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- the proportion of times a specific outcome occurs in a series of events
- eg. in a pregnancy: 1/2 girl, 1/2 boy
- the outcome of one event does NOT depend on outcome of other event
- eg. a previous pregnancy does NOT affect a future one
- each conception: 1/2 boys, 1/2 girls
- if two events are INDEPENDENT of each other, the probability of outcome of both trials occurring is the product (multiply) of each outcome
- eg. the chance of having 3 children and all of them be girls= 1/2 x 1/2 x 1/2 = 1/8
- the probability of one outcome OR another is the addition of each outcome; eg.
- boy or girl = 1/2 + 1/2 = 1
- probability of getting EITHER 2 heads in a row OR 2 tails in a row =
- (1/2 x 1/2) + (1/2 x 1/2) = 1⁄4 + 1⁄4 = 1
frequency of the DOMINANT allele in a population (present in people with both AA and Aa)
frequency of the RECESSIVE allele in a population (present in people with both Aa and aa)
how many/the incidence of homozygous recessive people there are (people who have aa genotype)
how many/the incidence of heterozygous people there are (people who have Aa genotype)
How do you calculate the chance that at least one child is affected?
- ONE - NONE
- chance unaffected = pedigree fraction x # of children
If a couple have two girls and wish to know the probability that all three of their children will be girls, what is the probability of producing a 3rd girl?
1/2 - the previous 2 events are no longer probabilities
- when a person has two recessive alleles for the same gene, but with those two alleles being different from each other
- disease causing
If a parent HAS an autosomal recessive disease, his children are all either:
- or have the disease, depending on his spouse's genetic make-up
If you're interested in determining the carrier rate of a person WHOSE SIBLINGS HAVE THE DISEASE (autosomal recessive), that person's carrier rate is usually:
- the parents are obligate carriers, meaning 1 of the four choices (aa) is removed from consideration
- the person's genotype can therefore be either AA, Aa, or Aa, making their chance of being a carrier 2/3
If someone is homozygous for an autosomal recessive trait, the chance they'll pass it on in that little formula thing =
1, NOT 1/2
What is the recurrence risk for most isolated birth defects?
it can be estimated to be about 4%
Why type of predisposition to cancer requires the presence of only ONE mutant allele to initiate disease?
At what point in a pregnancy can a dating ultrasound be administered?
- 8-10 weeks in
- checks/confirms how pregnant you are
- sees the number of babies in the uterus
- checks how the baby is developing
- growth restriction, abnormally low (oligohydramnios) or excess (polyhydramnios) amniotic fluid, brain structural anomalies, abdominal wall defects, neural tube defects (spina bifida), kidney and bladder abnormalities
- NO known risk to the baby or mother
At what point in a pregnancy can Chorionic Villus Sampling (CVS) be administered?
- 11-13 weeks
- trans-cervical or trans-abdominal ultrasound guided catheter or needle to aspirate chorionic villi
- allows for a rapid karyotype, detects mosaic trisomy, BUT has an elevated risk for fetal loss, and DOESN'T give you any info about neural tube defects
- good for detecting OI, for example
Advantages of CVS over amniocentesis:
- • Performed in 1st trimester
- • Restores privacy to reproductive decisions
- • Tissue obtained is preferable for DNA analysis • Cells are mitotically active; karyotyping is rapid • Detects mosaic trisomy, thereby identifying fetuses at risk for uniparental disomy (UPD)
Disadvantages of CVS
- • Elevated chance of miscarriage (0.5 versus 1%)
- • Slightly elevated risk of maternal infection
- • Possibly causes limb malformations
- • Confined placental mosaicism detection in 1% of cases
- • Amniotic fluid alpha-fetoprotein not assayed (open neural tube/abdominal wall defects)
At what point in a pregnancy can a maternal serum (mother's blood) test be administered?
- 15-18 weeks
- measurement of proteins produced by the fetus or placenta; results are reported as relative values compared to population standards (MoMs, multiples of the median)
- to interpret results, an accurate gestational age, maternal diabetes, maternal weight, maternal race, and smoking status must be known
What proteins produced by the fetus or placenta are used in the maternal serum screen?
- 1st trimester markers: PAPP-A, beta-hCG
- 2nd trimester markers: AFP, hCG, uE3 +- inhibin
What would the levels of a fetus with trisomy 21 be?
- 1st trimester -
- PAPP-A: lower
- Beta-hCG: higher
- 2nd trimester -
- AFP (alphafetoprotein): lower
- Free beta-hCG: higher
- u E3 (estriol): normal
At what point in a pregnancy can a fetal anomaly ultrasound scan be given?
around 18 weeks
At what point in a pregnancy can a Nuchal Translucency ultrasound test be administered?
Why would a Fetal Magnetic Resonance Imaging (MRI) technique be used?
- allow imaging of the fetus while the fetus is moving
- technique is mainly used when ultrasound examination suggests a brain, thoracic or abdominal abnormality; provides better resolution than ultrasound
At what point in a pregnancy can Amniocentesis be given?
- 15-19 weeks
- trans-abdominal aspiration of amniotic fluid
At what point in a pregnancy can Cordocentesis be given?
- 18-20 weeks
- percutaneous ultrasound-guided needle aspiration of 1-3 ml of fetal blood from the umbilical cord at the placental insertion site
- used to diagnose congenital infection, thrombocytopenia, 3rd trimester chromosome abnormalities, or anemia
- (risk of miscarriage or preterm labor is 1-5%)
NIPT (noninvasive prenatal testing)
- offered to pregnant women at risk for trisomies 13, 18, 21 and just tests maternal blood for free fetal DNA
- a safer procedure for high risk women
PGD (preimplantation genetic diagnosis)
- process of screening embryos for genetic abnormalities prior to transferring into uterus
- requires IVF, sometimes ICSI (remember, used for lazy sperm)
- embryo is biopsied on the 3rd day and FISH or PCR analysis is done on a single blastomere
all cancers are due to:
- DNA mutations – most mutations are acquired, not inherited
- predisposition to a cancer can be inherited as a single trait (there fore it's autosomal dominant)
- CANCER itself requires TWO mutations
What's the difference between sporadic and hereditary cancer?
- sporadic: two ACQUIRED mutations
- hereditary: one inherited and ONE acquired mutation
What types of genes that when mutated cause loss of function and subsequently cancer?
- 1) Tumor Suppressor genes - normally restrain cell growth (eg. Rb, NF1, p53, APC)
- 2) Mismatch repair genes - normally maintain correct DNA sequences (eg. MLH1, MSH2, MSH6)
mutations in mismatch repair genes can often result in lynch syndrome, which is a high risk for HNPCC (hereditary nonpolyposis colorectal cancer) – colon and uterine cancers most common, ovarian and other GI cancers also occur (endometrial, stomach and ovarian cancer)
Gain of Function Cancer-causing Mutations
- are unlikely to be inherited
- a single somatic gene mutation can cause cancer
- growth and transcription factors
- eg. Oncogenes, BCR-ABL, RET
What are red flags for hereditary cancers?
- early onset cancers (under 50)
- multiple or bilateral tumors
- rare or unusual tumors
- combinations of certain cancers (lynch syndrome)
- autosomal dominant pattern of inheritance
- lack of known contributing factors
concept which states that researchers should have the welfare of the research participant as a goal of any clinical trial (opposite of maleficence: any practice which opposes the welfare of any research participant)
the combined contribution of genetic and environmental factors in the causation of a particular disease or trait
- results from the combined influence of multiple genes
- eg. EYE color - controlled by multiple genes, CAN'T be changed by environment
- results from the combined influence of multiple genes AND environmental factors
- eg. HEIGHT
Quantitative Trait (continuous)
- can be measured on a numerical scale
- results from the additive effect of multiple genetic & environmental factors
- follows a normal, or ‘bell-shaped’ distribution in populations
- eg. height, weight, blood pressure, intelligence (these traits CANNOT be absent, you can't NOT have height)
- a trait that's either present or absent
- bell-shaped distribution in the population with respect to liability/total risk (an individual’s combined genetic + environmental predisposition to a disorder) of a trait
- only those individuals exceeding the threshold on the liability scale will express the trait
- eg. club foot, diabetes, cleft lip
What are signs that a disease or trait is inherited via multifactorial inheritance?
- a familial concentration without a clear Mendelian pattern of inheritance
- absence of clear biochemical defects resulting from a single abnormal gene
- considerable variation in severity and expression of the phenotype
- often gender differences in the frequency of occurrence
Are these traits more likely to be seen in males or females?
- Cleft lip and palate
- Pyloric stenosis (PS)
- Congenital hip dysplasia
- Cleft lip and palate: more males
- Pyloric stenosis (PS): more males
- Congenital hip dysplasia: more FEMALES
- males need a LOWER liability to exceed the threshold for Cleft lip/palate &
- Pyloric stenosis (PS)
Why does the recurrence risk decreases rapidly in more remotely related individuals?
- because you share more genes with the people you're more closely related to
- recurrence risk for 1st degree relatives = the square root of the population incidence of the trait
- can examine how much genes/genetics contribute to a disorder by observing familial aggregation, esp twin studies
- concordance rate in monozygotic twins can be compared to the concordance rate in dizygotic twins to estimate the heritability of a trait
- the greater the percentage of concordance within monozygotic twins, the more a multifactorial trait is based in genetics
Multifactorial traits show __________ concordance in monozygotic twins
- less than 100%
- they also show a higher concordance in monozygotic twins than dizygotic twins (b/c they have the exact same genes)
monozygotic twins are more often _________ than _________ for birth defects
more discordant than concordant for BIRTH DEFECTS
- 1) DNA (eg. CGH, SNP)
- 2) mRNA (for gene expression)
- 3) Protein
- used for characterizing developmental delay, dysmorphic features, tumor characterization, or identifying genes (genome wide association studies, GWAS)
Comparative Genomic Hybridization (CGH)
- two DNAs are compared (normal vs. patient, normal vs. tumor) to look for regions of duplication or deletion
- allows identification and fine mapping of smaller duplications and deletions in the 35 kb range
- change may be related to the reason for testing or may be a polymorphism (not significant)
- [like a higher resolution FISH]
- patient’s DNA sample is hybridized to a control DNA sample to detect extra or missing genetic info (i.e deletions and duplications)
SNP (single nucleotide polymorphism)
- patient’s DNA sample is compared with thousands of SNPs along each chromosome (SNPs serve as a marker)
- may or may not result in a change in the amino acid sequence
- generally inherited mendelianally (could be added or removed by a mutation)
- each chromosome will have many SNPs
a group of SNPs observed proximal/together (eg. 1,2,3,5,7…if look for 3, will always find 1,2,5,7)
In a single nucleotide polymorphism (SNP), loss of function indicates:
a deletion, duplication, UPD, or consanguinity
Both CGH and SNP tell us if there is a deletion or duplication, but what extra information can SNP can give us?
that there may be UPD or consanguinity
How many genes?
- 3 x 10^9 bp (<5% encodes genes)
- 24 different chromosomes (22 pairs of
- autosomes, X and Y sex chromosomes)
- estimated 30,000 genes (range 26,000 – 150,000)
- at least an equivalent number of regulatory elements
- a change in the gene sequence without disruptive effects
- one of the reasons the genome is up to 12% variable between people
Genome Wide Association Studies (GWAS)
- use SNP arrays to assess whether a particular SNP is associated with a trait or disease
- a region of interest is identified and mutations are looked for in known genes
What is the single gene mutation confers resistance to AIDS?
- CCR5 gene point (chromosome 3 delta 32) mutation limited to northern Europeans & Asians
- possibly selected for during black death (but increases risk for West Nile virus)
What is the single gene mutation confers resistance to HIV?
- IRF-1 (chromosome 5)
- discovered based on association with two SNPs that reside close to the allele
- used to say there's a linkage between the gene of interest and an SNP that can be targeted in the mapping process
- if LOD score is greater than 3, then there's a 1/1000 chance that the association is due to something random and not what you're trying to show (proves association)
- the lower the score is under 3, the less likely the gene is responsible for the trait you're trying to map
What are the caveats/drawbacks to GWAS?
- majority of SNPs identified are common variants
- majority of studies undertaken on individuals of European origin (risk associations may not transfer between groups)
- SNPs often many kilobases away from any gene (makes identifying the gene a slow process)
- can only examine the genes but not the control elements
chromosomal trisomy is ___ on a large scale
- CNV: copy number variation
- CNV arrises from breakpoints of chromosomal rearrangement
Next Generation Sequencing (NGS)
- high throughput sequencing
- is used when all other testing (eg. arrays) are normal and a trait still doesn't have an explanation
WES Technique (whole exome sequencing)
- isolation and purification of exons
- hybridization of DNA to genomic library
- capture of targeted sequences (in this case exons)
- amplify exons (PCR)
- sequencing (high through-put methods, colored pictures)
- data analysis
The gene for what syndrome was discovered using WES?
- Kabuki syndrome - MLL2 mutation
- Short stature, microcephaly, developmental delay, hearing loss, heart/kidney defects, feeding difficulties, characteristic facial features (long palpebral fissures, lateral eversion of eyelids, sparse & arched eyebrows, large ears)
What's the difference between a focused WES analysis and an expanded WES?
- focused: genes previously associated with the phenotype of the patient are examined
- expanded: survey all genes are reviewed
Variants of unknown significance (VUS)
- most difficult changes to interpret, perhaps because they are extremely rare (few phenotypes for comparison) or are seen in controls and patients
- over time some VUS will be reclassified to deleterious or benign (many early VUS in the BRCA1 were reclassified as more examples were identified)
- autosomal dominant condition that has to do with a mutated transcription factor in chromosome 2 important in development during birth
- major signs: seizures, distinctive facial features, intellectual disability, delayed development, high bridge under the mouth, deformed feet
- autosomal recessive osteochondrodysplasia
- very dense (easily breakable) bones, short legs and arms, average/above average head circumference, blue eye sclera, saddle back