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Fundamentals 3- Heme > Genetic Disorders > Flashcards

Genetic Disorders Flashcards

1
Q

What are SNPs and CNVs?

A

single nucleotide polymorphisms and common number variations that are common alterations in the protein coding genes OTHER than mutations

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2
Q

What is the incidence of diseases with genetic components in people less than 25 years old?

A

5%

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3
Q

When do the majority of chromosomal disorders occur in humans?

A

2-3 months is over 50% of chromosomal disorders in spontaneous abortions, miscarriages and stillbirths.
The most common cause is Turner’s syndrome

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4
Q

What is the incidence of chromosomal abnormalties that result in abortion, miscarriage and stillbirth?
What is the incidence of chromosomal abnormalities in newborns?

A

50% result in miscarriage, stillbirth or abortion

0.58% is the incidence of chromosomal abnormalities in newborns

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5
Q

In newborns, what is the incidence of autosomal abnormality?

What is the incidence of sex chromosome abnormality?

A

Autosomal 4/1000
Sex 2/1000

Sex linked chromosomal abnormalities are tolerated a lot better than autosomal due to the paucity of DNA on the Y chromosome and the inactivation of one of the Xs

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6
Q

What percent of the genome encodes proteins?
How much of the genome contains DNA with unknown function?
How many genes are in the human genome?
How many bp are there in a haploid genome?

A

2% encode proteins
50% is unknown function DNA
25,000 genes (less than a mustard plant)
3.2billion bp

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7
Q

What are 3 alterations to protein-coding DNA that does not constitute a “mutation”?

A
  1. sequence and copy number variation (SNPs and CNV)
  2. Epigenetics- modulation of a gene w/o mutation like methylation, histone modification, imprinting
  3. alterations in non-coding RNAs that inhibit translation
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8
Q

What are the 3 modes by which protein-coding genes can be silenced by epigenetics?

A
  1. methylation
  2. histone modification
  3. imprinting
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9
Q

What are the 2 non-coding RNAs that can inhibit translation of proteins?

A
  1. miRNA- post-transcriptional silencing
  2. long-non-coding RNA (lncRNA) - bind chromatin to inactivate DNA (ex. Xist which scrunches and silences one of the X chromosomes)
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10
Q

What is a mutation? What are the 4 categories of mutation?

A

It is a permanent change in the DNA.

  1. missense
  2. non-sense
  3. frameshift
  4. trinucleotide repeat mutations
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11
Q

What are the two types of missense mutations?

A

Missense mutations alter the meaning of the genetic code.

  1. Conservative- AA substitution has little effect on the protein function
  2. Non-conservative- AA substitution changes protein function and has a severe phenotypic effect. Ex. sickle cell glutamic acid–> valine causes RBC sickling
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12
Q

What is a non-sense mutation?

What is an example of a disorder associated with a non-sense mutation?

A

It is when the genetic change is from an AA to a stop codon interruption translation and causing a truncated protein that gets degraded.
Ex. B-thalassemia–> stop codon leads to degraded protein–> 4a instead of 2b2a which lyses RBC

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13
Q

What is a frameshift mutation?

Give an example when the outcome is benign and an example when the outcome is deleterious.

A

When there is a nucleotide insertion or deletion of a number of nucleotides OTHER THAN 3.
Ex. O blood type is a frameshift deletion of 1 base from the A phenotype that results in the O phenotype
Ex. Tay-Sachs is an insertion of TATC which mutates hexaminidase A gene leading to build up of hemamine (lipid)

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14
Q

What are the four major categories of genetic disease?

A
  1. Mendelian disorders (single gene defects)
  2. complex multigenic disorder
  3. cytogenetic disorders
  4. single-gene disorders with atypical patterns of inheritance
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15
Q

What are the four MAJOR inheritance patterns?

A
  1. AD- heterozygotes show disease, at least one parent affected, males/females equally
  2. AR- homozygous show disease, no affected parent, 25% recurrence in siblings, CONSANGUINITY
  3. XLR- heterozygote female to 50% sons, affected males have 100% carrier daughters
  4. XLD - SUPER rare, affected hetero females pass to 50% sons and 50% daughters. Males–> all daughters are affected, no sons
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16
Q

What are the 4 categories of Mendelian disorders caused by single-gene defects?

A
  1. defect in structural protein (mostly auto-dominant–Marfans, EDS)
  2. defect in enzymes (mostly auto-recessive)
  3. Defects in channels or receptor proteins (CF, Familial hypercholesterolemia)
  4. Defects in proteins that regulate cell growth
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17
Q

What type of Mendelian single-gene defect is Marfan’s? What is the pathology of Marfan’s?

A

It is a defect in structural protein Fibrillin 1 (FBN1) which is a glycoprotein component of microfibrillar fibers that scaffolds for elastin on the basement membrane

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18
Q

What are the clinical features of Marfan’s syndrome?

A
  1. tall stature, arachnodactyly, scoliosis, pectus excavatum
  2. subluxation of lens upward and bilaterally
  3. aortic dissection, cystic medionecrosis of the aorta, mitral valve prolapse
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19
Q

How does aortic dissection occur in Marfan’s?

A 
Basophilic ground substance is deposited in the aortic tissue and pools because there is no elastin organization. 
Intimal tears (that would go undetected in patients with organized elastin) allow bleeding into the aortic walls and nearly immediate death
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20
Q

What is the inheritance pattern of Marfan’s ?

A

Most mendelian mutations in structural proteins are autosomal dominant

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21
Q

What type of Mendelian single gene mutation is Ehlers-Danlos syndrome?
What is the pathology?

A

It is a structural protein disorder with various defects in collagen molecules that reduce the tensile strength of collagen.
There are 30 different collagens and 20 different mutations involved–> SIX kinds of EDS (4 are protein disorders, 2 are enzyme disorders and AR)

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22
Q

What are the general clinical features associated with Ehlers-Danlos Syndrome?

A
  1. hyperextensibility of joints and skin
  2. cigarette paper scars
  3. aortic, colonic rupture
  4. ocular fragility
  5. diaphragm hernia
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23
Q

What is the inheritance pattern and gene defect of classic (I and II) EDS?

A

Autosomal dominant
COL5A1
COL5A2

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24
Q

What is the inheritance pattern and gene defect of hypermobility (type III) EDS?

A

Autosomal dominant -???

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25
Q

What is the inheritance pattern and gene defect of vascular (Type IV) EDS?

A

Autosomal Dominant

COL3A1

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26
Q

What is the inheritance pattern and gene defect of kyphoscoliosis (VI) EDS?

A

Auto recessive

lysyl-hydroxylase

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27
Q

What is the inheritance pattern and gene defect of arthrochalasia (type VIIA) EDS?

A

Auto dominant
COL1A1
COL1A2

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28
Q

What is the inheritance pattern and gene defect of dermatosparaxis (VIIc) EDS?

A

Auto recessive

Procollagen-N-peptidase

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29
Q

What is the incidence of CF and who does it mainly affect?

A

1/3200 and it affects mainly causcasians

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30
Q

What is inheritance pattern of CF and what type of Mendelian single-gene defect is it?

A

It is Autosomal recessive and is a mutation in a receptor protein/channel

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31
Q

What are the two ways you can identify CFTR gene mutations?

A

In most mucousal surfaces there is a CFTR that allows Cl efflux in exchange for Na, H20 influx. This process is balanced, so there is hydrated, normal mucous. If there is a CFTR mutation, Cl does not leave the cell, Na and H20 rush in to correct the electrolyte imbalance and the mucus is dehydrated and sticky (plugs up organ, hotbed for infections).

In sweat ducts the CFTR channel is reversed with Cl- normally going into the cell and Na following it.
It CFTR mutation, the Cl- can’t go into the cell and the sweat will be high in Cl-

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32
Q

What are the six classes of mutations for CF?

A 
1- defective protein synthesis
2- abnormal protein folding/trafficking
3- defective regulation
4- decreased conductance
5- reduced abundance of channels
6- altered regulation of separate ions
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33
Q

What is a genetic modifier of the CF mutation?

A

Mannose-binding lectin- immunity with opsonization.

This makes CF infections more severe because they can’t clear infections and the infectious agents get stuck in the thick mucous

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34
Q

What are 3 genetic modifiers to CF mutations?

A
  1. organisms virulence (pseudomonas, burkholderia) that usually don’t affect immune competent people can affect CF
  2. infections by multiple organisms
  3. exposure to smoking and allergens
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35
Q

What are pathological changes associated with severe CF (+sweat test)?

A
  1. bronchiectasis
  2. hepatic cirrhosis
  3. pancreatic insufficiency
  4. male infertility
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36
Q

What are the pathological changes associated with milder CF (sweat test -)

A

azoospermia
sinusitis
absence of vas deferens

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37
Q

What are the 2 different types of mendelian single-gene mutations that show defects in enzymes?

A
  1. inborn errors of metabolism (galactasemia, PKU)

2. storage disorders (glycogen, lysosomal)

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38
Q

What are the two disorders classified as inborn errors of metabolism that we discussed?

A
  1. Phenylketonuria (PKU)

2. Galactasemia

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39
Q

Describe the phenylalanine hydroxylase system.

A
  1. Phenylalanine is converted to tyrosine by phenylalanine hydroxylase (PAH)
  2. Tetrahydrobiopterin –> dihydrobiopterin
  3. to convert di back to tetra to drive the first reaction, NADH is converted to NAD by dihydropteridine reductase (DHPR)
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40
Q

What is the cause of classic PKU?
What type of inheritance does it demonstrate?
What is the incidence and who does it likely affect?

A

It is caused by one of 500 mutations in phenylalanine hydroxylase (PAH)
It is autosomal recessive with an incidence of 1/12000.
It affects Scandanavians

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41
Q

What test will be positive for a patient with classic PKU?

A

Gunthrie test:

  1. inoculate patients serum
  2. bacteria will lyse an area if phenylalanine is present
  3. larger lysed area= more phenylalanine
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42
Q

What are the clinical features of classic PKU? (7)

A
  1. mousy odor
  2. mental retardation (evidenced by 6month)
  3. light pigmented hair/skin due to the inability to make tyrosine which is a component of melanin
  4. eczema
  5. gait disturbance and seizure
  6. NORMAL FACIAL FEATURES
  7. NO ORGANOMEGALY
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43
Q

Why are patients with classic PKU light-pigmented?

A

Because they can’t make tyrosine which is a component of melanin

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44
Q

What are the 2 types of PKU?

A
  1. classic

2. maternal

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45
Q

What is the cause of PKU in maternal PKU?

A

The mother has mild PKU but has discontinued her dietary control.
The excess phenylalanine acts as a teratogen for the fetus (which will be heterozygous but presenting with phenotypic PKU- mental retardation, microcephaly, 15% CHD)

Fetal abnormalities correlate directly with phenylalanine levels

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46
Q

What are the steps in the metabolism of galactose to glucose?

A
  1. galactose +ATP—>galactokinase–>galac-1-P
  2. Galac-1-P + UDP-glucose–> Galac-1-P Uridyl transferase—> UDP-galactose + glucose-1-P
  3. UDP-galactose-4-epimerase–> UDP glucose
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47
Q

What are the 3 enzymes that metabolize galactose to glucose?

Which is the most commonly defected for galactosemia?

A
  1. Galactokinase
  2. Galactose-1-phosphate uridyl transferase (GALT)3. UDP-galactose-4-epimerase

G-1-P uridyl transferase is most defective

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48
Q

What is the incidence of galactosemia?

What is its inheritance pattern?

A

Galactosemia caused by defective GALT has an incidence of 1/60000
(MORE RARE THAN PKU)
It is autosomal recessive

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49
Q

What are the 8 clinical features of galactosemia?

A
  1. vomiting, diarrhea
  2. neonatal jaundice and FTT
  3. Hepatomegaly with fatty change
  4. Cataracts (galactisol– disrupts osmotic gradient so runny eyes too)
  5. Liver failure- accumulate galactose in droplets–> fatty change and scarring
  6. Mental retardation- gliosis, loss of nerve cells **progress if not on a low galactose diet
  7. susceptibility to E. coli bc of high blood galactose
  8. aminoaciduria
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50
Q

How is galactosemia diagnosed and treated?

A

Diagnosed by:
1. reducing sugar other than glucose in urine
2. direct enzyme assay in leukocytes
3. Prenatal GALT activity or galactisol level in amniotic fluid
Treated by:
1. removal of galactose from diet w/in first 2 years
(prevents cataracts and liver damage, but you will still get the neurological symptoms like speech disorder, ataxia, gonadal failure)

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51
Q

What does a no galactose diet prevent in a patient with galactosemia?
What 3 things does it NOT prevent? Why?

A 
Prevents:
1. cataracts
2. liver damage 
DOES NOT prevent:
1. ataxia
2. speech disorders
3. gonadal failure
These aren't prevented because there is still a small level of endogenously made galactose
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52
Q

What are the 3 anatomic changes associated with untreated galactosemia?

A
  1. organomegaly
  2. liver fatty change and fibrosis
  3. cataracts
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53
Q

Why is there a newborn screening program for PKU and galactosemia?

A
  1. treatment is available
  2. early institution of treatment reduces/eliminates severity
  3. Testing is required. Observation/physical won’t reveal the disorder in the newborn
  4. tests are rapid/cheap, sensitive and specific
  5. conditions are frequent and serious enough to warrant it
  6. can get results, confirm, and institute treatment/counseling
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54
Q

How does the progression of inborn errors of metabolism differ from the progression of storage disorders?

A

IEM are fast (progress in days-wks)

Storage disorders are slow (months to years)

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55
Q

What are the four major lysosomal storage disorders?

A
  1. Tay-Sachs
  2. Neimann Pick A, B, C
  3. Gauchers
  4. Hunter and Hurler syndrome
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56
Q

What is the mechanism by which lysosomal storage disorders occur?

A

Lysosome contain hydrolytic enzymes that can break down complex substrates like hexaminidase A, mucopolysaccharides, sphingolipids, etc)

Lack or mutation in these enzymes causes incomplete catabolism and a buildup of non-metabolized endproducts

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57
Q

What are the 4 common features of lysosomal storage disorders?

A
  1. AR
  2. affects children
  3. Hepatosplenomegaly, CNS/neuronal damage
  4. Secondary events (inflammation, cytokine release, macrophage activation) due to the storage of undigested material
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58
Q

What is the mutation associated with Tay-Sachs?

What substance is unable to be degraded as a result?

A

Mutation : Hexosaminidase A (B-subunit) caused by a 4 nucleotide insertion/frameshift

Leads to a buildup of GM2 ganglioside (lipidosis)

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59
Q

What group of people have a high incidence of Tay Sachs?
What is the incidence of carriers within this group?
How do we test if someone is a carrier?

A

Ashkenazi Jews have a carrier rate of 1/30

This is detected by serum Hex A or DNA analysis

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60
Q

What are the prominent histological features of Tay Sachs?

A
  1. lipid vacuolization in large neurons

2. EM shows lysosomes filled with whorled configurations (onion layers)

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61
Q

What is the age of onset of Tay Sachs? The usual age of death?

A

Onset: 3-6 months
Death: 2-3 years

62
Q

What are the major clinical features associated with Tay Sachs?

A
  1. CNS (most involved with ganglioside metabolism)
  2. Membranous cytoplasmic bodies
  3. Cherry Red retina spot (on macula bc it is not affected where the rest of the eye is)
  4. Blindness
  5. motor/mental deterioration
  6. early childhood death
63
Q

What is the pathogenesis of damage presumed to be due to in Tay Sachs?

A

unfolded protein response (lack of chaperone stabilization)

64
Q

What organs are most affected by Neimann-Pick types A and B?

A

organs with high phagocytic function like spleen, liver, marrow, lymph nodes, lungs)

65
Q

What is the deficient enzyme in NP type A and B?

What does this lead to an excess of?

A

Sphingomyelinase which leads to accumulation of sphingomyelin

66
Q

What is the age of onset for type A Neimann-Pick?
What type of mutation is it?
What enzyme does it affect?
What is organs are affected?

A

Type A is severe infantile form (death by 3)
It is a missense mutation that results in complete deficiency of sphingomyelinase
It has extensive neurological involvement and visceral accumulation

67
Q

What is the age of onset of type B Neimann-Pick?
What enzyme does it affect?
What is the major effect?

A

Type B allows survival into adulthood
It is a depletion in sphingomyelinase (but not complete)
It causes organomegaly, but has little CNS involvement

68
Q

What is the histology of Type A and B Neimann Pick disease?

A
  1. vacuolated and foamy hepatocytes and Kupffer cells

2. Zebra bodies (lamellated myelin figures) on EM

69
Q

What are the 3 ways by which type A and B NP are diagnosed?

A
  1. enzyme analysis (leukocytes)
  2. biochemical assay for sphingomyelinase in liver or marrow
  3. Direct DNA analysis
70
Q

What is the mutated gene in Neimann-Pick type C? What does this lead to the buildup of?

A

It is a mutation in NPC1 and NPC2 genes that lead to lipid (GM1 and GM2) and cholesterol accumulation in the terminal axons and dendrites leading to degeneration

71
Q

What are the potential clinical features of NP type C?

A
  1. hydrops fetalis and stillbirth
  2. neonatal hepatitis
  3. chronic, progressive neurological damage
  4. ataxia, gaze palsy, dystonia, dysarthria, psychomotor regression
72
Q

What gene is mutated in Gaucher disease?
What does this lead to the accumulation of?
What is the inheritance pattern?

A

It is a mutation in glucocerebrosidase gene (cleaves glucose from ceramide).
It leads to an accumulation of glucocerebroside (membrane component of all cells that usually gets degraded in the spleen)
It is autosomal recessive

73
Q

What is the most common lysosomal storage disorder?

A

Gauchers

74
Q

What organs are most affected by Gaucher’s disease?

A 
Phagocytic system (and macrophage action causes cytokine release)
CNS
75
Q

Describe Type I Gaucher disease.

  1. what organs are involved?
  2. what is the survival likelihood?
  3. What group is affected most?
A
  1. Chronic non-neuronopathic form with no brain involvement, just skeletal and spleen
  2. it has reduced glucocerebrosidase activity so they can live to adulthood
  3. Ashkenazi predilection
76
Q

Describe type II Gaucher disease.

  1. what organs are involved?
  2. what is the survival likelihood?
  3. What group is affected most?
A
  1. Acute neuronopathic form - some organomegaly but progressive CNS involvement
  2. infantile and acute with NO glucocerebroside activity
  3. no Jewish predilection
77
Q

Describe type III Gauchers disease.

A

Juvenile with systemic involvement (type I) and CNS disease( type II)
It is less bad than 2 but worse than 1

78
Q

Describe the histological findings of Gauchers.

A
  1. Gaucher cells are NOT vacuolated, but rather are fibrillary in the cytoplasm
  2. purple “tissue paper cells” on bone marrow although these are not specific
79
Q

How do you diagnose Gauchers?

A

leukocyte or fibroblast glucocerebrosidase levels

80
Q

What are the 2 main therapies for Gaucher disease?

What can be done for symptom alleviation?

A
  1. Enzyme replacement- $$$$$
  2. glucocerebroside synthase inhibitors

Symptom alleviation:

  1. splenectomy
  2. blood transfusion
  3. analgesics
  4. joint replacement
  5. bone marrow transplant
81
Q

What are mucopolysaccharides?

A
  1. part of the ground substance of connective tissue produced by fibroblasts
  2. complex carbs linked to proteins :
    - dermatan sulfate
    - heparan sulfate
    - keratin sulfate
    - chondroitin sulfate
82
Q

How are mucopolysaccharides degraded?

A

lysosomal enzymes remove terminal sugars from polysaccharide chain (glucose of GAG). Once this sugar is removed, the rest of the chain degrades.

If there is a defect in the enzyme that cleaves the terminal sugar, the entire chain won’t degrade and MPS accumulates in lysosomes

83
Q

If there is a mutation in mucopolysaccharidoses, what are the clinical presentations?

A
  1. coarse facial features
  2. cloudy corneas (with exception of Hunter’s)
  3. joint stiffness
  4. skeletal deformities
  5. mental retardation
  6. hepatosplenomegaly
  7. cardio involvement ( heart valves, engorged chorda tendina, CAD, MI
84
Q

What is the deficient enzyme in Hurler syndrome?
What is the substance that builds up?
What is the inheritance pattern?
What is the clinical presentation?

A

MPSI- deficiency in a-L-iduronidase that leads to a buildup of dermatan sulfate and heparan sulfate
It is autosomal recessive

It presents with hepatosplenomegaly by 6 to 24 months and causes death by 6 to 10 years (cardio)

85
Q

What is the deficient enzyme in Hunter syndrome?
What substance builds up?
What is the inheritance pattern?
What is the clinical presentation?

A

It is a deficiency in MPSII- L-iduronate sulfatase that leads to accumulation of dermatan sulfate and heparan sulfate.

It is x-linked recessive
It is milder than Hurler with no CNS disease, no cloudy corneas, milder somatic course

86
Q

What are the three major diseases associated with glycogen storage ?

A
  1. McArdles
  2. Pompe
  3. von Gierke
87
Q

How would a glycogen storage disease appear histologically?

A

Glycogen appears translucent on stain

88
Q

Where is glycogen stored in vonGierke disease?
What enzyme is inhibited?
What are the 3 main clinical presentions?

A 
Hepatically
It is a mutation in glucose-6-phosphatase (which catalyzes G-6-phosphate --> glucose)
1. hepatomegaly (with cirrhosis)
2. weakness
3. hypoglycemia
89
Q

Where is the glycogen stored in McArdles?
What enzyme is inhibited?
What are the 5 presentations?

A 
muscle
Muscle phosphorylase (which catalyzes glycogen--> G-1-P)
  1. hypotonia
  2. muscle cramps w/ exercise
  3. weakness
  4. myoglobinuria
  5. failure of exercise to induce elevated blood lactate levels
90
Q

Where is the glycogen stored in Pompe disease?
What enzyme is inhibited?
What are the 2 presentations?

A 
In lysosomes (glycogen/lysosomal storage disorder)
Lysosomal acid maltase enzyme which converts glycogen directly to glucose is inhibited
  1. cardiomegaly/myopathy- GIANT muscle fibers, tiny heart chambers. large black circles on EM
  2. generalized storage (hepatomegaly included)
91
Q

What is the incidence and penetrance of neurofibromatosis? What is the % of mutations that are sporadic?

A

1/3000
penetrance is 100% (if you have the gene mutation you have some phenotype)
But expressivity is variable
50% are new mutations

92
Q

What are 4 signs of neurofibromatosis type I?

A
  1. café au lait, axillary freckling
  2. neural tumors
  3. Lisch nodules in the iris
  4. skeletal abnormalities
93
Q

How does NF type I cause exuberant growth?

What can it progress to?

A

Neurofibromin is a GTPase that can convert activated RAS back to Ras-GDP.
If it is mutated, RAS won’t be inactivated.

It can progress to NF sarcoma

94
Q

What is the incidence of neurofibromatosis type II?
What 3 areas of the body are affected by type II?
What is the difference from type I?

A

1/40,000 to /50,000

  1. acoustic (bilateral auditory canals)
  2. meningioma
  3. ependymal gliomas

IT IS NON-NEOPLASTIC

NF2 gene is mutated which is a tumor suppressor

95
Q

What is a multigenic disorder?

What are the two common features?

A

It is when the trait expression is determined by 2 or more polymorphisms (modest effect, low penetrance) that are co-inherited and influenced by the environment

  1. Polymorphism
  2. Quantitative trait loci
96
Q

What is a polymorphism?

A

It is a genetic variant that has atleast 2 alleles and is present in at least 1% of the population

  • some show no disease phenotype
  • vary in significance
  • multiple diseases or disease specific
97
Q

What is QTL?

A

quantitative trait loci- stretches of DNA that underly multigenic inheritance

98
Q

What are 7 examples of diseases that are multigenic?

A
  1. Diabetes 1 and 2
  2. immune mediated inflammatory diseases
  3. CAD
  4. hypertension
  5. gout
  6. pyloric stenosis
  7. cleft lip w/ or w/o cleft palate
99
Q

What are the 2 categories of cytogenetic disorders?

A
  1. numeric- polyploidy, aneuploidy

2. structural - chromosome breakage followed by loss or rearrangement of material

100
Q

Define :

  1. euploid
  2. polyploidy
  3. aneuploidy
A

euploid- multiple of n
polyploidy- 3n, 4n
aneuploidy- 45 XO, 47 XXY, etc

101
Q

What is non-disjunction?

What are the 3 types?

A

It is when the chromosomes fail to separate appropriately

  1. Meiosis I - chromosome homologues
  2. Meiosis II- sister chromatids
  3. Mitosis- sister chromatids
102
Q

What is anaphase lag?

A

The failure of chromosomes to homologously pair and separate with random assortment

103
Q

What is mosaicism?

A

the presence of two or more populations of cells with different genotypes in the same zygote.
Ex. extra 21 in brain, GI, but not skin

Generally a less severe phenotype that a trisomy 21 that occurs due to nondisjunction in meiosis

104
Q

When identifying structural abnormalities, what kind of stain would you use for the karyotype?

A

G-banding which is where trypsin degrades histones and then Giemsa stain is used to show banding (pro and meta phase have the most resolution)

105
Q

What is a region, band and sub-band of a chromosome?

A

Region- area of a chromosome between landmarks (telomeres, centromeres, etc)
Bands are allocated to certain regions and are distinguishable from other parts of the chromosome due to staining
Ex. 22q11.2 is chromosome 22, q arm (long arm), region 11, sub-band 2)

106
Q

What is the difference between a paracentric inversion and a pericentric inversion?

A

Para- the inversion does NOT involve the centromere. It creates a genetic instability/imbalance
Peri- the inversion involves the centromere so there is genetic and structural imbalance

107
Q

What is isochromosome formation?

A

When the chromosomes inappropriately align and when separation occurs you get one chromosome with 2 P arms and another chromosome with 2 q arms

108
Q

What is a Robersonian translocation?

What chromosome are normally involved?

A

When acrocentric chromosomes rearrange so you end up being 45 aneuploidy but you have all the necessary genetic material to be phenotypically normal

13,14,15,21,22

109
Q

Describe FISH.
What is the resolution?
What specimen can be evaluated?
What can it detect?

A

Fluorescence In-situ hybridization- a DNA sequence is labeled with fluorescence and hybridized to metaphase or interphase nuclei. Presence or absence of signal gives diagnostic info.
You can fish for a restricted # of probes
Resolution is 100kb
You can evaluate: prenatal specimen, peripheral blood, marrow, tissue, fibroblasts, tumors
It can detect: numeric abnormality, microdelections, complex translocations, gene amplification, gene mapping

110
Q

What is cytogenomic microarray analysis?
What is the resolution?
What specimen can be evaluated?
What is detected?

A

Genome wide analysis of a patient and control DNA
Patient DNA- green
Control - red
If they are expressed equally = yellow
If there is a deletion in the patient, it wil fluoresce red
If there are amplifications it will fluoresce green.
Resolution is 10kb
Specimen: DNA from any source
Detected: deletions, insertions

111
Q

What is the technique used to DIRECTLY analyze DNA?

A

PCR- you need to know the sequence you want to amplify, but then you can use primer/thermoregulator to exponentially amplify the DNA of the certain region you want to analyze, and sequence it

112
Q

Describe linkage analysis.

A 
Marker loci (SNPs) that are thought to be associated with a gene or chromosome linked to disease are evaluated 
(not used very much)
113
Q

What is GWAS?

A

genome wide association studies- where you get cohorts of patients with disease and control populations and analyze the DNA for SNPs in the patients but not controls

114
Q

What 4 factors are indications for prenatal genetic analysis?

A
  1. advanced maternal age (>35)
  2. confirm carrier status
  3. chromosome aberrations in previous child
  4. fetal sex for carriers of X-linked disorders
115
Q

What 7 situations would you do postnatal genetic analysis?

A
  1. MR/developmental delay
  2. multiple congenital anomalies
  3. suspected aneuploidy
  4. suspected autosomal or sex chromosome aberration
  5. suspected fragile X
  6. infertility
  7. multiple miscarriages/spontaneous abortions (associated with balanced translocations)
116
Q

What is the most common constitutional chromosome abnormality?

A

Down Syndrome (trisomy 21)

117
Q

What is the incidence of having a child with Down syndrome for women under 20?
For women over 45?

A

Under 20 = 1/1550

Over 45= 1/25

118
Q

Why is the incidence of Down syndrome higher for women of advanced maternal age?

A

Trisomy 21 most commonly occurs because of non-disjunction of meiosis I.
Womens eggs are in suspended in dictyotene which is extended prophase in which the primary oocyte persists from late fetal life until discharged from the ovary at or after puberty. The longer its in dictyotene, the higher chance of non-disjunction

119
Q

What are the three variations of trisomy 21?

A
  1. nondisjunction in meiosis I
  2. Robertsonian t(14,21)
  3. mosaic
120
Q

What are the physical features of someone with Down syndrome?
What 2 diseases are people with Down Syndrome predisposed to?

A
  1. flat occiput
  2. epicanthal folds, upturn palpebral
    3 macroglossia
  3. single palmar crease
  4. MR
  5. abundant neck skin
  6. congenital heart defects
  7. over 40–> alzheimers
  8. intestinal stenosis (double bubble)
  9. umbilical herniation
  10. hypotonicity

Predisposition to megarkaryoblastic leukemia and increased infections due to T-cell defects

121
Q

What are the lethal trisomies?

A

13 and 18… they can make it through gestation but usually only live a few weeks

122
Q

What disease is associated with trisomy 18 and what are the two most prominent physical features?
What is the incidence of this disease?

A

Edward’s disease - 1/8000

  1. prominent occiput
  2. micrognathia (small chin)
123
Q

What are the clinical features of Edward’s disease?

A
  1. CHD
  2. hypertonicity with clenched fists (can be seen on sonogram)
  3. overlapping fingers with clinodactyly
  4. Intrauterine growth retardation
  5. Rocker-bottom feet
  6. Renal defects
124
Q

What syndrome is associated with trisomy 13?
What is the incidence?
What are the major clinical defects?

A 
Patau syndrome- 1/4000 
Midline defects so:
1. cleft lip/palate
2. holoencephaly
3. fusion of frontal lobes
4. agenesis of cerebellar vermis
5. polydactyly 
6. cardiac defects
7. rocker bottom feet
125
Q

What is microdeletion syndrome?
How are they detected?
What was the first one discovered?
What is the most likely cause of this microdeletion?

A

class of genetic disorders involving deletions of small chromosomal regions that cannot be seen with normal cytogenetic analysis

Microdeletions are detected with FISH and the first was 22q11.2 most likely caused by non-homologous recombination where the same amount is deleted each time

126
Q

What is the incidence of 22q11.2 microdeletion?

The clinical features are heterotrophic, but what severe genetic disorder is this microdeletion associated with?

A

1/4000
It is associated with DiGeorge Syndrome- TBX1 implicated.
Patients have thymic aplasia with no T cells and parathyroid aplasia with hypocalcemia

127
Q

What are the 6 potential clinical features of a 22q11.2 microdeletion?

A
  1. congenital heart defects
  2. palatine abnormalities-nasally speech
  3. facial dimorphism
  4. developmental delay
  5. hypocalcemia due to parathyroid hypoplasia
  6. T-cell immunodeficiency
128
Q

What is the method of diagnosis for a 22q11.2 microdeletion?

A

FISH plus CMA
FISH shows a HIRA deletion (only one red signal)

CMA will show dimmer signal intensity at the 22q11.2 region showing a deletion
There is a reduction of size of the light band

129
Q

What are the 2 reasons why sex chromosome abnormalities are better tolerated than autosomal?

A
  1. Lyonization/inactivation of one X

2. modest amount of genetic material on Y

130
Q

What are the 4 tenets of Lyon hypothesis?

A
  1. One X chromosome is genetically active
  2. One X chromosome is inactived via Xist which makes the chromosome undergo hyperpyknosis
  3. Inactivation is random
  4. Inactivation occurs at 16 days post conception and persists for the rest of the persons life
131
Q

What is the incidence of Turner syndrome?
What is the genetic abnormality?
What are clinical features?

A 
1/2000 to 1/3000
45 XO or 46 XXiq (one of the x's has 2 q's)
1. short stature (SHOX haploinsufficiency)
2. webbed neck, low hairline
3. widely spaced nipples
4. multiple nevi
5. streak ovaries
6. coarctation of the aorta
7. horshoe kidney
NO MENTAL RETARDATION
132
Q

What is the incidence of Klinefelter’s syndrome?
What is the genetic abnormality?
What are clinical features?

A 
1/500
XXY is the most common but it can have multiple Y's 
1. MR 
2. hypogonadism
3. pear shaped "feminine" figure
4. long legs
5. can get breast cancer
133
Q

What are the 4 different sex classifications?

A
  1. genetic sex- XX or XY
  2. gonadal sex- histology of gonads
  3. ductal sex- wolffian or mullerian
  4. phenotypic- appearance of external genitalia
134
Q

What is a “True hermaphrodite”?

A

They have both ovarian and testicular tissue (gonadal sex undetermined)
XX or XY bearing cell lines

135
Q

What is a female pseudohermaphrodite?

What is the most likely cause?

A

XX with ovaries (genetic/gonadal female)
External genitalia is male

Most likely cause is congenital adrenal hyperplasia with defective 21-hydroxylase that overproduces androgens

136
Q

What is a male pseudohermaphrodite?

What is the most likely cause?

A

XY with testes, but external genitalia is female.
Defect is in an androgen receptor.
They are making enough androgen but the patient cannot respond to the androgen

137
Q

What type of abnormality is Fragile X?
What is the incidence?
What are clinical features?

A

It is a tri-nucleotide repeat syndrome
1/1550 male births and 1/8000 female births
1. long face
2. MR (second most common to Down syndrome)
3. Large ears
4. macroorchidism

138
Q

What gene is mutated in fragile X? Where is this gene highly expressed?

A

FMR1 (familial mental retardation gene)
It is highly expressed in the brain.
Mutation is repeats of CGG (# of repeats =size of unstable region)

139
Q

When does expansion of CGG happen in fragile X?

A

Expansion is during female but not male meiosis
Normal CGG repeat # is 29
1. small increase–> permutation (50-200)
2. Large increase–> full mutation (>200)

140
Q

Who expresses a fragile X phenotype?

A

20% of males carrying fragile X are clinically normal.
They pass it to all their daughters so all daughters will be carriers
30-50% of female carriers are affected with MR
Half the female carriers children will be affected

141
Q

What is the Sherman paradox?

A

A persons risk of being affected by a trinucleotide repeat depends on their position in the pedigree

142
Q

What is anticipation?

A

The phenotype of trinucleotide repeat syndromes get worse for each subsequent generation

143
Q

What are 3 trinucleotide repeat disorders affect non-coding regions ?

A
  1. Fragile X (in the promoter)
  2. Friedreich ataxia
  3. myotonic dystrphy
144
Q

What are 4 trinucleotide repeat disorders that affect coding regions?

A
  1. spinobulbar muscular atrophy
  2. Huntington’s
  3. dentatorubral-pallidolusian atrophy
  4. spinocerebellar ataxia
145
Q

What type of disorder is Leber Hereditary Optic Neuropathy?

What is transmission?

A

A mitochondrial disorder so it has complete maternal transmission and no paternal transmission

146
Q

What is the affected organ system in Leber Hereditary optic neuropathy?

A

oxidative phosphorylation so affects:

  1. CNS
  2. muscle- progressive muscle weakness
  3. liver
  4. kidney
147
Q

What is heteroplasmy?

A

tissue of the entire organism harbor mutant and wild-type mitochondrial DNA

148
Q

What is threshold effect for mitochondrial disorders?

A

a minimum # of mutant mit. DNA must be present to have phenotypic affect

149
Q

What is uniparental disomy?

A

When both chromosome from the mother or the father go to the child. The result is the same phenotype as imprinting

150
Q

The maternal chromosome 15 has imprinted _______ and active_ __________.
Paternal chromosome 15 has imprinted _______ and active ________

A

MAternal has imprinted prader-willi and active angelman

Paternal has imprinted angelman and active prader-willi

151
Q

What is gonadal mosaicism?

A

Post-zygotic mutation that affects gonadal tissue.

Abnormal gamete from a phenotypically normal parent

Fundamentals 3- Heme (19 decks)

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