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Cystic Fibrosis Frequency

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25-35,000 people in US (1:2500 white births in US; 1:17,000 in African Americans, 1:90,000 in Asians)

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Cystic Fibrosis Pathogenesis

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altered electrolyte transport of chloride ion across epithelial cell membrane
Defect in CFTR – cystic fibrosis transmembrane

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Cystic Fibrosis most common error

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in codon 580 of the 1480 aa protein

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True/False Cystic Fibrosis is a repiratory Disease?

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False- Even though most die from respiratory complications its really an exocrine disease.

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Should Cystic Fibrosis be screened for at birth?

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Yes.

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True/False Cystic Fibrosis is not a candidate for gene therapy>

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False

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X-linked defects include:

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Hemophilia, color blindness, fragile X syndrome, some forms of muscular dystrophy)

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True/False X-linked defects are almost always associated with the x chromosome and are predominately dominant.

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False. They are predominately recessive.

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--------patients more susceptible for x-linked defects

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Turner's

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Can a father transmit a X-linked disease to his son?

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No- Father passes Y chromosome to son

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Most disorders are caused by

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Cooperation of many genes and environmental risk factors

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True/False with Polygenetic/multifactorial diseases a pattern of disease cannot be predicted but we can say if will have a strong or weak tendency for a particular trait.

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True

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Teratogenic disease are the Study of factors related to

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developmental defects arising during the embryonic period of development

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most frequent agents implicated in Teratogenic Diseases

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Environmental agents include radiation, chemical, drugs, infection (TORCH- toxoplasmosis, other, rubella, cytomegalovirus, and herpes.) -.

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Frequency of Teratogenic Diseases

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Over 200,000 births in US have defects and over 600,000 infant deaths, spontaneous abortions, still births and miscarriages. Most from genetic abnormalities but large % due to teratogenic inputs

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Most clearly defined example of intrauterine infection as teratogen

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the congenital rubella syndrome

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the congenital rubella syndrome nearly eradicated in US. How?

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Immunization-Although now on an upswing.

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Thalidomide (tranquilizer) tragedy

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(banned worldwide in 1962 after some 12,000 babies born with missing or malformed limbs)
-first 20-30 days of pregnancy

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Thalidomide Mode of action of drug is to

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reduce TNF alpha – a cytokine --to inhibit portions of the inflammatory system and arrests blood vessel growth

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True/False Thalidomide is no longer around?

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False. It is still used for the treatment of Lupas, cancer, and leprosy.

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Implications for future usage of Thalidomide based on mode of action?

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1. Inhibit grouw of cancer cells.
2. Potential used in AIDS patients-blocks viral replication.

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3 Major clinical sighns/syndroms of Fetal Alcohol Syndrome?

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1. Cranofacial
2. Growth- No postnatal catch-up growth
3. CNS abnormalities
See PP for more details.

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MOST KNOWN TERATOGENIC CAUSE OF MENTAL DEFICIENCY IN THE WESTERN WORLD

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Alcohol.

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Incidence Rate of Fetal Alcohol syndrome?

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a) 1979-1:10,000
1996-6-7:10,000
As of 1989 there is a checkbox on the birth certificate
b) highest incidence – American Indians 9-10/1000

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Possible pathogenesis of Fetal Alcohol Syndrome:

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Zinc Deficiency, not malnutrition.

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End result of teratogens acting on developing embryonic tissues

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either death, malformation, retardation of growth, or functional disturbance.

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What are the three ways teratogens can cause birth defects?

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a) direct exposure to mother (may alter the metabolism of agent) and fetus
b) exposure to mother (prior to pregnancy) of agent that is retained during pregnancy
c) mutagenic effects from an environmental agent that takes place before pregnancy and effects reproductive cells

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True/False FDA has established a system to classify drugs according to the risk to the fetus: A, B, C, D, AND X

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True. - if marketed before 1983 – not classified

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Two most common genetic disorders that can be detected in the second trimester of pregnancy

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Down Syndrome
Neural Tube Closure Defects

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Down Syndrome Frequency

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5000 new cases/yr

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Neural tube closure defects include

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include spina bifida (1-4/1000) and anencephaly – open spine disorders

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Neural Tube Closure Defects Frequency

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~2500 births/yr / ~ 4000 conceptions /yr

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Neural Tube Closure Defects Characteristics

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increased recurrence risk
relationship to folic acid

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Two most common genetic disorders that can be detected in the second trimester of pregnancy

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Down Syndrome
Neural Tube Closure Defects

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Down Syndrome Frequency

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5000 new cases/yr

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Neural tube closure defects include

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include spina bifida (1-4/1000) and anencephaly – open spine disorders

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Neural Tube Closure Defects Frequency

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~2500 births/yr / ~ 4000 conceptions /yr

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Neural Tube Closure Defects Characteristics

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increased recurrence risk
relationship to folic acid

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True/False 2-3 fold increase in incidence of NTD if increased body temperature over 100 F during first 12 weeks of pregnancy

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False- During first 6 weeks of pregnancy.

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Used to Diagnosis Neural Tube Disorders

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Alpha fetal protein
Must be 4-5 SD above the mean before reasching diagnostic criteria.

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Purpose of prenatal diagnosis (4)

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1. detect fetal abnormalities 2. provide parents with resources/support groups to make informed choice
3. provide reassurance and reduce anxiety in high risk groups
4. assure parents at risk and who want a family to proceed with assurance that the disorder can be confirmed by testing

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triple screen test is performed between --- weeks of gestation

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16-20

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Maternal blood sample - triple screen test

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Alpha fetal protein (FP)- (peaks at 32 weeks in maternal blood)
If high suggestive for NTD; if low suggestive for Trisomy 21

Unconjugated estriol- low suggestive for Tirsomy 21

Chorionic gonadotropins- high suggestive for Trisomy 21

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if combine all three markers of Triple Screen MAY detect up to

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60% of Trisomy 21

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Other current blood tests can be used to detect: (3)

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-cystic fibrosis
-sickle cell anemia
-thalassemia

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True/False For great majority of birth defects and inherited diseases there are no specific chromosomal or biochemical tests at present

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True

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Visualization of fetus (ultrasound) Features

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- can detect 11-35% of chromosomal abnormalities
confirm most NTD
weeks 16-18

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True/False With a level 3 ultrasound you can detect several different types of chromosomal abnormalities?

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False-Level 2

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Sampling of amniotic fluid and cells is known as

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amniocentesis

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Amniotic fluid represents primarily

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fetal urine and contains cells sloughed off from the skin, respiratory tract and urinary tract

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________ wk of pregnancy (2nd trimester) before obtain amniotic fluid sample

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15-16 week

Takes takes 2-3 weeks to complete tests

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True/False a Normal amniocentesis test necessitates a normal child.

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False. Recognize that 3 to 5% of live born babies have serious congenital anomalies and an additional 1-2% will develop mental retardation so a normal amniocentesis test does not necessitate a normal child

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Indications for amniocentesis? (5)

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35 years of age
previous child with cytogenetic, NTD
abnormal ultrasound finding x-linked carrier
heterozygote parent of autosomal recessive disorder

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Sampling of amniotic fluid can show (5)

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Cytogenetic disorders
x-linked disorders
NTD
Inborn errors of metabolism (with more extensive testing)

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Example of Sampling fetal blood serum and tissue

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PUBS – Percutaneous Umbilical Blood Sampling

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PUBS – Percutaneous Umbilical Blood Sampling Features

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usually sample after 16 week (2nd trimester)

results (cytogenetic) within 48-72 hours

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Chorionic Villi Features

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Can only be perform in 1st trimester (8-12 week)
-Most results within hours to days – depending of what evaluating

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Can Chorionic Villi Sampling (CVS)– detect NTD and/or Trisomy 21?

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NTD-No levels of Alpha Fetal Proten won't be up yet

Trisomy 21- Yes, can take Karyotype.

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Newborn screening identified -----children/yr that were in need of some form of treatment.

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3,400 children

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True/Flase It is not possible to trear genetic disorders in utero at at birth

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False.

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Future Trends- (2)

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• Treatment of existing disease with gene therapy

• Modification of drug therapy based on genetics.

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True/False: diseases are routinely screened in newborns?

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True