Final Exam Review Flashcards
(149 cards)
1
Q
What are the two functional roles of genes?
A
- Housekeeping: maintenance of cell structure and function; in all cells (ex: actin, tubulin)
- Specialty: tissue specific proteins with unique functions (ex: liver enzymes)
2
Q
Describe the impacts of mutations of housekeeping genes and specialty genes
A
Mutation in housekeeping genes: ebryonic lethal or genetic redundancy if there is genetic redundancy
Mutation in specialty gene: tissue/ organ specific effect
Both can have broader effects if the defect impacts a diffusible factor or global physiology
3
Q
What is allelic heterogeneity?
A
In different families, distinct/unique allelomorphs impacting the same gene cause distinct phenotypes between families
Due to presence of multiple alleles at a single locus
4
Q
What is the difference between allelic heterogeneity and penetrance/expressivity?
A
Allelic heterogeneity describes differences in different families with mutations in same gene, but different alleles
Penetrance/expressivity describes differences within a family that has mutations in a single allele, but show different phenotypes
5
Q
What is locus heterogeneity?
A
Different, unique gene mutations have impact on the same trait. This is because multiple locii may be associated with a specific clinical condition
6
Q
Why does locus heterogeneity complicate clinical interventions?
A
Drugs usually target specific proteins or receptors, but locus heterogeneity results in different proteins/receptors that are affected, so different drugs would be needed
7
Q
What is clinical heterogeneity?
A
Distinct phenotypic characteristics are seen in different patients with the same or very similar genotypes
8
Q
What is pleiotropy?
A
When a mutation affects different biochemical pathways, or anatomical, biochemical or behavioral characteristics, distinct effects in different regions of the body are often seen
9
Q
Compare the impact of typical hypomorphic mutations and amorphic mutations
A
Hypomorphs often have less severe impacts on health than amorphs
Some function is better than none
10
Q
In enzymopathies, are genotype and phenotype usually correlated?
A
Yes. Catalysis happens in real time, so affected enzymes are unable to properly produce the proteins that are responsible for the phenotype
11
Q
Describe the most common mutations found in aminoacidopathies.
A
Most involve loss of function alleles in genes coding for degrading enzymes or mutations of genes that impact cofactors
12
Q
What is the name of the enzyme responsible for phenylalanine degration?
A
Phenylalanine hydroxylase (PAH)
converts phenylalanine to tyrosine
requires a co-factor tetrahydrobiopterin (BH4)
13
Q
In what organs can you find PAH?
A
The liver and the kidney
14
Q
Describe Phenylketonuria (PKU)
A
Phenyl-keton-uria = phenyl ketones detected in urine
Disease of amino acid metabolism where Phe accumulates in all body fluids because it can’t be converted to Tyr due to the absence/deficiency in PAH
15
Q
What is the genotype of most PKU patients?
A
They are usually compound heterozygotes with combinations of hypo/amorphic alleles that impact the disease course and treatment
16
Q
What is hyperphenylalaninemia?
A
Dramatic increase in blood [Phe] seen in PKU patients
17
Q
What is the clinical impact of hyperphenylalaninemia?
A
Almost all untreated PKU have severe mental retardation due to neurotoxicity
Need to diagnose within 4 weeks of birth to prevent negative outcomes (>24 hours after birth because of peak in [Phe] at birth)
18
Q
What is the main treatment for Classic PKU?
A
Maintaining a low phenylalanine diet
19
Q
What is the blood phenylalanine level typically seen in PKU? What is the normal range?
A
Classic PKU: >20 mg/dL Phe
Wildtype” ~0.5-1 mg/dL Phe
20
Q
What type of alleles are associated with Variant and Non-PKU/Benign HyperPhe?
A
Hypomorphic alleles
The impact is less severe than classical PKU
21
Q
What are the typical phenotypes observed in PKU heterozygotes?
A
They show minor or no phenotypes
22
Q
Describe the steps taken for treating pregnant mothers with PKU
A
They must treat the PKU by watching their diet in order to prevent the fetus from being flooded with Phe, which leads to mental retardation, heart defects…etc.
23
Q
Describe the locus heterogeneity of BH4 metabolism
A
BH4 acts as a hydrolase cofactor in biosynthetic pathways including:
Phe –> Tyr
Tyr –> L-dopa
trp –> 5-OH trp –> serotonin
24
Q
What are the supplements and medication needed to treat compound heterozygotes or homozygotes with reduced BH4?
A
Oral BH4
Low Phe diet
L-dopa
5 OH-Trp
Folinic Acid
25
Why is it important to distinguish patients with PAH mutations from BH4 metabolism defects?
Treatment of these patients differs
26
What are lysosomes?
Membrane bound organelles containing many hydrolytic enzymes where many proteins and lipids are degraded
27
What is the typical effect of lysosomal storage diseases?
Overaccumulation of substrates leads to cell death
Organ mass changes and/or neurodegeneration are common
28
What are the relevant molecules involved in spingolipid degradation diseases?
The GM2 Gangliosides accumulate because hexosaminidase A function is lost
29
Describe hexosaminidase A
It is a multisubunit enzyme that requires a recognation subunit (activator) to present GM2 to the HEXA and HEXB Enzyme Core
It cleaves off the monosaccharide N-acetylgalactosamine (GalNAC)
Without this cleavage, GM2 accumulates in the lysosome
30
Describe the mutation seen in Tay-Sachs disease
Compound heterozygotes for loss of function alleles of the HexA alpha subunit gene
31
What are three population genetics theories that could explain why Tay-Sachs disease is common in some populations? Which is the predominent theory?
1. Heterozygote advantage
2. Founder effects in a small population
3. Genetic drift
32
Describe the phenotype seen in Tay-Sachs disease
Normal behavior and growth until about 3-6 months of age
Seizures common at early age, the rapid neurological degeneration occurs with a loss of motor control
Can see neuronal death in the eye's Fovea Centralis
33
Describe the allelomorphy seen in Tay-Sachs disease
A complete loss of function (amorphic) allele prevents Hex A from having any activity
This is a 4 nucleotide insertion that alters the reading frame leading to a premature stop codon
34
Describe HexA Pseudodeficiency
have about 20% residual hexA activity, which is enough to prevent the neurodegeneration. Homozygotes display normal phenotypes.
35
What aminio acid is associated with homocystinuria?
Methionine
36
What happens in homocystinuria?
There is a build up of homocysteine in the cells which causes:
Lens dislocation, mental retardation, osteoporosis, and increased bone length
Thromboembolism of veins and arteries
37
What happens in patients with α-Antitrypsin Deficiency?
In liver there is a neomorphic mutation (Glu342Lys) which leads to aggregation into long polymer strands in the hepatocyte Rough ER
The α1AT is a serine protease inhibitor (serpin) that binds and inhibits elastase
The improper balance of α1AT/Elastase leads to lung disease
38
What behavior significantly lowers the 60 year survival rate on α-Antitrypsin deficient patients?
Smoking
39
What is the main characteristic seen in hyperlipoproteinemias?
High levels of blood plasma lipids and lipoproteins
40
Describe the mutation usually seen in hyperlipoproteinemias
Dominant traits from loss of function alleles
Most common: LDL receptor loses function due to autosomal dominant inheritance pattern. This causes LDL cholesterol level to rise to ~350 mg/dL in heterozygotes (700 in homozygotes)
41
What is pathway interaction theory?
A thoery that explains the interactions between enzymes and substrates in a linear fashion
Linear dependent: A--\>B--\>C "A is required for B, is required for C"
Linear negative: A--||B--||C "A inhibits B, which inhibits C"
Partner effect pathways: A\<---\>B "A is required for B is required for A ..."
42
Describe hypercholesterolemia using pathway interaction theory
Hypercholesterolemia is a complex partner effect pathway inhibited by a linear negative feedback pathway.
43
What are the proteins associated with hypercholesterolemia?
1. Mature LDL receptors on cell membrane
2. Apoprotein B-100 protein surrounding cholesterol ester core, binds to LDL receptor
3. PCSK9: protease that degrades LDL receptor
4. ARH adaptor protein: required for clustering the LDL receptor in the clathrin coated pit
44
What is the gene dosage effect, and how is it related to hypercholesterolemia?
Homozygotes with this disease have twice the serum cholesterol level of heterozygotes, symptoms manifest earlier and are more severe
45
What are the classes of mutations in the LDL receptor?
1) Receptor synthesis
2) Receptor transport from ER to Golgi
3) LDL binding by receptor
4) Receptor clustering in coated pit
5) Failure to discharge LDL in endosome
6) Defective targeting to basolateral membrane
46
What are the structural domains of the LDL receptor?
1) Ligand binding domain
2) EGF precursor homology domain
3) Transmembrane domain
4) Cytoplasmic tail
47
Describe the general genetic effect of Cystic Fibrosis
An autosomal recessive allele that is usually loss of function
Chloride Ion Transporters (CFTR) mutations cause abnormal fluid balance across the membrane
Problem in epithelial tissues that secrete fluid (i.e. Lungs, pancreas ...)
48
What are the 3 domains of the CFTR protein?
Membrane Spanning domain
Nucleotide binding domain
Regulatory domain
49
What are the classes of mutations in CFTR gene and cellular effects?
1) no synthesis of gene product
2) Defective protein product destroyed in proteosomes
3) Protein gets to cell surface, abnormally regulated
4) Defective chloride ion conductance
5) Promotor, intron/exon splicing mutatnts
6) Increased rate of turnover of Cl channels at the cell surface
50
Is the presence of the CFTR genotype a good predictor of pulmonary disease?
No. Amorphs and Hypomorphs have variable impacts on lung function. Different alleles moderate/enhance the CFTR mutation
51
What are the major examples of a structural protein mutation?
Dystrophin mutations that cause Ducenne and Becker Muscular Dystrophy.
Collagen mutations can cause Osteogenesis Imperfecta
52
Describe Duchenne Muscular Dystrophy
An X-linked disorder, which meens most affecteds are males
A deletion or point mutation leads to no Dystrophin production (Amorph)
Progression: 3-5 y.o. develop muscle weakness, confined to a wheelchair by 12 y.o. and dead by 20 y.o.
Respiratory and cardiac failure usually cause death. Elevated levels of serum creatine kinase are seen
53
What is the difference between Becker Muscular Dystrophy and Duchenne Muscular Dystrophy?
BMD has a much milder phenotype than DMD because BMD affecteds still produce some dystrophin (Hypomorph)
54
Describe the histological changes seen in the muscles of patients with DMD
Normal muscle tissue has tight muscle fiber bundles pressed together evenly, but DMD affecteds have accumulation of fat and connective tissue between the muscle cells.
55
What is the prognosis for patients with BMD?
Ambulatory until 16-30 y.o.
Extensive survival into adulthood
Reproductively fit males
56
What genes are affected by Osteogenesis Imperfecta?
The collagen genes: COL1A1 or COL1A2
57
Describe the phenotype of individuals with Osteogenesis Imperfecta
Characterized by brittle bones due to malformed collagen fibers.
Phenotypes are highly variable due to many allelomorphs
58
Describe the normal collagen structure
Collagen is a heterotrimer containing 2 procollagen-1A1 and 1 procollagen-1A2 molecules that form into a triple helix
59
What are the differences between Type I and Type II, III and IV Osteogenesis Imperfecta
Type I: Diminished Type 1 Collagen production usually due to a premature stop codon in COL1A1
Type II, III, IV: Structurally defective collagen usually due to the replacement of a Glycine residue with a more bulky amino acid residue
60
How does amorphy change the dose of normal collagen seen in the body?
Amorphy leads to a null allele from one of the parents, but they will still have a good allele from the other.
Half dose of normal collagen will be seen
61
What is the ratio of normal to mutant collagen molecules seen with a dominant negative allele for Osteogenesis Imperfecta?
1:3
3 out of the 4 possible combinations of the 4 proteins (Pro alpha 1 M, Pro alpha 1, and 2 Pro alpha 2) will contain the mutant chain
62
What percentage of human genes are transcribed in the CNS?
~60% according to the Allen Brain Map
63
What are the different types of defects seen in Neurodegenerative Diseases?
Energy (Mitochondrial disorders)
Proteinopathies (AD)
Unstable repeat diseases (Huntingtons)
64
Why has Familial Alzheimer's disease been easier to study than the more common sporadic AD?
FAD has a simple inheritance due to a highly penetrant allele in one of three genes
65
What is the phenotype associated with Alzheimer's disease?
Progressive memory loss, neurodegeneration, cell death and amyloid plaques with neurofibrillary tangles
66
What are teh 4 genes associated with FAD?
βAPP, Presenilin 1 and 2 (Autosomal dominant in FAD)
APOE
67
What type of disease is Huntington disease?
An unstable repeat expansion disease
68
Describe the repeats and their effects seen in Huntington's disease
Repeat: CAG repeated more than 40 times in the exon for the huntington protein.
This polyglutamine tract confers novel properties on the protein leading to increased and/or promiscuous protein:protein interactions with transcription factors which causes a loss in their function
69
Explain the predominant theory for why repeats are unstable in diseases like Huntington's disease.
Slipped Mispairing Mechanism
The template strand can slip during DNA replication in Meiosis which can lead to new repeats
New strand: CAG -**_CAG-_**CAG-CAG
Template strand: CAG-CAG-CAG
\*\* The bolded repeat can slip out of position after it is synthesized, allowing the next repeat to slide over and then produce a 4th repeat that should not be there
70
What are the 3 classes of unstable repeat expansion diseases?
1) Diseases due to expansion of noncoding repeats that cause a loss of protein function
2) Disorders resulting from expansions that confer novel protein properties
3) Diseases due to repeat expansion of a codon (Huntingtons)
71
What is the general definition for cancer?
One of a variety of processes that lead to cell proliferation that have variable results
72
What is a neoplasia?
A cellular disease with a change in growth regulation, uncoordinated growth, and different grads and levels of development
73
What is metaplasia?
Adaptive change in tissue type that is controlled
ex: growth and differentiation
74
What is hyperplasia?
Cell proliferation
In other words: an increase in the number of cells
75
What is dysplasia?
Changes in histology or phenotype in a tissue, but not a true neoplasia
Typically an expansion of immature cells with a corresponding decrease in mature cells.
Can be pre-neioplasia
76
What tissue does desmoplasia affect?
Connective tissue is proliferated in desmoplasias
This is usually associated with neoplasms in the form of a "Tumor Capsule"
77
What are the characteristics of a malignant neoplasm?
Clonality
Invasiveness
Metastasis
78
What are the differences between a benign and a malignant neoplasm?
**Growth rate**: benign is slow, malignant is fast
**Mitosis**: benign is normal, malignant is abnormal
**Cellular differentiation:** malignant is poor
**Metastasis:** benign NO, malignant YES
79
What are the type classifications of cancer based on? What are the types?
Tissue origin
Ex: Carcinoma from epithelial cells
Sarcoma from mesenchymal/mesodermal cells
Lymphoma from hematopoietic cells
Germ tumors: totipotent stem cell
Blastomas: embryonic/immature cell type histology
80
What are the hallmarks of tumors?
Environment independent growth
Ignore contact inhibition and suppressive growth factors
Promote angiogenesis and vascularizations
Depress cell death system
No division limit (Immortalized)
Invade and metastasize
81
What is the 1 kg rule?
When a tumor reaches a mass greater than 1 kg, something will almost certainly go wrong and cause death due to the sheer size of the tumor
82
What are common causes of cancer that lead to the "plasias"?
Environmental or Genetic Insults including:
Mutagenesis, esophageal reflux, HPV, EBV, Colitis, Inflammation, inheritance
83
What is familial adenomatous polyposis?
FAP
An inherited condition in which numerous polyps form in the epithelium of the large intestine. They start out benign, but often turn into malignant colon cancer over time.
84
What are oncogenes?
Genes that normally regulate cell division whose gain of function somatic alleles can lead to uncontrolled division processes
85
What are tumor suppressors?
Loss of function leads to cell division, loss of normal apoptosis, genomic instability, errors in DNA repair
Effect only seen in homozygotes
Analogy: Breaking of the brake pedal
86
Explain how a rare mutation could develop into a malignant tumor.
Dysplasia and hyperplasia arise by rare initial mutations that promote cell division. As the cells divide and experience genomic instability, additional mutations within the unstable region begin to destabilize more, eventually leading into evolution into a malignant tumor
87
What is the APC gene?
Adenomatous polyposis coli
A tumor suppressor gene, which when mutated can lead to colorectal cancer.
88
What is beta-catenin?
The gene encoding beta-catenin can be an oncogene
Elevated levels of beta-catenin have been associated with various cancers (Hypermorph)
89
Why don't all crypts form adenomas?
"Second-hit" theory
An initial insult is from a mutant allele, in other words, if from the inherited DNA
A second insult mutation accelerates the disease rapidly
The somatic cell is converted from into a compound heterozygote or "Loss of Heterozygosity"
90
How does "Loss of Heterozygosity" occur?
Nondisjunction and aneuploidy, somatic recombination, deletion mutation or gene conversion
In the end you are either homozygous or hemizygous for the familial disease allele
91
How did the study of familial retino blastoma support the "Second Hit" theory?
Individuals with familial RB had an early time of onset during childhood. They were typically bilaterally affected.
This suggests that they were born with "1 hit" in a gene involved with the development of the eyes, and then acquired the second hit in the retina.
92
What is the model for APC function?
APC orients beta Cat for phosphorylation
In the absence of GSK function, the APC/bet Cat complexes disassociate at a set rate, providing a steady influx of the factor into the nuclei
An APC mutation will dramatically increase the nuclear beta Cat which can be seen histochemically in adenomas
93
What is chromosomal instability?
CIN
Chromosomes that are likely to change and develop into malignant neoplasms
94
What is the "double whammy" associated with APC mutations?
1) Failure to down regulate the nuclear accumulation of beta Catenin
2) Failure to do normal spindle microtubule capture, leading to aneuploidy and rearrangement.
95
What is KRAS?
Molecular on/off switch for cellular growth
A GTPase that, when mutated, becomes locked into the GTP bound active form.
This mutation is found in about 50% of highly invasive FAP carcinomas
96
What do the Smad4 and TGFbeta genes code for?
They are receptors that are involved in inhibition of growth.
Mutations in these genes will remove the inhibition, thus leading to uncontrolled growth.
97
What is the function of the p53?
"The guardian of the genome"
p53 is important for regulation of the cell cylcle
It is able to pause the cell cycle for DNA repair when mutations are found, thus protecting the genome
It is also able to initiate cell apoptosis, programmed cell death
Mutations of p53 make the cancer cells immortal
98
What are the 5 stages of breast cancer?
TDLU: Normal lobular duct cells
ADH: ductal hyperplasia (mitotic proliferation)
DCIS: Ductal carcinoma *in situ**s*, not invasive
IBC: Invasive breast cancer
MET: Metastatic breast cancer
99
Describe cancer stem cells
Cancer cells have self-renewal and differentiation pathways just like embryonic stem cells.
Based on the differentiation programming, cancer cells can have:
1) A mixed lineage and cell type if the mutation occurs before differentiation
2) A luminal cell type if the mutation occurs after differentiation, affecting only the luminal cells
3) A basal cell type if the mutation occurs after differentiation, affecting only the basal cells
100
Why is it useful to isolate mRNA from tumors?
Different genes are turned on in different tumor types
These expressed genes strongly predict the survival outcomes of cancer patients.
This may be important for designing new drugs to treat cancer
101
Why does cell type heterogeneity in cancer tissue create a challenge?
The sample of tumor tissue could have varying compositions with more or less of the tumor actually present in a given sample. This lowers the signal to noise ratio due to the presence of non-tumor tissue in samples
102
How can cell type heterogeneity be overcome?
Microdissections allow for pure tumor samples to be analyzed, thus raising the SNR
103
Describe Laser Micro-dissection
The human eye, with the assistance of a microscope, is used to identify target tissues
A plastic sheet laid over the tissue slide turns into an adhesive when exposed to laser pulses
The laser pulses follow the selected path, and the contained tissue can be extracted in order to analyze mRNA, protein or DNA
104
Why might it be more useful to look at cancer at the protein level instead of the DNA or mRNA level?
We dont know what is actually transcribed by looking at the DNA or RNA
105
What is a signalling network protein chip and why is it useful?
Arrange antibodies on an array and use fluorescent tags in order to see which are present in the sample.
This is useful to identify differences between patients with the same types of cancers
106
What are the different levels of intervention for genetic disorders?
Mutant gene
Mutant RNA
Mutant protein
Metabolic or other biochemical dysfunction
Clinical phenotype
Family
107
What are the 3 major categories of responses to treatment of monogenic disorders?
1) Complete response (12%)
2) Partial response (54%)
3) No effective treatment (34%)
108
What is substrate limitation, and why is it a valuable treatment in many disorders?
Removing toxic intermediates by limiting the available substrates for a reaction. This reduces the substrate level to an amount that the enzyme is able to handle
109
Why might product replacement therapy be useful for treating various disorders?
A defective enzyme is unable to produce any (or enough) of it's product. By administering the product through a drug, the enzyme is effectivelly skipped and the biochemical process that it is involved in can be continued.
110
Why is treatment difficult with many genetic disorders?
1) The pathogenesis or normal role of the gene/protein are not well understood
2) The damage may be done before fetal diagnosis can be performed
3) Phenotypes are severe, so the treatments may include surgery, drugs, and therapy
111
What are some exapmles of surgical interventions that are effective for treating genetic disorders?
Transfusions in thalassemias
Surgical correction of a congenital heart defect
Surgical correction of cleft lip/pallet
Pre-emptive surgery in familial cancers
112
What is the major effective treatment for retinoblastoma?
Removing the tumor that is contained in the eyeball
This results in blindness, but prevents the disease from progressing
113
What are the different pathway interventions that can help treat loss of function mutations
A --\> B --\> C --\> D --\> E
A --\> B x *_C --\> D --\> E_*
Curative: replace function of E by improving C function
Avoidance: prevent exposure to the substrate that cannot properly be processed (dietary restriction)
Replacement: provide product, thus skipping over defect
Diversion: using a shunt pathway, "detour"
Inhibition: change product, substrate or intermediate concentrations by inhibiting another enzyme
114
What disease is a good example of using Diversion as a pathway intervention?
Hypercholesterolemia
Usually bile acids are formed via the oxidation of cholesterol, and are excreted into the intestine and then resused.
A resin is used to bind to anion exchange proteins in the intestine that prevent the recycling of bile acids. This depletes the blood cholesterol level.
Removing the recycling makes the body attempt to form more bile salts by uptaking more cholesterol, thus lowering the blood concentation.
115
How do statins work?
They inhibit the formation of cholesteral by inhibiting the activity of HMG-CoA Reductase.
HMG-CoA Reductase is an enzyme that produces cholesterol in the liver. By inhibiting this enzyme, the liver attempts to compensate by pulling more LDL out of the blood stream than before, thus lowering the serum cholesterol
116
How can alpha1-antitrypsin be treated at the protein level?
By correcting the imbalance of elastase/alpha1-antitypsin by delivering alpha1-antitrypsin intravenously
117
Describe the process of RNA interference, and what diseases it may be useful to treat
Triplet repeat diseases may be treated in this manner:
We can target specific mRNAs within a cell in order to deplete the cell for a dominant disease causing allele, while leaving the wild type allele functional
118
What are some challenges associated with RNA Interference?
Off Target Effects: similar RNAs destroyed, both mutant and wildtype allele could be targeted
Efficient delivery to specific tissues
Dosing: high concentrations of siRNA will likely be needed
119
How are hematopoietic stem cells useful for treating sickle cell anemia?
A closely matched bone marrow donor is found and transplanted into the patients bone.
Irradiation and immune suppression are used to allow the graft to displace the host stem cells
New blood can then be produced with wild type hemoglobin instead of the HbS
120
What are the 2 major gene transfer strategies?
1) Ex vivo: cells isolated from a patient are transformed and then replaced
2) In vivo: cells in tissues in patients are directly transformed by viral infection or direct DNA transfer
121
What are ways that DNA can be transfered into cells?
Naked DNA via electroporation, sonofication, or liposomes
## Footnote
Viral transfer: Retroviruses allow for RNA to be reverse transcribed
Adenoviruses DNA viruses
Adeno-associated viruses DNA viruses
122
What are the risks of gene therapy?
Immune response to the injected viral load
Insertional mutagenesis leading to a loss of function mutation
Insertional mutagenesis leading to gain of function mutation
123
What is compaction?
Following the 8 cell stage of embryo development
The process by which a blastocyst begins to be formed.
Water eners the inner portion of the blastocyst to form blastocoel cavity.
124
How many days after fertilization does the blastula implant?
6-8 days after fertilzation, the blastula implants onto the endometrial epithelium
125
What is the syncytiotophoblast?
A multinuclear cytoplasm that invades into the endometrium from the implanted blastula
This invasion allows for the interface for chorionic expansion into the maternal tissue to form
126
Describe the epidemiology of pregnancy loss
Loss of "Chemical Pregnancy" during the first trimester occurs 25-50% of all successful fertilizations
Miscarriage rates "Recognized pregnancy":
15-20% before 10 weeks
2-5% after 10 weeks
127
Why does the risk for pregnancy loss decrease after 9 weeks?
There are various testing approaches available
The placenta, amnion, and fetus are all formed
128
What are the indications for prenatal testing?
Advanced maternal age (\>35 y.o.)
Previousl child with a chromosomal aneuploidy
Structural chromosomal abnormality in either parent
Family history of genetic disorder
Family history of neural tube defect
Positive results from non-invasive test
129
What are the two fetal testing alternatives?
Invasive (ex: retrieval of amniotic fluid)
Non-invasive (ex: ultrasound)
130
Describe chorionic villus sampling
CVS
Usually guided by ultrasound. A spinal needle is inserted into the chorion from the anterior side while a cannula is inserted through the vagina
Samples are taken from the fetal cells that invade the maternal tissue
\*You want to sample the smallest tertiary villi as possible to minimize risks
131
Why is chorionic villus sampling (CVS) more adventageous than amniocentesis (AC)
Timing: CVS allows for earlier assessment
CVS: Can sample highly branched tertiary villi
There are more markers in AC, so there is a broader spectrum of biological markers
CVS does have a higher risk (+1%) than AC (+1/1600)
132
What is alpha-fetoprotein?
A major serum protein in fetuses and newbornds that makes up a large fraction of the blood
Thought to be a fetal analog to albumin
133
Describe what defects changes in AFP may be indicative of
High AFP in maternal circulation: Open neural tube defects
Low AFP in maternal circulation: Down syndrowme
134
What is omphalocele?
A problem with the embrionic turning/folding process that results in incomplete ventral closing.
Organs form outside of the body cavity,
Easy to fix with surgery early on in fetal development
135
What is a biomarker, visible via ultrasound, of a trisomy?
Edema (fluid accumulation) in the nape of the neck
This occurs because the lymphatic system does not yet exist at 10-14 weeks, so fluid just pools in the nucal translucency
136
How can spina bifida be detected on an ultrasound?
You can see the returns from the vertebral columns and meninges/skin on ultrasound images
If a meningomyelocele sac (a bubble of spinal fluid) is seen, then the fetus has spina bifida
The nerves grow into this sac instead of down into the lower extremities.
137
Theoretically, what drives clinical and life-style decision making?
Associations between genotype and health/disease risk
138
How does the threshold for screening for colon cancer differ between those with family history of colon cancer and those without?
Those with family history need to be tested at age 40, those without don't need testing until age 50
139
What is clinical validity?
Test result is predictive of disease
140
What is Clinical utility?
Test results impact treatment plan and result in positive health outcomes
141
Describe the 2x2 grid used to determine the predictive value of a test
Relative risk ratio (RRR) = a/(a+b) / c/(c+d)
= disease prevalence in carriers of susceptibility genotype/ disease prevalence in non-carriers of susceptibility genotype
142
If the RRR = 1, what does that mean about your genotype?
It means the genotype that you think is associated with the disease isn't really indicative of the disease
143
What is the sensitivity?
fraction of individuals with disease who have the susceptibility of the genotype
a/(a+c)
144
What is specificity?
fraction without the disease who do not have the susceptibility genotype d/(b+d)
145
What is positive predictive value?
Proportion of individuals with the susceptibility genotype who have or will develop a particular disease
a/(a+b)
146
What is negative predictive value?
Proportion of individuals without the susceptibility genotype who do not have or will not develop a particular disease
d/(c+d)
147
What are the requirements for a good newborn screening test?
Analytical validity
Clinical validity
Clinical utility
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