Genetics Exam 2

Front 1

Down Syndrome genetics

Back 1

Trisomy 21:

47,XY,+21

Front 2

Down syndrome cause

Back 2

Maternal Meiosis 1 Non disjunction = 95%

5% = roberstonian translocation or mosaicism for Trisomy 21

Front 3

Down syndrome clinical presentation

Back 3

Redundant skin, short fingers, hypopigmented patches (brush field spots) in iris of the eye , simean crease

Severe retardation

Gastrointestinal obstruction 3%
Respiratory infections Common
Leukemia 15-20 X
Congenital heart defect 40%
Moderate to severe mental retardation 100%
Development:

Front 4

Edward Syndrome

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Trisomy 18

47,XY,+18

Front 5

Edward syndrome appearance

Back 5

"Little Old man"

a. •Prominent occiput
b. •Micrognathia
c. •Microcephaly
d. •Low set malformed ears
e. •Characteristic clenched fists
f. •Rocker-bottom feet
g. •Congenital anomalies of lungs, diaphragm, and kidneys

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Trisomy 18 incidence

Back 6

1:6000 live births

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Trisomy 21 incidence

Back 7

1 in 800 live births

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Trisomy 13 appearance

Back 8

Distinctive malformation pattern
i. (Craniofacial and Central Nervous System)



Cleft lip +/- palate
Low set ears with abnormal helices
Holoprosencephaly
Cardiac defects
Polydactyly of the hands and feet

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Trisomy 13 incidence

Back 9

1: 10,000 live births

95% spontaneously abort

Front 10

Turner syndrome cytogenics

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45x - 50%
45x/46XY (mosaic)- 30-40%
Structural x abnormalities -10-20%
80% due to paternal meiotic error
15-20% abort

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What trisomy is the most common abnormality in stillbirths with mulitple congenital abnormalities?

Back 11

Trisomy 18

Front 12

Turner syndrome incidence

Back 12

1:5000 female births (but many spontaneously abort)

Front 13

Turner syndrome appearance

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c. Individuals are very short, they are usually infertile. Characteristic body shape changes include a broad chest with widely spaced nipples and may include a webbed neck
i. Coarctation of aorta 20%
ii. Structural kidney defects 50%

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Turner syndrome RX

Back 14

Growth hormone & estrogen

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Klinefelter syndrome cytogenics

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47xxy

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Klinefelter incidence

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1:1000 males

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Klinefelter syndrome inheritance

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50% maternal/50% paternal in origin

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Linefelter syndrome phenotype

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c. Small testes, poorly developed secondary sex features due to low testosterone
d. Tall and thin, slightly lower IQ

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Wolf-hirschhorn syndrome cytogenics

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Deletion 4p16.3 Karyotpe

(loss of tip of 4p) - terminal portion

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Wolf-hirschhorn incidence

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1 in 50,000

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Wolf-hirschhorn phenotype

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c. Fetal growth restriction
d. Microcephaly
e. Hypotonia
f. Characteristic facial appearance (greek helmut facies)
g. Severe mental retardation
h. Seizures
i. Posterior midline scalp defects

Front 22

DiGeorge/Velo-cardio-facial syndrome

Back 22

Most common MICRODELETION syndrome in humans

22q11 microdeletion syndrome

Front 23

DiGeorge/Velo-cardio-facial syndrome phenotype

Back 23

i. Very variable
ii. DiGeorge = more severe
iii. Velo-Cardio-faicial syndrome = less severe (hole in soft palate)
iv. Appearance: Hypernasal speech, characteristic facial appearances, specific learning disabilities

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DiGeorge/Velo-cardio-facial syndrome Incidence

Back 24

1 in 4000

Front 25

Short arm name

Back 25

P arm

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Long arm name

Back 26

Q arm

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Sub-metacentric

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P arm is shorter than Q arm

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Heterochromatin

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Not transcribed

Large heterochromatin regions on 1,9,16, and Y arm

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Euchromatin

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Transcribed

Front 30

Achrocentric

Back 30

Specialized very small P arm that has repetitive RNA sequence and ribosomal RNA genes (satellites)

Occurs on 13,14,15,21,22

Front 31

When can you see chromosome?

Back 31

Metaphase

Front 32

G-Banding

Back 32

Routine Banding method in the US

GTG: G bands produced with Trypsin using Giemsa

Standard G-banding karyotype scans whole genome for deletions/duplications at least 5mb

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Q banding

Back 33

First banding developed

Uses fluorochromes that bind to DNA and flourescence - requires flourescence microscope

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C Banding

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Stains constitutive heterochromatin around the centromeres and other heterochromatin regions (1, 9, 16, Y)

CBG - C bands produced with Barium using Giemsa

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R banding

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Opposite (Reverse) of G banding

Front 36

What's more lethal? Monosomy or Trisomy

Back 36

Monosomy

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Aneuploidy

Back 37

Complete: Gain or loss of whole chromosome

Partial: Gain or loss of part of chromosome

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Polyploidy

Back 38

Extra set of chromosomes ex 69XXX

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Triploidy

Back 39

i. One complete extra set of chromosomes.
ii. Caused by polyspermy, fertilization of an egg by more than one sperm.
iii. Usually spontaneously abort.
iv. Fetus with IUGR and very small placental when complement is maternal (digyny)
v. Well grown fetus and large cystic complement is paternal (diandry)

Front 40

Abnormalities related to advanced maternal age?

Back 40

Trisomy 13, 18, and 21 and Monosomy X

Front 41

Sex chromosome aneuploidy

Back 41

Because of X-inactivation and the paucity of genes on the Y chromosome, aneuploidies involving the sex chromosomes are far more common and less severe than those involving autosomes.


Some genes on the X-chromosome are also present on the Y chromosome (pseudoautosomal regions) and some escape X-inactivation.

ex Klinefelter

Front 42

Unipatental disomy (upd)

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Both genomes originate from the same parent

Front 43

Hydatidiform moles

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Parental origin Uniparental diploidy

No fetal parts only trophoblast hyperplasia

Sperm reduplicates its genome and fertilizes empty egg - 46xxis most common karyotype

Front 44

Ovarian teratormas

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Maternal origin UPD

Disorganized embryonic material
Activated unovulated oocyte

Front 45

Uniparental disomy

Back 45

two of same chromosome from one parent and none from the other, will give you a phenotype if one of the ones that carry imprinted genes – 6, 7, 11, 14, 15, 16

Affects a SINGLE PAIR of chromosomes

Front 46

Trisomy Rescue

Back 46

a genetic phenomenon in which a fertilized ovum containing three copies of a chromosome loses one of these chromosomes to form a normal, diploid chromosome complement. If both of the retained chromosomes came from the same parent, then uniparental disomy results.

Front 47

Robertsonian Translocation

Back 47

Translocation between acrocentric chromosomes. Short arms are lost and long arms fuse at centromere (5% of Down syndrome cases) [46,XX,der(14;21)(q10;q10),+21]

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Inversion

Back 48

a. An inversion consists of two breaks in one chromosome. The area between the breaks is inverted (turned around), and then reinserted and the breaks then unite to the rest of the chromosome.
i. Pericentric: includes centromere
ii. Paracentric: does not include centromere

Front 49

deletions

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Loss of a chromosomal segment

partial deletion can be viable: ex 4p Wolf-Hirschhorn Syndrome

Front 50

Microdeletions

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Not visible by routine Karyotype analysis

Recurrent sporadic rearrangement

Partial monosomy or trisomy (1-4 MB of DNA)

DOSAGE SENSITIVE

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Contiguous gene deletion syndrome

Back 51

syndrome caused by a microdeletion that spans two or more genes tandemly positioned along a chromosome. Microdeletion is often too small to be visualized using conventional cytogenetic techniques; detection often requires fluorescent in situ hybridization (FISH).

Front 52

Isochromosomes

Back 52

a. two P arms go to one daughter and two Q arms go to the other… splitting of chromatids during miosis, can happen that you misdivide the centromere and two p arms go to one and two q arms go to the other and then get an ISOCHROMOSOME of either P or Q arm

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Ring Chromosome

Back 53

Chromosomes
a. Break on P arm and Q arm leading to “sticky ends” b/c you lose the telomeres, in order to protect the chromosome, a ring will form to keep chromosome from being degraded

ex Ring X - r(X) is most common cause of Turner syndrome

Front 54

Supernumary marker chromosomes (SMCs)

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Additional piece of a chromosome - too small to identify w/ molecular methods; if it has euchromatin, will have phenotype associated w/ it

Front 55

FLOURESCENCE IN SITU HYBRIDIZATION (FISH)

Back 55

a. FISH is a physical DNA mapping technique in which a DNA probe labeled with a marker molecule is hybridized to chromosomes on a slide, and visualized using a fluorescence microscope
b. The marker molecule is either fluorescent itself, or is detected with a fluorescently labeled antibody.

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Interphase FISH

Back 56

Prenatal diagnosis aneuploidy by FISH looks at interphase nuclei derived from direct chorionic villi or amniocytes

FISH investigates small regions of the genome for deletions/duplications of about 50-500 kb, but is targeted.

Front 57

Metaphase FISH

Back 57

Performed on CULTURED cells and probe will hybridize to both nuclei and metaphase chromosomes

Front 58

FISH Applications

Back 58

Chromosome identification
ii. • Aneuploidy Detection in prenatals
iii. • Marker chromosome identification
iv. • Total chromosome Analysis
v. • Translocation Analysis
vi. • Microdeletion Syndrome Analysis
vii. • Gene Amplification Analysis in cancer

Front 59

Unique Sequence Probes

Back 59

Identifies a specific region on a particular chromosome

1.Microdeletion syndrome analysis
2.Translocations
3.Oncology/Pathology\

Front 60

Telomeric Specific Probes

Back 60

Identifies the subtelomeric region of a particular chromosome

1. Translocations
2. Cryptic translocation
3. Terminal deltions/duplications

Front 61

Array CGH (comparative genomic hybridization)

Back 61

In situ hybridization of differentially labeled specimen DNA & normal reference DNA to DNA targets spotted onto glass slides


The relative amounts of specimen & reference DNA hybridized at a particular chromosome position are contingent on the relative excess of those sequences in the two DNA samples & can be quantified by calculation of the ratio of their different fluorescent colors.

Front 62

Copy number variant (CNV)

Back 62

a. range from 1 kb to several Mb in size
b. up to 12% of the genome
c. thousands present in the human genome
d. contribute to human genetic variation and complex disease – but not yet well understood

Front 63

What percent of first trimester spontaneous abortions are chromosome abnormalities?

Back 63

2/3

Front 64

What percent of patients w/ mental retardation have chromosomal abnormalities?

Back 64

20-30%

Front 65

Incidence of liveborns w/ chromosomal abnormalities?

Back 65

1 in 125

Front 66

What diseases are disorders of Protein Metabolism

Back 66

Amino Acid Metabolism: PKU
Organic Acidemias: Propionic Acidemia
Urea Cycle defects: OTC deficiency

Front 67

What diseases are disorders of carbohydrate metabolism

Back 67

Disorders of galactose metabolism: Galactosemia

Disorders of glycogen storage: GSD1A

Front 68

Disorders of fat metabolism?

Back 68

Fatty acid oxidation defects: MCAD

Front 69

Disorders of lysosomal storage?

Back 69

Sphingolipid metabolism: gaucher disease

Disorders of MPS metabolism: Hurler's disease

Front 70

Mitochondrial Diseases

Back 70

Respiratory chain defects: MELAS, NARP, MERF, Leigh's disease

Front 71

PKU pathology

Back 71

Lack of Phenylalanine Hydroxylase ergo cannot convert Phenyalanine into Tyrosine (or subsequently dopamine or melanin)

Front 72

Treatment of PKU

Back 72

Restrict Phenyalanine
Provide BH4 cofactor (tetrahydrobiopterin)
Provide Tyrosine

*clinical trials to replase enzyme

Front 73

Outcome of treated PKU

Back 73

If stop treatment after six years: executive fxn problems, concentration problems, memory problems

Front 74

Maternal PKU (fetal exposue to high levels of Phenylalanine)

Back 74

Microcephaly
Congenital heart disease
Craniofacial abnormalities
Small for gestational age

PHE IS A TERATOGEN!!!!

Front 75

Pathwayws effected by Tetrahydrobiopterin deficiency

Back 75

Phe--> Tyr
Tyr --> Dopa
Tryptophan --> serotonin

Front 76

What is an organic acid?

Back 76

Essentially an acid w/ no amino group on it??

Front 77

Propionic labs?

Back 77

High ammonia
High acid in baby's bood
Not responsive

Baby's vomiting... and ill appearing and low level of consciousness

Front 78

What enzyme is effected in Propionic Acidemia?

What are the substrates?

Back 78

Propionyl-CoA Carboxylase

VOMIT
Valine, OCFA, Methionine Isoleucine, Threonine,

Front 79

Treatment for Propionic Acidemia

Back 79

Restrict VOMIT & provide antibiotics to decrease gut bacteria

Provide Biotin cofactor

Use Carnitine to bind & eliminate propionic acid

Treat secondary effects: ammonia detox & bicarbo to neutralize acid

Front 80

Outcomes of Propionic Acidemia

Back 80

Mental Retardation
Recurrent metabolic decompensation:
Infection
Protein load
Essential amino acid deficiency
Severe injury
Surgery
Fasting
End organ failure
Basal Gangliar Infarcts
Renal Failure
Pancreatitis
Cardiomyopathy

Front 81

Case report of what disease?

Male infant
DOL # 3, refused to breast feed
Given one bottle of infant formula
Within one hour of finishing bottle, became apneic
Brought to ER, noted to have seizures
Became unresponsive
Ammonia extremely elevated
Admitted to PICU for hemodialysis, intravenous medications
Despite heroic efforts, the infant died 12 hours after admission

Back 81

OTC

Front 82

OTC pathology

Back 82

A mutant enzyme protein impairs the reaction that leads to condensation of carbamyl phosphate and ornithine to form citrulline. This impairment leads to reduced ammonia incorporation, which, in turn, causes symptomatic hyperammonemia (see Hyperammonemia). The gene for this enzyme is normally expressed in the liver and is intramitochondrial.

Front 83

OTC treatment

Back 83

restrict all protein
Provide Citrulline (product)
Replace enzyme via LIVER TRANSPLANT
Dialysis & ammonia scavenging medicine to reduce ammonia

Gene therapy trial - fail

Front 84

OTC symptoms

Back 84

some mental retardation
Recurrent metabolic decompensation - infection, protein load, injury, surgery, fasting, etc

Males can have less severe forms of OTC might have hyperammonemic crisis with stressor

Front 85

OTC GENETICS

Back 85

X - LINKED RECESSIVE!!!

Front 86

Galactosemia pathology

Back 86

Missing UDP-GLC-Gal1-puridyltrandferase

Galactose -1 -phosphate -->glucose 6 phosphate

Front 87

Galactosemia symptoms

Back 87

Newborn coagulopathy
Liver dysfunction/failure
Cataracts
E. Coli sepsis
Primary ovarian failure
Learning disabilities

Front 88

Galactosemia Treatment

Back 88

Restict lactose & galactose
Treat Secondary effects via antibiotics for E. Coli (b/c they feed off the galactose)

Front 89

GSD1A labs

Back 89

VERY low blood sugar
Blood lactate elevated
Blood triglycerides elevated
Blood uric acid elevated

Front 90

GSD1a pathology

Back 90

Most common is G6Phosphatase deficiency so cannot rip 6 phosphate off to make glucose

Front 91

Von Gierke's Disease

Back 91

GSD 1a

Cannot convert G6P to Glucose

Front 92

GSD 1a Treatment

Back 92

Frequent feedings of cornstarch

Treat secondary effects
Treat uric acid w/ allopurinol
Maintain normal base status
Antilipidemic medications

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Long term outcome of GSD 1a

Back 93

Severe hypoglycemia
Lactic acidosis
Growth restriction because of lactic acidosis
Osteopenia
Hypertriglyceridemia
Pancreatitis
Hepatic steatosis
Hyperuricemia (HIGH URIC ACID)
Gout
Kidney stones
Glycogen accumulation
In liver: Hepatic adenomas
In kidneys: Nephromegaly

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MCAD INCIDENCE

Back 94

1: 6500 to 1: 17,000

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MCAD symptom

Back 95

Sudden death (18% of all pediatric age groups)

Fasting HYPOKETONIC and HYPOGLYCEMIA!! - low ketones!

Neurologic: lethargy, coma, seizures

Front 96

Treatment of MCAD

Back 96

Avoid Fasting
Low fat, high carb diet
Give Carnitine to bind and eliminate fatty acid intermediates

Front 97

What are sphingolipids

Back 97

Found in neural tissue
Play a role in signaling & involved in cell recognition

Front 98

What disease is a disorder of sphingolipid metabolism?

Back 98

Gaucher Disease

Front 99

Gaucher Disease symptoms

Back 99

Hepatosplenomegaly
Pancytopenia
Thrombocytopenia can be severe
Skeletal disease
Osteoporosis
Bone infarcts
Fractures
Erlenmeyer Flask deformity of femur (storage inside marrow)

Front 100

Gaucher Type 1

Back 100

More common in Ashkenazi Jews
Non-neuronpathic
Visceral and skeletal disease

Older people

Front 101

Gaucher Type 2

Back 101

Neurodegenerative disease, fatal by 2 years of age

Brain disease

Type 2 = death by 2

Front 102

Gaucher Type 3

Back 102

Intermediate phenotype
More common in Sweeds

Front 103

Gaucher pathology - what is wrong

Back 103

mutations in ß-glucocerebrosidase

Front 104

Treatment for Gaucher

Back 104

Replace enzyme - Cerezyme
Restrict substrate via ZAVESCA (inhibits the pathway)
Treat secondary effects - Bisphosphate for osteopenia; pain management

Front 105

HURLER'S DISEASE

Back 105

MSP 1

Disorder of Mucopolysacccahride Metabolism

Front 106

What is accumulated in Hurler's disease?

Back 106

Dermatan and Heparan sulfate

Front 107

Symptoms of Hurler's

Back 107

Corneal clouding
Organomegaly - spleen & liver
Heart disease
Mental retardation
Death in childhood

Alpha-Iduronidase Deficiency

Front 108

Treatment of Hurler's

Back 108

Bone Marrow Transplant
Recombinant enzyme (aldurazyme)

Secondary tx: physical therapy, cardiac care, hearing aids, management of respiratory difficulties

Front 109

What is Replicative Segregation

Back 109

Random allotment of daughter cells during replication

Mitochondrial populations may change in the same tissue --> cause genetic Drift

Front 110

MELAS DISEASE

Back 110

NORMAL then come in paralyzed and or blind

Mitochondria encephalopathy
Lactic acidosis
Stroke like episodes

Front 111

How is newborn screening done?

Back 111

Heelstick NBS test performed w/in 48 hours and results back in 4- 7 days

Front 112

Common Disease-Common Variant (CD-CV) versus Common Disease-Rare Variant (CD-RV) Hypothesis

Back 112

Originally thought common diseases had a common set of polymorphisms associated w/ those disease, when look through common varients, don’t explain a lot of disease…opposite of mendelian where things are rare but highly penetrant.

Front 113

GWAS

Back 113

Genome Wide Association study - – select huge pool of SNPs up to 2.5million SNPs; genotype all at once, and applying unbiased approach to analyze the multiple SNPs in the cases (NO HYPOTHESIS)

Front 114

Candidate disease approach

Back 114

Biologic candidate genes (pathways);

Candidate genes from animal [knockout] models;

Look at SNPs in pathways and see if associated w/ disease

Front 115

Limitations of Association studies

Back 115

Require large sample sizes (thousands of individuals)

Require phenotypically homogeneous groups of cases and controls

Sensitive to populations stratification
Produce false positive results

Hard to replicate

Front 116

Genome-wide significance (GWS):

(value)

Back 116

0.05/1,000,000=5*10-8

Front 117

What are interactions?

Back 117

When other factors modify genetic effect


Gene-Environment interactions:

Gene-Diet (nutrigenomics)
Gene-Drug (pharmacogenetics)
Gene-Life style (e.g., smoking, exercise)

Front 118

Principles of Natural selection

Back 118

More organisms are produced than can survive and reproduce

Organisms differ in their ability to survive and reproduce, based on genotypic differences

The genotypes that promote survival are favored and are reproduced

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Hardy Weinberg Equation

Back 119

P+Q = 1

P^2 +2PQ+ Q^2 = 1

Front 120

What causes deviation from Hardy weinberg equation?

Back 120

Genotyping error
Mutation
Migration (immigration and emigration)
Natural selection
Nonrandom Mating/Inbreeding
Genetic drift

Front 121

What is stabilizing selection?

Back 121

Extremes have decreased fitness

(second generation is higher peak in middle w/ fewer outliers)

Front 122

What is Disruptive selection?

Back 122

Intermediates have decreased fitness

Two hump second generation

Front 123

What is directional selection?

Back 123

Extremes have increased fitness
- moves in one direction

Front 124

Genetic Drift

Back 124

Genetic drift affects the genetic makeup of the population but, unlike natural selection, through an ENTIRELY RANDOM PROCESS

--> DOESN'T PRODUCE ADAPTIONS, RANDOM ex huntington's disease in south african settlers

Front 125

Haplotype

Back 125

is a combination of alleles (DNA sequences) at different places (loci) on the chromosome that are transmitted together.


collection of alleles together in a physical block – over generations haplotypes get smaller and smaller and smaller, so when populations have different linkages of equilibrium, older population – more recombination in population = haplogype smaller; more recent population through bottle neck = reset the clock = longer haplotype blocks

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Linkage Disequilibrium

Back 126

Likeliness that it will be inherited as a block - shorter LD means not homogenous

Can be measured by D' or r^2

When r2 = 1, two SNPs are in perfect LD; allele frequencies are identical for both SNPs, and typing one SNP provides complete information on the other

D' varies from 0 (complete equilibrium) to 1 (complete disequilibrium)

Front 127

Linkage Disequilibrium uses

Back 127

Knowledge of patterns of LD can be quite useful in the design and analysis of genetic data

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How are Linkage disequilibriums used in GWAS

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By using LD they can identify a few SNPs that represent a block and therefore don't have to sequence entire genome

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GWAS susceptibility?

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GWA studies are susceptible to population stratification which occurs when there are differences in:
1) disease prevalence
2) allele frequencies

i.e. When allele frequency is more common in one population than other, screening for the population not disease…

The problem
arises if case and control populations have different frequencies of
ethnic groups

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Ancestry-Informative Markers

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polymorphisms, which exhibit substantially different frequencies between populations from different geographical regions.

By using a number of AIMs one can estimate the geographical origins of the ancestors of an individual and ascertain what proportion of ancestry is derived from each geographical region.