Genetics I

Front 1

Mendel's Laws

Back 1

Unit inheritance (from each parent), segregation (parental units are paired, one is transmitted), independent assortment (loci transmitted independently)

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Achondroplasia

Back 2

-short-lived dwarfism
-autosomal dominant
-FGFR3 gene

Front 3

Expressivity vs. Penetrance

Back 3

Expressivity: phenotype expressed to different degrees
Penetrance: how many people with gene express phenotype

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Advancing paternal age

Back 4

-increases risk for new AD mutations

Front 5

Mitochondrial genome

Back 5

-maternal inheritance
-37 genes (tRNA and rRNA and ox-phos)

Front 6

Hetero- vs homoplasmy

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each cell contains many copies of mtDNA
hetero - contains a mixture
homo - contains all the same

Front 7

Mitochondrial threshold effect

Back 7

threshold % that abnormal mtDNA is tolerated (due to heteroplasmy)

Front 8

Mitochondrial disorders

Back 8

organ systems most likely affected: CNS, skeletal muscle, eye/heart muscle
diagnosis: elevated lactate/pyruvate

Front 9

MI vs MII key differenes

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chiasmata during MI
MI non-disjunction -> heterodisomy: gamete w/ one copy of each parental chr
MII non-disjunction -> isodisomy: gamete w/ two copies of the same chr

Front 10

Chromosomal banding

Back 10

After cells harvested and mitotic spindle blocked treat with trypsin and stain with Geimsa

Front 11

Ploidy (Triploidy)

Back 11

Ploidy refers to sets of chromosomes
Aneuploidy - abnormal # chromosomes (45, 47, 48)
Triploidy - 69, two sperm fertilize one egg

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Robertsonian translocations (chr# and cause of 21+)

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Between acrocentric 13, 14, 15, 21, 22 (eg der(13;14)(q10;q10)
Count is 45!
No effect on phenotype
In meiosis a rob. t/l can lead to trisomy if gamete gets rob + normal 21 -> chr# is 46!!

Front 13

Philadelphia chromosome

Back 13

t(9;22)(q34;q11)
90-95% CML

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Loss of function:null mutation

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gene has complete loss of function w/ mutation
50% function is sufficient
autosomal recessive inheritance

Front 15

Loss of function: dosage effects (AR vs AD)

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50% of normal gene product causes abnomal phenotype - haploinsufficiency (Auto Dom)
inheritance of two copies is more severe (incomplete dom and AR)
-LDLR in familial hypercholesterolemia

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Loss of function: dominant negative

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mutant protein interferes with normal protein
AD

Front 17

Multiple ligation-dependent amplification

Back 17

multiple exons are amplified at the same time and run on gel to determine presence of region (make PCR products different lengths to detect deletions)

Front 18

Short tandem repeat polymorphisms (STRP)

Back 18

to identify people
13 STRPs is sufficient

Front 19

Isochromosome

Back 19

In meiosis a diploid splits pp and qq so that gametes have only p or q arms of a chromosome

Front 20

Trisomy 21: incidence, clinical (4), chromosome changes, recurrence risk

Back 20

1:700
birth defects, flat midface, IndDis, congenital heart disease
95% 21+, also t/l or mosaicism
recur < 1%, but higher with adv mat age

Front 21

Trisomy 18: incidence, clinical/NH, chromosome changes

Back 21

1-2:6000 liveborns
Stillborn, rocker bottom feet, overlapping fingers, 95% die w/in 1 yr
> 95% 18+ w/ adv mat age

Front 22

Trisomy 13: incidence, clinical/NH, chromosome changes

Back 22

1-2:10000 liveborns
95% die w/in 6 mo, cleft palate, polydactyly
80% 13+, t/l are common and robertsonians

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Cri-du-chat (5p- Syndrome): clinical, chromosomes

Back 23

IntDis, dysmorphic features
Deletion of terminal 5p
85% sporadic del, but can be parentally derived t/l

Front 24

Turner Syndrome: incidence, clinical (4), chromosomes

Back 24

45, X or variant
1-2:10000 liveborns
short stature, ovarian dysfunction, normal intell, treated w/ growth hormone
50% 45, X; variants include ring, isochr, del, and mosaicism

Front 25

Klinefelter Syndrome: incidence, clinical (3), chromosomes

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47, XXY
1:1000 male liveborns
tall/thin, infertility, slight low/normal IQ
rarely XXXY or XXXXY w/ more severe IntDis

Front 26

XYY males: : incidence, clinical, chromosomes

Back 26

1:1000 liveborn males
Mostly normal, slight low IQ and stature
47, XYY due to non-disjunction MII

Front 27

XXX females:: incidence, clinical, chromosomes

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1:1000 liveborn females
Mostly normal, like XYY

Front 28

Williams Syndrome

Back 28

deletion on chr7
high social, thin upper lip

Front 29

DiGeorge/VCFS

Back 29

chr22 contiguous deletion
long face/mild IntDis

Front 30

Segmental Neurofibromatosis + McCune-Albright Syndrome

Back 30

Somatic mosaicisms that would be lethal if full
SN: cafe au lait spots, freckles tumors
MA: constitutively activated endocrine

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Gonadal mosaicism (how to recognize in tree)

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Mutation occurred in precursor sperm or egg cell leading to presence of mutation in all or part of germ line
When 2+ offspring present with an AD disorder w/ neg family history means one parent as gon mosaicism

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Uniparental disomy, mechanisms

Back 32

Presence of two homologous chromosomes inherited from one parent. Can either be two copies of the same chromosome (isodisomy, MII) or one of each homolog (heterodisomy, MI)
Mechanisms: trisomic conception w/ postzygotic loss, fertilization of nullisomic gamete by disomic, duplication in a monosomic cell
1)

Front 33

Prader-Willi Syndrome: clinical and genetic

Back 33

hypotonia, IntDis, obesity
loss of PATERNAL allele chr15 (normally maternal allele is imprinted to be off)

Front 34

Angelman Syndrome: clinical and genetic

Back 34

IntDis, movement disorders, seizures
loss of MATERNAL allele chr15

Front 35

Trinucleotide repeat disorders (examples)

Back 35

Unstable trinucleotide repeat segments lead to expansion of repeats w/ each generation
Fragile X, Myotonic Dystrophy, Huntington Disease

Front 36

Trinucleotide repeats: anticipation

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Increase in severity of phenotype in successive generations. Direct relationship between severity and repeat copy #

Front 37

Trinucleotide repeats: premutation

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When repeat # is greater than normal but unstable, so offspring are at risk. Can be dependent on which allele repeat is passed thru: eg Fragile X always expands when passed through maternal

Front 38

Multifactorial trait

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trait resulting from combined influence of genetics and environment

Front 39

Threshold trait

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normally distributed w/ respect to liability of the trait
if liability if exceed, trait is expressed (eg club foot)
less commonly affected sex has higher threshold so there is greater recurrence risk for relatives of the less commonly affected sex

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Recurrence risk for common birth defects

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4%

Front 41

Risk 1st cousins have child with genetic condition

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4-5%

Front 42

Recurrence risk rules for multifactorial inheritance of common birth defects (5)

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1. greater if > 1 fam member affected
2. greater severity = greater rec risk
3. greater if proband is less commonly affected sex
4. decreases in more remote relatives
5. risk for 1st dg relatives is square rt of pop incidence of trait

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Ultrasound (risk, detections) (3)

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No risk
Fluid filled structures
Increased nuchal translucency associated with 21+

Front 44

Maternal serum screening (4)

Back 44

Measure proteins produced by fetus or placenta
1st trimester: PAPP-A, betaHCG
2nd: AFP, UE3, betaHCG
Combined screening results in 96% detect of 21+ : high: HCG and inhibin A, rest are low

Front 45

Fetal MRI

Back 45

For better resolution than ultrasound
Used when ultrasound suggests brain, thoracic, or abdnominal abnormality

Front 46

Indications for invasive prenatal diagnosis (5)

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1. Maternal >35
2. Fetal structural abnormality on ultrasound
3. Abnormal maternal serum screen
4. Family history of chr abn or Mendelian disorders
5. Mat anxiety

Front 47

Fetal cell-free nucleic acids in maternal blood/plasma

Back 47

DNA originating from placental cells circulate in maternal blood
Can only detect unique sequences from the father
Diagnostic for fetal Rhesus D +/- and aneuploidy

Front 48

Amniocentesis (2)

Back 48

Collect amniotic fluid w/ fetal mouth/bladder cells in 2nd trimester
Protein or chromosome analysis

Front 49

Chorionic villus sampling (when, advantages (4), disadvantages (2)

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Aspirate chorionic villi in 1st trimester
Advantages: earlier, better tissue, cells are dividing, detect UPD
Disadvantages: elevated risk of miscarriage, mat infection, limb malform; cant assay AFP for neural tube defects

Front 50

Preimplantation genetic diagnosis

Back 50

Screening embryos prior to transplantation into uterus
Requires IVF
Single gene diagnosis by PCR
Chromosome rearrangement by FISH
Gender testing for x-linked conditions

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Birth defect

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Condition present at birth that requires medical, surgical, or cosmetic intervention (congential hearth disease, polydactyly, neural tube defect)

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Dysmorphic features

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Variants of physical features that are found in less than 2-3% of pop.
3+ minor anomalies are strongly associated w/ major malformations

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Syndrome vs Association vs Sequence

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Syndrome - pattern of anomalies thought to be pathogenetically related (Down Syndrome)
Association - non random occurrence of anomalies in 2+ individuals (VATER, VACTERL)
Sequence - pattern of anomalies derived from single known or presumed prior anomaly or mechanical factor (Pierre-Robin: in utero: small chin, cleft palate; after birth: tongue obstructs airway. Potter: in utero: lack of fetal urination, no amniotic fluid, neonatal: death due to fetal compression and pulm. hyperplasia)

Front 54

Malformation vs Deformation vs Disruption vs Dysplasia

Back 54

Malformation - poor formation of tissue (cleft lip, syndactyly)
Deformation - unusual forces on normal tissue (congenital hip dislocation)
Disruption - breakdown of normal tissue (amniotic band synd)
Dysplasia - abnormal organization of cells in tissue (osteogenesis imperfecta)

Front 55

Teratogens

Back 55

Substances that lead to birth defects when a pregnant woman is exposed: infections, medications, drugs, external agents (radiation)

Front 56

Fragile X (3)

Back 56

Most common inherited form of mental retardation
Unstable repeat on X
Expansion from pre to full only occurs through female meiosis