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M2M > M2M Unit 2 > Flashcards

M2M Unit 2 Flashcards

1
Q

Standard pedigree symbols:

A 
male= square
female= circle
unknown= diamond
black=phenotype positive
white= phenotype negative
deceased= diagonal line through
3 generations to be "complete"
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2
Q

Patterns of Mendelian Inheritance- generic

A

genes come in pairs
(note x-linked and mito diseases)
genes’ alleles lead to observed phenotypes

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3
Q

Law of Segregation

A

Alleles segregate at meiosis into the gametes

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4
Q

Law of Independent Assortment

A

The segregation of each pair of alleles is independent

exception: genes close together are linked

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5
Q

define hemizygous

A

a person only has 1 particular gene, not 2
i.e. males have a single copy of each X chromosome gene
also anyone who only has 1 working copy of a gene via deletion (or imprinting)

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6
Q

Horizontal pattern of affected phenotype

A

tends to be autosomal recessive- more likely affected in siblings and not parents

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7
Q

Rare disease and consanguinity

A

the rarer the disease/allele, the greater proportion of affected persons will be due to consanguinity (blood related to affected person)

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8
Q

autosomal dominant

autosomal recessive

A

dom: tends to appear in every generation
phenotypically normal parents tend to not pass it on equally to males and females. (new mutations can occur)

rec: can skip generations; normal parents can pass it on to their children

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9
Q

x-linked recessive

A

incidence much higher in males.
appears to “skip” through unaffected females
affected males pass on mutations to ALL daughters and NO sons.
Carrier females’ offspring have 50% chance of inheriting

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10
Q

x-linked dominant

A

disease incidence is much higher in female children

affected males pass it on to all daughters but not sons

carrier females’ children have 50% chance of inheriting phenotype

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11
Q 
pedigree AKA
useful for...
proband
consultand
consanguineous mating
A

family history

useful for identifying possible patterns of inheritance and est. genetic risks

starting point of genetic study

person bringing the family to attn

couples w/ >1 known ancestor in common

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12
Q

penetrance
expressivity
pleiotropy

A

penetrance: fraction who has a genotype and shows the phenotype (can be age dependent, etc.)
expressivity: the extent that the genotype is expressed (severity) (depends on sex, environmental effects, stochastic effects, and modifier genes)
pleiotrophy: a mutation affecting multiple different phenotypes (NOT variable expressivity)

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13
Q

population genetics:

A

the study of allele frequencies and changes in allele frequencies in populations

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14
Q

Hardy Weinberg principle

and assumptions

A 
p^2 + 2pq + q^2 = 1
p + q = 1
p= common allele freq
q= rare allele freq
assume: pop is large
random matings
allele freq's are constant over time because:
no mutations
equally fit genotypes
no sig immigration/emigration
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15
Q

3 events in meiosis that produce genetic variability in offspring

A

crossing over
assortment of alleles
reduction in genetic material from diploid to haploid

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16
Q

mitotic vs meiotic cell division

A

Meiosis: paternally and maternally derived homologous chromosomes pair at the onset of meiosis- Prophase 1

Meiosis: reciprocal recombination events between maternal and paternal sister chromatids generate chiasmata between homologs

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17
Q

meiotic recombination vs chromosome nondisjunction

A

nondisjunction events are related to the positioning of chiasmatas
crossovers occurring too near or far from the centromere increase nondisjunction
centromere-distal exchanges are less effective in ensuring appropriate spindle attachment and sep of paired homologs in meiosis 1
centromere-proximal or excessive exchanges lead to entanglement of paired homologs in meiosis 1 that then undergo reductional division leading what appears to be meiosis 2 errors
nondisjunc events are related to freq of crossover events- the reduction/absence of recombination events increases the likelihood of nondisjunction
*trisomies often result from meiosis 1 nondisjunction

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18
Q

3 common human trisomies

A

trisomy 13, 18, 21

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19
Q

clinical features of trisomy 13

A

Patau syndrome
characteristic faces
severe mental retardation
congenital malformations- holoprosencephaly, facial clefts, polydactyly, renal abnormalities

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20
Q

clinical features of trisomy 18

A

Edwards syndrome
intrauterine growth retardation
characteristic faces, severe mental retardation, characteristic hand positioning
congenital malformations- valvular heart disease, posterior fossa CNS maldevelopment, diaphragmatic hernias, renal abnormalities

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21
Q

clinical features of trisomy 21

A

Down syndrome
characteristic faces, short stature, hypotonia, moderate mental retardation
congenital malformations- endocardial cushion defects, duodenal atresia and other gastrointestinal anomalies, Hirshprung disease

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22
Q

fundamental principles regarding human genome evolution and organization

A
  • reflects results of different selection pressures that have occurred over evolutionary time and shaped our genome
  • genes and genomic features that have been adaptive have been retained
  • genotype + environment = phenotype
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23
Q

why is genome variation an essential fuel of evolution and adaptation (and disease)

A

random variation in a highly ordered structure = almost always deleterious consequences

genetic disease is the price we pay as a species to continue to have a genome that can evolve (adapt to new/changing environments)

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24
Q

organization of the human genome

A

dynamic; non-random
~30 new mutations per individual
shuffling of regions at each meiosis due to recombination
can produce somatic and germ-line DNA changes

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25
Q

SNP frequencies

A

average of 1 SNP every 1000 bp between any 2 randomly chosen genomes
99.9% identical and 3,000,000 differences

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26
Q

5 types of variations that occur between genomes:

A
  • insertion-deletion polymorphisms (indels)
  • SNPs
  • CNVs
  • Genome “structural” variation
  • others- chromosomal or larger scale variations, rearrangements, translocations, etc.

majority of variants are silent, but some can have functional effects

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27
Q

Insertion-deletion polymorphisms:
minisatellites
microsatellites

A

minisatellites: tandemly repeated 10-100 bp DNA blocks
VNTR (variable # of tandem repeats)

microsatellites: di-, tri-, tetra- nucleotide repeats; >5x10^4 per genome
STRPs (short tandem repeat polymorphisms)

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28
Q

SNPs

A

frequency of 1 in ~1000 bp’s

PCR-detectable markers, easy to score, widely distributed

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29
Q

CNVs

A

variation in segments of genome to 200bp-20 Mbp’s
can range from one additional copy to many
array comparative genomic hybridization (array CGH)

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30
Q

genome “structural” variation

A

broadest sense: all changes in genome are not due to single bp substitutions

CNVs: primary type of structural variation
CNV loci may cover 12% of genome
implicated in increasingly larger number of diseases
some CNV regions involved in rapid and recent evo change… such regions are often enriched for:
human specific gene duplications
genome sequence gaps
recurrent human diseases

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31
Q 
characteristics of the genome:
gene-rich
gene-poor
stable
unstable
GC rich
AT rich
euchromatin
heterochromatin
A 
gene-rich: Chr 19
gne-poor: Chr 13, 18, 21
stable- majority of genome
unstable- dynamic and often disease-associated (SMA Chr 5q13; DiGeorge Syndrome Chr 22q; 12 diseases 1q21)
GC rich: 38% of genome
AT rich: 54% of genome
euchromatin- relaxed, less repeats
heterochromatin- less relaxed, more repeats, generally near centromeres
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32
Q

completely sequenced human genome?

A

no completely sequenced and assembled human genome

-sequencing focused on euchromatic regions: easiest to access and interpret; repeats are often difficult to decipher

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33
Q

gaps remaining in the euchromatic regions

A

341 gaps
1% of euchromatic genome
many contain segmental duplications that require more work and new methods

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34
Q

categories of genomic DNA sequences

A

1.5% translated (protein coding)
20-25% genes (exons, introns, flanking sequences in regulatory gene expression)
50% “single copy” sequences
40-50% classes of “repetitive DNA”
sequences that are repeated 100s to millions of times

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35
Q

2 types of repetitive DNAs

A

tandem repeats AKA satellite DNAs

dispersed repetitive elements

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36
Q

tandem repeats AKA satellite DNAs

A

incl micro and minisatellites
some are used in cytogenetic banding
some are found on specific long-arm heterochromatin regions of Chr 1, 9, 16, and Y hotspots for human-specific evo changes

incl alpha satellite repeats- 171 bp repeat unit near centromere (may be important in chromosome segregation)

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37
Q

dispersed repetitive elements

A

Alu family- (ex. SINEs)
~300bp related members
500K copies in genome

L1 family- (ex. LINEs)
~6K bp related members
100K copies in genome

  • both can be sig med relevance
  • retrotransposition may cause insertional inactivators of genes
  • repeats may facilitate aberrant recomb events between diff copies of dispersed repeats leading to diseases (called Non-Alleltic Homologous Recombination (NAHR)
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38
Q

estimated number and types of human genes

A

25-30 thousand different genes, comprised of:
protein-encoding genes
RNA-encoding genes
pseudogenes (nonfunc, but homologous copies of existing genes; split into intron-containing and intronless?)

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39
Q

gene families

A

genes with high sequence similarity;
perform similar functions
arise by gene duplication

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40
Q

gene duplication as an evolutionary mechanism

A

advantageous
when a gene duplicates, it frees one copy to vary while the other copy continues to perform its function

ALTHOUGH more copies means more chances for errors and negative impacts

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41
Q

2 methods of current genome sequencing and “missing heritability” problem

A

nextgen DNA sequencing-

  • no genome has been completely sequenced/assembled
  • relies on short read sequences
  • complex, high duplicated areas are often unexamined, but these are implicated in numerous diseases

genome-wide association studies (GWAS)

  • many regions are unexamined by “genome wide” screening tech’s;
  • “missing heritability” for complex diseases- many large-scale studies implicate loci (SNPs) that account for only a small frac of the expected genetic contribution
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42
Q

genetic variability from meiosis

A
  • meiotic recombination: homologs cross-over (chiasmata); offer steady support for smooth division
  • can also occur X-Y in males
  • random segregation of chromosomes (2^23 possible combos)
  • 1/4 haploid female products becomes an egg
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43
Q

mitosis vs meiosis cell divisions

A

mitosis- 1 round of chr seg.
2 identical daughter cells
DNA replication preceeds each round of chr segregation
no homolog pairing
infrequent recomb
sister chromatids separate
occurs in somatic cells (and pre-meiosis germ cells)

meiosis- 2 rounds of chr seg
4 unique haploid daughter cells
homolog pairing 
crossing over
homologs THEN sister chromatids separate 
occurs only in germ line cells
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44
Q

banding of karyotypes

A

giemsa- dye used to create banding patterns based on selective binding (G-banding)

ideogram- banding pattern depiction, w/ bands numbered prox-> distal from centromere

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45
Q 
p and q
chromosome types:
metacentric
submetacentric
acrocentric
A

p- short arm
q- long arm

m- central centromere

s-offset centromere; longer and shorter arm

a- centromere is near the end, with “stalk” rRNA- producing DNA and “satellite” region in the nub

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46
Q

noting chromosome abnormality

A

general format:
total # of chromosomes,
gender chromosomes,
type of mut (loc of mut)

\+ additional chromosome
del
inv
dup
ins
r (ring)
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47
Q

aneuploidy

A

loss/gain of selected chromosomes usually fatal)
often due to selective meiotic disjunction
specifically maternal meiosis 1

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48
Q

polyploidy

A

extra copies of all chromosomes (triploidy);
almost always fatal
complete meiotic disjunction
2 sperm + 1 egg, or a diploid sperm/egg

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49
Q

mosaicism

A

when a zygote contains 2 cell lines differing in chromosome number

  • post-zygotic mitotic event results in chromosomal abnormality
  • affects various tissues, depending on nature of abnormality
  • can be poly or aneu-ploidy mosaic, but generally less severe than a complete poly/aneu
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50
Q

3 common trisomies

A

trisomy 13, 18, 21

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51
Q

Patau Syndrome

AKA Trisomy 13

A 
most clinically severe of trisomies
polydactylity
CNS abnormalities
omphalocele (GI organ herniation outside abdomen)
renal dysplasia
congenital heart disease
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52
Q

Edwards Syndrome

AKA Trisomy 18

A

SGA
rocker bottom feet
clenched fists
congenital heart disease
hypertonicity (clenched hands, narrow hips)
severe CNS abnormalities, severe retardataion

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53
Q

Down Syndrome

AKA Trisomy 21

A 
most common survivable trisomy
congenital heart disease
hypotonia
GI abnormalities
early-onset Alzheimer's
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54
Q

2 common mech’s of chromosomal structural rearrangements

A

1- dsDNA break and repair by NHEJ (info lost)

2- crossing over between repetitive DNA sequences. this can delete segments of a stretch, can delete on one and duplicate on another, invert, reciprocally translocate, etc.

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55
Q

balanced vs unbalanced structural rearrangements

A

balanced- normal, but rearranged, complement of chromosomal material. often phenotypically neutral
no gain or loss

unbalanced- abnormal chromosome content. often phenotypically abnormal

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56
Q

3 types of balanced rearrangement

alternate segregation

A 
inversion- ds segment flipped
paracentric- excl centromere
potential to have dicentric and acentric outcomes
pericentric- incl centromere
chromosome has to loop in meiosis
ex. Rec8 infants- term births; wide face

reciprocal translocation-
break/reform create recombination of 2 non-homologous chromosomes
observed in ~1/500
creates “quadravalance”- 4 homologs align instead of 2
disease states- chronic myelogenous leukemia
lethal risk 5-10%

Robertsonian translocation-
2 acrocentric long arms fuse; you lose the p arms
chr count goes down by 1, and can give you DS w/o Trisomy
21 (ex. Chr 14 stuck w/ Chr 21)
(13, 14, 15, 21, 22 are acrocentric)
leads to potentially giving your children a trisomy

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57
Q

4 types of unbalanced rearrangement

adjacent segregation

A

deletion-
1- del seg on 1 chromsome arm- terminal deletion
2- del seg contains centromere- interstitial deletion

duplication- generally less harmful than deletion

isochromosomes-
1 missing arm; other has mirrored itself to replace the missing arm
most common on X chr, sometimes 21
(100% of viable offspring are abnormal, since it’s either three or a single Chr 21)

marker (ring) chr’s-
an interstitial deletion frag becomes circ and is stably transmissible to offspring, due to its containment of the centromere

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58
Q

family risks with balanced translocations leading to unbalanced progeny

A

most chromosomal abnormalities aren’t likely to recur, but if the mother has the translocation, it’s more likely the child will be unbalanced
some stable rearrangements are transmissible
ranges from 0-30%

risk of unbalanced progeny is low due to:
size of exchanged material
whether genes are involved (DGAP)
tolerated mono/trisomies
sex of carrier
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59
Q

the most common contiguous gene syndroms in humans

A

deletion or duplication of 22q11.2
a disorder due to overexpression or deletion of multiple gene loci that are adjacent to e/o
ex. velocardiofacial syndrome and DiGeorge Syndrome

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60
Q

define epigenetics and how modifications may affect gene expression

A

epigenetics- heritable changes in gene expression that occur without a change in DNA sequence

ex. patterns of reversible post-translational modifications of histones and pattern of DNA methylation

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61
Q

genetic imprinting and its molecular basis

A

small subset of genes that are inherited in a transcriptionally active state from one parent and transcriptionally inactive state from the other parent

clinical interpretation- we’re normally hemizygous for all imprinted genes, so we’re particularly vulnerable at all of those genes since there’s no backup

act/inactivation seems to depend on methylating CpG islands in promoter regions of particular genes

1st- meiosis
2nd- erasure
3- sex specific gene silencing (myelination)
4- fertilization

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62
Q

3 rules for epigenetic DNA methylation

A

1- modification must be est during gamete genesis (all maternal (and paternal) must be imprinted the same way
2- modification must be stably maintained in somatic cells (which will contain half paternal/maternal
3- modifications must be reversible so that they can be reset during gametogenesis to transmit the appropriate sex-specific imprint to progeny (ex. if they’re female, maternally methylated; males are paternally methylated)

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63
Q

genetic imprinting with Prader Willi Syndrome and Angelman Syndrome

A

both have a deletion on chromosome 15
PW= 15q11-q13
-maternally activated region on maternally inherited 15 (inactive= Angelman)
-paternally activated region on paternally inherited 15 (inactive = PW)
imprinting pattern is determined by your parents, NOT your gender

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64
Q

uniparental disomy with PW and Angelman Syndrome

A

one gamete has 2 copies of a chromosome
if this gamete fuses w/ another normal gamete, the zygote will be trisomy for that chromosome
if zygote has nondisjunction in an early mitosis, it may continue w/ normal chr # but has both chromsomes from 1 parent….
15 maternal disomy= PW
15 paternal disomy= Angelman

PW= 70% deletion; 25% disomy
Angelman- 70% deletion;

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65
Q

2 of the most common leukemia translocations

CML and APML

A

chronic myeloid leukemia CML- night sweats, fatigue, weight loss, anemia, large/lobulated cells
translocation w/ 9 and 22 (BCR/ABL rearrangement)
treat w/ Gleevec- tyrosine kinase Inhibitor

acute pro-myeloid leukemia APML- auer rods, excess bleeding (teeth), incr blood blasts
translocation w/ 15 and 17 (PML/RARA rearrangement)
treat w/ Vit A for immediate remission

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66
Q

childhood B-cell leukemia

AKA ALL

A

high hyper-diploidy revealed by chromosome and FISH analyses (hypodiploidy doesn’t have good prognosis)
pain in extremities;
abdominal distention;
high blast count in peripheral blood but none in CSF;
fever;
irritability;
scattered bruising

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67
Q

6 types of FISH probes

A

centromere- “cen”
(enumeration- prenatal trisomy, etc) ALL, p53 cancer

locus-specific- “LSI”
gene deletion/duplication

dual fusion/fusion- “DF/F”
translocations
MCL and APL leukemias

break apart- “BAP”
rearrangement + translocation
MLL cancer

Whole chromosome paint- “WCP”

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68
Q

FISH basic definition

A

fluorescence in situ hybridization
method to examine subtle deletions or changes in chromosomes that may not be picked up by banding patterns alone:
small deletions
test host vs donor marrow cells after transplant
can look at large # of cells at once
usually done after prelim chromosome dye banding

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69
Q

chromosomal microarray analysis CMA roles and limits

A

can detect genomic deletions (200kb) or duplications (400kb), but NOT translocations
uses DNA oligomer probes to interrogate for SNPs

reveals info on intensity and runs of homozygosity > 5Mbs (reporting threshold 10Mbs), possibly revealing autosomal recessive conditions

investigates whole genome simultaneously via DNA amplicfication and labeling

deletions/dups w/o a phenotypic consequence can’t be detected at the chromosomal level

translocation can’t be detected- whole genome is interrogated, not sensitive to location; only detects gains and losses

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70
Q

lab test algorithm for children w/ learning disorders, developmental delays, autism, dysmorphic features, failure to thrive

A

run microarray to see whole genome and chromosomes (high-res w/ chr banding)
aCGH to detect deletions/dups
FISH w/ specific probes
then compare to gene report

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71
Q

Down Syndrome- 3 chromosomal abnormalities

A

Trisomy 21- 95%;
nondisjunction or error in maternal meiosis

unbalanced translocation between Chr 21 and another acrocentric Chr- 3-4%; important to check parents’ karyotypes

mosaic Tri 21- 1-2%
mix of normal and Tri 21 cells
typically more mild phenotype

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72
Q

testing for Down Syndrome

A

genetic testing- timing of results for karyotype and FISH (more important for other trisomies)

FISH- usually looking for trisomy; results within hours

Karyotypic analyses to confirm suspicions: amniocentesis to look at prenatal chromosomes (1.5-2 weeks); early 2nd trimester
chorionic villous sampling- fetal tissue attached to uterine wall; (quicker results); after 1st trimester

fetal ultrasound- look for webbed neck; short femurs; nuchal fold translucency

blood screens- look for fetal blood markers

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73
Q

Down Syndrome Phenotype

A 
flattened occiput- bracheocephaly
midface hypoplasia (incomplete midface dev)
epicanthal folds (corners of eyes)
ears small and set low in head
bilateral transverse palmar creases
accentuated space between 1st and 2nd toes
hypotonia (low muscle tone)
abnormal tooth development
GI tract problems
normal tongue, but small oral cavity
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74
Q

Down Syndrome medical problems

A

Congenital heart disease
commonly- AV canal (hole between chambers- surgery)

GI- esophageal atresia (immediate surgery)
dudodenal atresia
Hirshprung's
constipation
feeding problems
GERD
Celiac disease
endocrine problems- autoimmune disorders
thyroid disease (hypthyroidism)
insulin dependent diabetes
alopecia areata
reduced fertility (normal puberty)
ophthalmological- 
blocked tear ducts
myopia
lazy eye
nystagmus (giggly eyes)
cataracts

hematologic issues
inc risk of leukemia
iron deficiency anemia

ENT problems
ear infections
deafness
nasal congestion
enlarged tonsils and adenoids (obstructive sleep apnea)

orthopedic problmes
hips
joint sublaxation
atlantoaxial sublaxation

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75
Q

Down Syndrome developmental and behavioral phenotype

A

developmental issues-
hypotonia affects gross motor development
intellectual disability spectrum
speech problems (sign language)

psychiatric issues-
depression
early Alzheimer’s
Autism- 1/10 patients

neurologic problems-
hypotonia spectrum
seizures, esp infantile spasms

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76
Q

Prader Willi Syndrome chromosome abnormalities

A 
DEL on a paternal 15q11-q13 
maternal disomy (gamete has 2 copies of a chr), leading to zygotic trisomy (could have early mitotic nondisjunction and have normal chr #, but 2 from same parent- mom)

70% from paternal gene del
25% from maternal disomy

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77
Q

Diagnose PW

A

made with FISH or microarray

methylationg tests on maternal and paternal alleles

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78
Q

imprinting regions and disorders on Chr 15

A

PW and Angelman syndromes both have deletions on Chr 15
2 imprinted regions on each of your 2 chromosomes- one is maternally and other is paternally activated

deactivating paternal region on paternal chr= PW
deactivating maternal region= Angelman

imprinting pattern is dependent on your parents, not your gender

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79
Q

Prader Willi phenotype

A

infancy-
hypotonia and dysmorphic features, almond eyes, undescended testicles, light pigmentation, feeding issues

toddler- feeding problems reverse; persistent hunger

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80
Q

PW medical problems

A

early failure to thrive and feeding problems- reverse to hyperphagia and weight gain; growth hormone treatments to promote height and hinder obesity

ophthalmologic problems common, esp nystagmus (jiggly) and strabismus- (lazy) eyes

ortho- scoliosis

resp- obstructive sleep apnea

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81
Q

PW developmental and behavioral phenotype

A

mild to mod dev delay leading to intellectual disabilities as adults
behavioral issues are common

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82
Q

other abnormalities associated with Chromosome 15 abnormalities

A

Angelman- associated w/ deletion on maternal chromsome 15
mildly dysmorphic facial features which evolve w/ age;
hypotonia in infancy, progressing to spasticity
intellectual disabilities
seizures
autism

marker chromosmes- inverted dup (autism, NOT dysmorphic; often hypotonic; seizures common)

interstitial duplications- dup of part of chr (partial trisomy)
phenotype only if derived from mother (autism, NOT dysmorphic, seizures common, hypotonia common in infancy)

linkage disequilibrium between patients w/ autism and polymorphisms in the GABAa-b3 locus (2 15’s put together?)

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83
Q

pharmacogenetics vs

pharmacogenomics

A

genes vs genome

pharmacogenetics- study of how variance in a single gene influences variability in drug response, usually based on prior knowledge of drug action pathways

pharmacogenomics- study of how variance across multiple genes influences variability in drug response, usually not based on prior knowledge of drug action pathways

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84
Q

pharmacodynamics vs pharmacokinetics

A

2 major physiologic responses to drugs

pharmacodynamics- response of drug binding to its targets and downstream targets (receptors, enzymes, metabolic pathways); ACTION of a drug once it reaches target

pharmacokinetics- rate at which the body absorbs, transports, metabolizes, or excretes drugs on their metabolites

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85
Q

Phase 1 and Phase 2 in drug metabolism

A

Phase 1- “first pass” metabolism; hydroxylates drug, usually by cytochrome P450 enzymes in the liver

Phase 2- conjunction rxns; glycosylation or acetylation to deactivate drug, make it more soluble, and excrete it faster

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86
Q

central role of CYP450 enzyme sys in drug metabolism

A

3 families that break down 90% of all drugs
while most CYP genes are important in the rate of inactivation of a drug, in some cases the CYP gene(s) is required to activate a drug
classic example- CYP2D6 activty needed to convert inactive codeine to active morphine

diff combo’s of 2 chromosomes give you normal, poor, and ultrarapid/ultrafast phenotypes

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87
Q

substrates, inhibitors, and inducer of

CYP450 gene CYP3A

A

sub- felodipine and cyclosporine

inhibitors- ketoconazole, grapefruit juice

inhibitor- rifampin

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88
Q

substrates and inhibitors of

CYP450 gene CYP2D6

A

sub- tricyclic antidepressants and codeine

inhibitors- quinidine, fluxotine, paroxetine

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89
Q

substrate and dosing of CYP450 gene CYP2C9

A

sub- Warfarin
overdose- clotting
underdose- bleed out
start w/ 5mg/day and adjust

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90
Q

NAT gene substrate

A

isoniazid for tuberculosis

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91
Q

TMPT gene substrates and comments

A

sub- 6-mercaptopurine and 6-thioguanine
can kill a child w/ ALL
classic pharm mech that can be fatal if ignored

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92
Q

G6PD gene substrates, mech, and comments

A

sub- sulfonamide, dapsone
mech- x-linked enzyme
deficient individuals subject to hemolytic anemia after drug exposure

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93
Q

VKORC1 gene substrate, and comments

A

sub- Warfarin
blood thinner
prescribed to >20 mil patients annually

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94
Q

population genetics and relevance of “population field”

A

the study of allele frequencies and changes in allele frequencies in populations
nuclear DNA >99% similar in humans
“polymorphism” refers to any common genetic variant of an allele- it occurs in greater than or equal to 1% of pop

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95
Q

mutation rate for autosomal dominant- direct and indirect methods

A

direct- assuming 100% penetrance, count number of new cases with no family history and divide by pop TIMES 2 (for alleles)

indirect- reproductive fitness is 0, so all cases represent new mutations; incidence rate is 2x the mutation rate

autosomal recessive less likely to be affected by fitness and selective criteria

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96
Q

how physicians managing genetic diseases could affect prevalence of genetic diseases

A

theoretically improve fitness and health; alter chances for reproductive success, so mutation rates for disease X may increase, depending on inheritance and severity

recessive- mutant allele increases are slow

dominant/x-linked- rates could be higher

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97
Q

biological advantages of sexual reproduction

A

diploidy- protects against effects of some mutations (still 1 working copy)
recombination- creates new combos of haploid genes in germ line
sex- allows random chrosomal assortment by combo of haploid cells
sex- gender-dependent epigenetic imprinting
permits rapid evolution and increases survival via genetic variability
sexual dimorphism allows for division of labor and cooperation

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98
Q

x chromosome inactivation and implications

A

all diploid somatic cells have a single active X chromosome
normal females- one is inactivated in every cell, and the other is a barr body (mosaicism)
inactivated via methylation and histone modification
XIST region on inactive X transcribes an RNA that coats X to attract methylators and HDACs
(10-15% Barr body genes are still transcribed)

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99
Q

non-random X inactivation

A

occurs when an X chromosome is abnormal, so abnormal X is preferntially inactivated; almost all cells have same abnormal X inactivation due to non-viability of cells with abnormal X

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100
Q

genetic regulation of sexual differentiation-

WT gene, SRY, MIF

A

WT gene directs the differentiation of embryological genital ridge (for gonads)
gonadal differentiation is dependent largely on whether or not genes promoting testes are present (SRY gene on Y chromosome)
SOX9 gene (also interacts w/ SRY), SF1, and DAX1 other important genes

Mullerian inhibiting factor (MIF)- allows form. of ductus deferens, etc from mesonephric ducts

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101
Q

true hermaphroditism vs. pseudohermaphroditism

A

true- 46XX /46XY
show ovaries, testes, partial uterus

pseudo- ambiguous external genitalia but normal ovaries or testes (NOT both)

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102
Q

sex reversals

A

XX males in which the Y chromosome has translocated autosomally

XY females in which regions of the Y chromosome have been deleted or certain sex-developing genes on the X chromosome have been duplicated

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103
Q

45XO Turner Syndrome

A

normal early female gonadal development in utero, but degerneration of developing ovaries later in fetal life

clinical features- short height; perceptual disorders; coarction of the aorta; fused kidneys

mostly driven by meiotic nondisjunction events

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104
Q

47XXY Kleinfelter Syndrome

A

develop as anatomic males, but have degeneration of gonads.

infertile, low levels of testosterone development
clinical- tall stature, gynecomastia (breasts)

mostly driven by meiotic nondisjunction events

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105
Q

Androgen insensitivity

A

46XY
presents as non-menstruating females
does not result in a uterus (testes still produce working MIF even if testosterone isn’t able to affect development)

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106
Q

clinical apporach to disorders of sexual differentiation

A

1st day of life:

  • obtain FISH for sex chromosomes and a karyotype (or CMA)
  • order hormone studies (LH, FSH, testosterone, dihydrotestosterone, +/- AMH)
  • consider US study (gondads and uterus)
  • consider consult w/ specialized team (endocrine, genetics, urology, psych)
issues to be considered:
underlying genetics
family cultural/social perspective
medical and surgical outcomes
risks for tumor development
fetal brain development in context of hormone exposure and future gender identity
future sexuality
future fertility
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107
Q

multifactorial inheritance

A

combo of genetic variants and nongenetic factors

spectrum of disease- simple Mendelian to extremely complex multifactorial; tend to aggregate in families but don’t follow simple inheritance modes

diseases w/ characteristics not explained by the genotype at the causative locus; and diff alleles at the same gene can result in diff levels of severity

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108
Q 
complex traits characteristics-
incomplete penetrance
variable expressivity
phenocopies
heterogeneity
A

incomplete penetrance- not everyone w/ genetic variance develops the disease (type 1 diabetes)

variable expressivity- people w/ same genetic variant have different disease characteristics (age of diagnosis)

phenocopies- people w/ same clinical presentation, but for reasons that aren’t primarily genetic (ex. thalidomide-induced limb malformations vs genetically induced)

heterogeneity- same or similar diseases caused by different alleles at 1 location or alleles at alleles at different locations in one gene or among many genes

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109
Q

heterogeneity

allelic vs locus

A

allelic heterogeneity- different alleles in same gene result in same OR different traits
(cystic fibrosis- lots of alleles lead to CF, variable severity)

locus heterogeneity- variants in different genes result in very similar clinical presentation
(Alzheimer’s- mutations in 1, 14, 21 all lead to same presentation of Alzheimer’s)

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110
Q

multifactorial inheritance disease examples

A 
cystic fibrosis
Alzheimer's
some cancers
diabetes 1 and 2
inflammatory bowel disease
asthma
Schizophrenia
hypertension
cleft lip/palate
rheumatoid arthritis
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111
Q

strategies to determine importance of genetic vs non-genetic factors contributing to variations in complex traits

A

epidemiologic twin, adoption, and immigration studies
twins- mono vs dizygotic
adoptive vs biological siblings, or biological siblings raised apart

examine disease freq and risk patterns in relatives
(lambdaS= risk of disease in siblings of affected/risk of disease in general pop)

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112
Q

heritability and difficulties w/ quantifying role of genetics in populations and individuals

A

heritability- proportion of total variance in a trait that is due to genetic variation
high h^2= differences are more due to genetics (low= environ)
divide it up based on what you think is genetic and what is environmental

roles of these 2 factors vary so much that it’s hard to lay down strict guidelines for genetic markers and disease predispositions

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113
Q

rationale for finding disease genes

A

both genes and environment play major roles in disease
no systematic way to discover environ risk factors, but we can find disease genes, providing clues to disease pathogenesis
understanding pathogenesis may allow dev of treatment/prevention
discovery of disease gene causal variants may enable genetic testing/screening/surveillance of high-risk individuals

114
Q

personalized medicine paradigm

A

discover risk genes/high-risk combos
carry out DNA predictive diagnostics based on genetic risks
apply individualized treatments/preventions

Both genes and environmental factors play major roles in virtually all diseases
Genes for Mendelian (single-gene) disorders are fairly deterministic (confer disease yes/no)
However, most genes for common diseases confer relatively small risks (odds ratios; ORs)
Highly predictive genetic testing may be difficult or impossible
Odds ratio: risk of disease if carrying a given gene variant/risk of disease if not carrying a given gene variant

115
Q

genetic linkage study

A

search genome for segments disproportionately coinherited along with disease in “multiplex” families
assumes affected relatives w/in a family share susceptibility genes “identical by descent”
can discover new, unknown genes
can provide very fine localization
best for Mendelian traits; less for “complex traits”

116
Q

genetic linkage studies- recombination

A

more recombination- genes are probably farther apart and not inherited together

117
Q

genetic linkage studies- LOD

A

LOD score criteria- likelihood that loci are linked given the inheritance pattern

LOD= log10 (likelihood of data if loci linked at __ cM) / (likelihood of data if loci unlinked)

sig level LOD >3.0 considered linked

118
Q

genetic linkage studies- centiMorgan

A

1 cM= 1% recombination between any 2 genetic loci per meiosis

used to measure “genetic distance” /linkage between 2 genes

average 2.44 chiasmata/chromosome/meiosis

2 genes on same chromosome appear unlinked if >50cM apart

119
Q

genetic association studies

A

all these people w/ same disease- let’s test this gene

gene specific:
uses markers to test gene/causal variant indirectly
depends on a priori biological hypothesis or positional hypothesis
most powerful for common risk alleles w/ small to moderate effects
case-control study design

***most a priori biological hypotheses are wrong!

***2 fatal flaws

120
Q

case-control design for genetic association studies

A

genotype marker in candidate gene in case and control
compare allele freq in both
conceptually simple
can be done w/ hundreds of cases and controls
uses simple stats- Chi-square; Fisher exact test

if you test multiple variants (2), you must apply multiple testing correction (divide your p by 2 in order to be significant)

real association doesn’t imply causation by the associated variant, but does imply at least LD w/ a causal mutation (you can say it’s somewhere on the haplotype, but you can’t specifically identify that it’s a specific gene on that haplotype)

almost always yields false positives

121
Q

genetic association studies- 2 fatal flaws

A

true multiple-testing correction must include all tests, even those done by others and perhaps never published (you can only correct for things you’ve done, and not everybody even does that)

must ethically match cases and controls; otherwise, observed differences in allele freq’s may reflect different genetic backgrounds of cases vs. controls, not true disease association, not possible to achieve (genomes are too different to match up- impossible; no such thing as a pure population)
even in a “homogenous” pop, occult population differences (stratification) can lead to false-positives (pop’s never completely mixed)

122
Q

genome-wide association study (GWAS)

A

also a case-control association study
test all parts of genomes simultaneously between individuals for patterns of SNPs; look for stat sig differences
still need to match cases and controls ethically, but can accurately measure and correct for pop stratification
you know number of tests performed genome wide; can perform appropriate multiple-testing correction (assume 1 million tests at stat sig is p

123
Q

exome/genome sequencing study

A

high-throughput DNA sequencing
biological candidate genes
GWAS signals (specific genes or genes w/in regions)
full-genome or exome (coding) sequencing
difficult to distinguish potentially causal variants from non-pathological variation
prioritize for follow-up functional analyses

exome sequencing will eventually be replaced by genome sequencing

data interpretation difficult (“Variant of Unknown Significance” VUS)

124
Q

types of genetic studies

A

genetic linkage
genetic association
genome-wide
exome/genome sequencing

125
Q

3 most commonly used types of DNA polymorphisms as tools for finding genes

A

-microsatellites
simple sequece repeat; multi-allelic; used for forensics

-SNPs
occur near other SNPs
non-random recombination at micro level (linkage disequilibrium)

-Copy-Number Variants (CNVs)
common large deletions; typically detected by local SNP patterns; differ by population, individually rare, collectively common,
mostly in genes

126
Q

Turner Syndrome clinical presentation

A

XO karyotype
coarctation of aorta
systemic hypertension
eye abnormalities (inner canthal folds, ptosis, blue sclera)
skeletal abnormalities (cubitus valgus, short 4th metcarpal, short stature)
gonadal dysgenesis
characteristic unusual face
webbed neck
broad chest w/ wide nipples
learning abnormalities (math, visual spatial skills, non-verbal)
at birth- edema of dorsal foot

127
Q

Turner syndrome challenges across lifespan

A

infertility, stature, sexual development, concerns regarding health and aging

10% developmentally delayed
risk of impaired social adjustment
common spontaneous abortions
elevated freq of renal and cardiovascular problems
lymphedema in fetal life
thyroid issues
128
Q

Turner syndrome and medical community pitfalls

A

secret keeping, difficulty communicating an infertility diagnosis, perceived negative experiences with physicians

129
Q

common autosomal recesive characteristics

A 
phenotype in homozygotes
equal across males/females
horizontal inheritance pattern
parents are affected or carriers
predisposition in certain populations
130
Q

allelic heterogeneity
compound heterozygote
high-risk groups

A

allelic hetero- existance of multiple alleles of the same gene in a pop

compd hetero- a person who carries 2 diff mutant alleles of the same gene at the same locus

high-risk groups- an ethnic group w/ high risk for autosomal recessive disease; due to increased allele frequency and potential inbreeding (in a population)

131
Q

phenylketoriuria (PKU)

A

defect of phenylalanine (F) metabolism
results in high F levels in blood and F metabolites in urine
shows as hyperactivity, epilepsy, intellectual disability, and microcephaly

132
Q

PKU patient biochem deficiencies and appropriate treatments

A

> 98% defect in gene coding for phenylalanine hydroxylase (PAH), which converts F to tyrosine Y
1% defect in PAH cofactor BH4

has large variety of mutant alleles- so incidence of compd heterozygosity is very high (varied phenotype severity)

preventable- treat w/ low-F diet during school years to prevent mental problems
BH4 supplementation
neutral AA suplements; ERT; gene therapy

133
Q

maternal PKU and treatment

A

pregnant women w/ PKU who are not on F-restricted diet have high miscarriage and dev problems w/ children

caused by high F in maternal circulation, not child’s genotype, called maternal PKU

low-F diet; BH4 supplementation
neutral AA suplements; ERT; gene therapy

134
Q

PKU newborn screening procedures

A

test baseline blood w/ mass spec to find abnormally high F levels (and low Y metabolites)

then a few days later to give F time to potentially accumulate

135
Q

alpha-1-antitrypsin deficiency (ATD)

A

inherited genetic disorder that causes defective alpha-1-antitripsin production, a protease inhibitor; suicide substrate of elastase

136
Q

ATD clinical features and ecogenetics

A

late-onset and underdiagnosed; more common among Northern-Europeans
increased risk for dev emphysema and liver cirrhosis
smoking aggravates both problems

137
Q

primary enzyme target of ATD

A

mainly targets and inhibits elastase (a serum protease) via irreversible binding

elastase is released by neutrophils in the lung to break down elastin for lung structure remodeling

if elastase isn’t inhibited by ATD, the lung tissue breaks down more quickly, causing inflammatory responses that cause lung tissue to break down even faster

138
Q

2 most common mutant alleles that cause ATD

A

Z allele- most severe and common form (ZZ = 15% normal phenotype)
makes improperly folded protein; gets stuck in liver cells; elevates rate of liver cirrhosis (possibly need liver transplant)
ZZ smokers live avg 40 years vs 60 years for non-smokers

S allele- less severe; makes unstable ATD proteins (no liver disease, but still not effective)

3 common M (normal) alleles

treatments- inhalation meds; vaccines; lung transplant; pulm rehab for COPD; ERT; gene therapy; drugs to release misfolded protein into blood/out of liver

139
Q

Tay-Sach disease (T-S)

A

early-onset; fatal disease progressively targeting the CNS; born normal, symptoms show about 9-12 months, usually death occurs 2-4 years

first signs- muscle weakness and increased startle response to sounds

advanced- loss of vol movement, seizures, intellectual disabilities, vegetable state

140
Q

T-S biochem defects

A

defect in ability to rid of a ganglioside lipid that makes ~5% brain mass
instead of being able to break it down and turn it over, the ganglioside gets stuffed into lysosomes until the lysosomes are massively engorged

141
Q

Tay-Sachs vs
Sandhoff vs
AB variant of Tay-Sachs

A

T-S- mutant alpha subunit of the enzyme required to break down ganglioside; only HexA protein activity is affected since it is a heterodimer w/ an alpha and beta subunit (HexB is a protein w/ BB subunits)

Sandhoff- mutant beta subunit of the enzyme required to break down ganglioside, so both HexA and HexB protein activities are affected (both incl beta subunits)

AB variant- HexA and HexB genes are normal; GM2 accumulates due to a protein deficiency in the GM2 activator- cannot activate the ganglioside breakdown

142
Q

T-S high risk groups and screening methods

A

high risk: Ashkenazi Jews
2 mutant alleles account for >95% of mutations in that pop;
DNA testing for these 3 alleles are offered for carrier and prenatal screening; also
Enzymatic activity tests

143
Q

different forms of Hb during development

A

alpha gene cluster on Chr 16;
beta gene cluster on Chr 11
2 alpha’s + 2 betas = 1 tetramer

zeta–> 2 alpha copies
epsilon–> gammaG–> beta
epsilon–> gammaA–> delta

Globins:
early embryo: zeta-epsilon
fetus: alpha-gamma’s
birth: alpha-beta

144
Q

erythrogenesis location during development

A

yolk sac to liver/spllen in utero, then bone marrow after birth

145
Q

locus control region LCR

A

10-20 kbs upstream of gene clusters
each gene cluster has its own promoter; and upstream LCR controls which are turned on/off
controls timing and level of expression

most hemoglobinopathies are either structural (alt globin properties), thalassemias (low syn levels of a globin), or defective globin switching (hereditary persistence of fetal Hb- continued elevated gamma Hb levels)

146
Q

sickle cell anemia and

Hemoglobin C mutations

A

SC- affects beta-globin gene; caused by mutation in exon 1 (A to T mut at codon 6; 2nd base pos); glutamate to valine; decreases solubility, more likely to polymerize; causes sickle-cell shape agglomerations and blockages
(Hetero’s usually phenotypically normal- “trait”)

HbC- also A to T mutation in exon 1, codon 6 of beta-globin gene, but the 1st base; changes glutamate to lysine, decreases solubility; less severe than sickle-cell

147
Q

sickle cell DNA diagnosis

A

use a restriction enzyme that cleaves at the normal site sequence in exon 6; the SC mutation can’t cleave there, so there’s a larger fragment in that position;
can cause a DNA probe to detect these fragments and run PCR to detect larger/smaller amounts of site-specific cleavage

148
Q

6 possible genotypes of alpha-globin locus (due to 4 copies of alpha)

A

alpha-thal-1 (–)
1- Major; homozygous (–/–) death
2- heterozygous (aa/–)- mild anemia “trait”

alpha-thal-2 (a-)
3- homozygous (a-/a-) mild anemia “trait”; none-mild anemia; low-normal MCV
4- heterozygous (aa/a-)- silent carrier; no anemia; normal MCV

alpha-thal-1/alpha-thal-2 (a-/–)
5- compd heterozygous; low MCV; severe anemia; “HbH disease- 3 deletion”

6- aa/aa; normal phenotype

149
Q 
beta thalassemia-
thalassemia major
thalassemia minor
B0
B+
trait

simple vs complex

A

major- AKA “Cooley’s anemia”
severe anemia; most RBCs are destroyed before circulation; need blood transfusions and clinical intervention; low I-MCV

minor- clincially normal carrier of 1 beta-thalassemia allele; mild-moderate anemia; low MCV
B0-thalassemia- zero beta syn; leads to death shortly after birth
B+ thalassemia- common; some B made, but still thalassemia

B thalassemia trait-
1 normal and 1 abnormal gene
non-mild anemia
low-normal or low MCV

simple b-thalassemias- only target the beta globin gene

complex- target beta globin gene and other genes in the beta cluster, or the LCR; can cause HPFH

150
Q

Hereditary Persistence of Fetal Hemoglobin HPFH and

2 known mutations

A

HPFH- not switching gamma-globin to beta-globin after birth
gamma Hb can partly sub for defective beta Hb

mutations:
large deletion: brings enhancer closer to gamma gene and overcomes repressors (persistent gamma expression)
point mutation: in gamma gene; destroys repressor targets, so genes can’t be turned off

understanding these mech’s may make it possible to treat beta-thal and sickle cell by expressing HbF in patients

151
Q

Thalassemia- qualitative changes in global chains

A 
qualitative- 
HbS- SS= sickle cell
hetero- "trait"
HbSC hemoglobinopathy
SB0 thalassemia- no normal beta with SC
SB+ thalassemia- SC, but beta being made

HbC- CC= hemoglobinopathy
hetero- “trait”
C-Beta thalassemia

HbE-
homo/hetero E
combination: E-Beta thalassemia

152
Q

Thalassemia- quantitative distribution

A

269 million Hb disorder carriers
15% Africans S carriers
7% SE Asians E carriers
4-5% SE Asians and Med are beta thal carriers
350K babies born/yr w/ major Hb disorders
majority of children die undiagnosed/untreated

153
Q

geographic distribution of common Hb variants

SE Asia
Africa
West Pacific
East Mediterranean

A

SE Asia-
a/b thalassemia and HbE

Africa-
a/b thalassemia and HbS, HbC

West Pacific-
a/b thalassemia and HbE

East Med-
b thalassemia and HbS

154
Q

autosomal dominant
characteristics
problems

A 
expressed in hetero/homozygotes
usually at least 1 affected parent
vertical pedigree
autosomal
frequently have late-onset
frequently involve structural protein defects

problems-
tend to have wide range of clinical presentations
often “reduced penetrance”
often variable expressivity

155
Q

genocopy vs phenocopy

A

genocopy- a mutation in a different gene causing the same syndrome
(Hemophilia A, Hemophilia B, and Von Willebrand’s disease)

phenocopy- a syndrome caused by environmental factors that mimics a genetic disease

156
Q

Acondroplasia

A

autosomal dominant
most common form of dwarfism; 100% penetrance (80% de novo mutations)
mutation in FGF-R3 protein, leading to ligand-dependent activation and inhibiting chondrocyte synthesis

small stature; rhizomelic limb shortening; short fingers; genuvarium; trident hands; large head/frontal bossing; midfacial retrusion; small foramen magnum/craniocervical instability

157
Q

Marfan Syndrome

A

autosomal dominant
CT disorder; ocular, musculoskeletal, CV problems
mutation in fibrilin gene on Chr 15 reduces microfibril numbers
25% new mutation rate; variable expressivity

diagnosis- aortic root enlargement; ectopia lentis; FBN1 mutation; systemic scores vary depending on fam history (incl scoliosis, thumb/wrist sign, Pectus excavatum)

158
Q

neurofibromatosis-1

A 
autosomal dominant
50% new mutation rate
mutation in NF-1 gene on Chr 17 
Although dominant, you must have both genes to show the phenotype
variable expressivity

show cafe-au-lait spots and peripheral nerve/bone tumors later in life
neurofibromas
axillary/inguinal freckling
Lisch nodules on eyes

159
Q

tuberous sclerosis

A

autosomal dominant
locus heterogeneity
2/3 new mutation rate
variable expressivity but 100% penetrance

loss of func mutation on TSC1 and TSC2 genes on Chr 9 and 16 that regulate cell growth/proliferation

hypopigmented skin patches
kidney, lung, heart, CNS, seizures, neuropsychiatric (cognitive impairment, autism, ADHD, etc)

160
Q

osteogenesis imperfecta type 1

A

autosomal dominant
variable expressivity

mutation in COL1A1 on Chr 7- reduced production of pro-alpha 1 chains that reduces type 1 collagen production by half

clinical- multiple fractures, mild short stature, adult onset hearing loss, blue sclera

161
Q

retinoblastoma

A

autosomal dominant
malignant tumor of retina
RB1 gene on Chr 13
90% penetrance

162
Q

trinucelotide disorders

slipped mispairing
anticipation
parental transmission bias

A

autosomal dominant
expansion of a segment of DNA consisting of 3 or more nucleotides

slipped mispairing- mispairing of repeats coupled w/ inadequate repair- mispairing increases as repeat grows

anticipation- severity and/or onset increases in next gen

parental transmission bias- trinucleotide expansion more likely to occur during gametogenesis

AD,AR, X-linked transmission- nonfunc protein; protein w/ novel func; novel RNA

163
Q

how trinucleotide repeat disorders expand-
replication
repair
recombination

A

rep- may be in hairpin loop formation on lagging strand

repair- may be mismatch repair proteins putting in too many repeats, forming DNA hairpin

recomb- may involve recomb within repeat tract, esp when chromosomes aren’t aligned properly

164
Q

mytonic dystrophy type 1

A

trinucelotide repeat disorder
anticipation
maternal transmission
DMPK mutation on Chr 19 (important role in muscle, heart, brain cells)

adult onset MS; progressive muscle waste/weakening; myotonia; cataracts; heart problems

165
Q

polyglutamine-containing proteins and trinucleotide repeat disorders

A

occur in Huntington’s from CAG-repeats

cause trouble- aggregate w/ each other in beta-sheets and alter a lot of transcriptional regulators

166
Q

Huntington’s Disease

A

autosomal dominant
usually late-onset in 30s-40s
expansion of CAG-repeat in HD gene on Chr 4

causes neuronal atrophy in caudate nucleus of basal ganglia (results in muscle twitching/jerking)
slowly progressing to death in 5-15 years
(early onset typically inherited from father)

167
Q

x-linked pedigree
x-linked recessive vs
x-linked dominant

A

pedigree- primarily males; can’t go father-son
affected father to all daughters (carrier or phenotype)
if disease is lethal- 1/3 of male cases are de novo mutations (not from mother)

recessive- phenotype in all males and homo females

dominant- phenotype in all males (typically severe) and female carriers

168
Q

5 x-linked recessive disorders

A 
Lesch-Nyhan syndrome
duchenee muscular dystrophy
becker muscular dystrophy
DMD- associated CM
hemophilia A
169
Q

Lesch-Nhyan syndrome

A

x-linked recessive
HPRT1 gene mutation- recycling of purines

cerebral palsy; cognitive behavior disturbances; overproduction of uric acid; self injury;

170
Q

Dystrophinopathies

Duchenne MD
Becker MD
DMD-associated CM

A

DMD gene mutation- dystrophin; largest human gene
spectrum of muscle diseases

Duchenne- progressive proximal-distal muscle weakness; calf hypertrophy; dilated cardiomyopathy; CK levels 10x normal; onset before 5; wheelchair before 13; death in 30s; absence of dystrophin

Becker- progressive proximal-distal muscle weakness; dilated cardiomyopathy; CK levels 5x normal; later onset; wheelchair after 16; death in 40s; abnormal quantity/quality of dystrophin

DMD-assoc CM- dilated cardiomyopathy presenting 20-40 yrs; early death; no skeletal muscle involvement; no dystrophin in myocardium

171
Q

hemophilia A

A

x linked rececessive
10% female carriers affected
F8 gene mutation on X chr; Factor VIII deficiency;

blood disorder- fails to clot appropriately due to low Factor VIII; spontaneous bleeds into joints, muscles, or intracranial; excessive bruising; prolonged bleeding after injury or incision; delayed wound healing

Royal family

172
Q

3 X linked dominant disorders

A

Rickets
Fragile X Syndrome
Rett syndrome

173
Q

Rickets-

A

x linked dominant
PHEX gene- regulates fibroblast growth factor; inhibits kidneys reabsorbing phsophate back into blood stream
hypophosphatemia
short stature; bone deformities;

174
Q

Fragile X syndrome

A 
x linked dominant
FMR1 gene (trinucleotide repeat disorder)
anticipation
maternal transmission bias
common cause of inherited dev delay

intellectual disabilities; dysmorphic features; large ears; long face; macroorchidism; autistic behavior; social anxiety; hand flapping/biting; aggression

FMR1 assoc condtions-
Fragile X assoc tremor ataxia syndrome- white matter lesions on MRI; intention tremor and gait ataxia
FMR1- related primary ovarian insufficiency- cessation of menses before age 40

175
Q

Rett Syndrome

A

x linked dominant
MCEP2 gene mutation; essential for normal func of nerve cells
95% new mutation rate
loss of normal movement and coordination; acquired microcephaly; loss of communication skills; failure to thrive; seizures; abnormal hand movements

176
Q

mitochondrial inheritance features

A

mother to all of her children
affected males don’t pass it on
mitochondrial defects- encodes 37 genes

homo/heteroplasmy; threshold effect;
replicative segregation- at cell division, the multipple copies of mtDNA replicate and sort randomly among newly synthesized mito; this could be normal or mutated DNA

177
Q 
mitochondrial inheritance diseases
Leber's hereditary optic neuropathy
Kearns-Sayre Syndrome
MELAS
MERRF
A

usually assoc w/ oxidative phosphorylation; occur in tissues w/ high E requirements- (brain, eyes, muscle, heart, kidneys, liver)

Leber’s hereditary optic neuropathy- young adulthood; eye problems; cardiac conduction probs; ataxia; deafness; kidney probs

Kearns-Sayre

MELAS- mito encephalomyopathy; 2-10 y/o; lactic acidosis and stroke-like episodes; muscle weakness; seizures;

MERRF- myoclonic epilepsy w/ ragged-red fibers; MT-TK genes; muscle symptoms; seizures; ataxia; dementia; ragged-red fibers

178
Q

4 main characteristics of epigenetic phenomena

A
  • diff gene expression/phenotype, but identical genome
  • inheritance through cell division, even through generations
  • like an on/off switch
  • erasable (inter-convertible; opportunity for therapeutic potential)
179
Q

Waddington’s epigenetic landscape

A

ball at the top of a hill represents a pluripotent/embryonic stem cell;
make a choice to divide into different cell states (valleys); but once you roll down one valley you have other humps/hills you can’t overcome and switch

180
Q

3 examples of epigenetic phenomena

A

chromatin mediated gene silencing
heterochromatin domains, x-inactivation, imprinting

1-centromere marking by histone variant CENP-A
2- prions (mad cow and Kreutzfeld-Jacob disease)
3- reinforcing feedback loops involving transacting factors that have a specific intiation event and are “inherited” in the cytosol during cell division

(also bacteriophage lambda repressor mechanisms)

181
Q

how DNA methylation is inherited through cell division

A

meiosis
erasure of imprinting
sex-specific gene silencing via methylation
fertilization

DNA methylation occurs on CpG islands- solidifying repressed state
semiconservative replication- uses symetric antiparallel CG interactions to trigger proper methylation pattern on new strand

182
Q

3 chem modifications to DNA or histones that can potentially be inherited

A

methylation
acetylation of histone tails
phsophorylation

restablishment- new histones need to become like the original ones

183
Q

specific type of gene that can lead to cancer when aberrantly methylated with 5meC

A

5meC will silence Tumor Supressor Gene (TSG)
aging, environment, mutation, etc.
methylating a TSG will cause tumors to develop

184
Q

4 major mech’s of genetic mutations leading to disease and examples

A
  • loss of function of protein
  • gain of function of protein
  • acquisition of a novel property by the mutant protein
  • perturbed expression of a gene at the wrong time, place, or both
185
Q

loss of func protein examples

A 
Duchenne MD; 
alpha-thalassemia; 
Turner Syndrome; 
hereditary neuropathy w/ liability to pressure palsies (HNPP)- deletion of PMP22 gene
osteogenesis imperfecta type 1
186
Q

gain of func protein examples- 2

A

hemoglobin Kempsey- beta Hb gene; high O2 affinity so less O2 unloads at tissues

Charcot marie tooth syndrome type 1A- (CMT1A; duplictation of PMP22 gene) nerves are over-stimulating muscles
muscle atrophy and weakness; skinny calves

187
Q

acquisition of a novel protein function examples- 2

A

not necessarily altering its normal function

Sickle cell anemia- novel property of polymerizing under low O2 conditions; NO EFFECT in oxygen carrying ability of Hb

osteogenesis imperfecta types 2,3,4- creating half abnormal protein (worse than deletion of normal)

Leukemias- APM, CML

188
Q

perturbed expression of a gene at wrong time/place

A

wrong time- heterochronic
wrong place- ectopic

alter regulatory regions of a gene
ex. Fetal Hb after birth

189
Q

8 steps where mutations can disrupt normal protein production

A

transcription
translation
polypeptide folding
post-translational folding
assembly of monomers into holomeric protein
subcellular localization of polypeptide or holomer
cofactor or prosthetic group binding to the polypeptide
func of a correctly folded, assembled, and localized protein in normal amounts

190
Q

genetic anticipation in tri/tetra-nucleotide repeat disorders

A

mech- expansion of noncoding repeats:
loss of func
novel property
expand exons

ex Fragile X
myotonic dystrophia
Huntington’s Disease

191
Q

2 definitions of a genetic test

A

1- analyzing DNA to determine predisposition OR diagnosis

2- examining non-DNA and DNA that can indicate the presence/absence of a disease (looking at risk and disease)

192
Q

order of DNA tests broad to specific

A

Chromosome analysis
microarray
FISH
DNA sequencing

193
Q

chromosome analysis

A

looking at big picture differences in karyotype

large deletions/dups; resolution is 3-5Mb

194
Q

microarrary

A

you don’t know what you’re specifically looking for, so you use tons of probes to look at the chromosomes
can detect unbalanced, but cannot detect balanced translocations
different deletion/duplication thresholds

195
Q

FISH

fluorescent in situ hybridization

A

similar resolution to microarray, but you can see balanced translocations
you still have DNA with relevant probes
needs a known DNA sequence to work
works best in interphase

196
Q

DNA sequenicing

A

used to look for SNPs
amplify and study sequences with PCR
don’t know what gene you’re looking for- then use next gene to study the whole genome
Sanger sequencing if you’re know where you’re looking for one gene; cheaper

197
Q

informative vs non-informative results

A

informative- the genetic test definitively proves/disproves presence of disease

non-informative- if your confidence isn’t 100% even after receiving a result for a risk/no risk predisposition based on family history

198
Q

allelic heterogeneity vs genetic heterogeneity

A

allelic- multiple mutations in a gene can cause the same disease
ex. cystic fibrosis has >1000 mutation possibilities in a gene

genetic- mutations in multiple genes can cause same disease
ex. hypertrophic cardiomyopathy has mutation possibilities in >10 genes

199
Q

ways genetic diseases can be managed, even if non-curable

A

can’t regulate chromosomal material strictly enough, and gene-environment relationships aren’t understood well enough

can treat via meds or behavior
supportive, cognitive/physical therapies, surgeries, meds, expectant management, prenatal screening

200
Q

genetic disorders treated on basis of ERT/ protein replacement therapy

A

alpha-1-antitripsin deficiency- give patient recombinant AT1; catching early can prevent accumulated lung injury

Fabry disease- deficient alpha-galactosidase A enzyme; leads to buildup of galactosides in lysosomes, kidney disease, neuropathy, and cardiac complications; can be treated via alpha-galactosidase

Pompe disease- alpha glucosidase enzyme missing that breaks down glycogen; leads to muscle failure; can be treated w/ IV drugs

201
Q

3 gene therapy methods

A

retroviral
adenoviral
non-viral

202
Q

retroviral gene therapy

A

advantages- integrate into host genome, minimal host immune response

disadvantages- limited insert size, able to infect only dividing cells

risk of insertional mutagenesis/germline integration

can be passed to daughter cells

203
Q

adenoviral gene therapy

A

advantages- wide variety of cell types able to be targeted, large insert size, stable

disadvantages- doesn’t integrate into host genome, transiently expressed, risk of malignant transformation, can be a severe immune response

low risk of insertional mutagenesis

can infect non-dividing cells, but typically short-lived

204
Q

non-viral gene therapy

A

advantages- very large insert size , minimal host immune response

disadvantages- low efficiency, transiently expressed

doesn’t integrate into host genome
quick degradation by cellular mechanisms

205
Q

present day goals of genetic counseling

A

comprehend medical facts
understand conditions’ heridatries
understand options for dealing with recurrence risks
adjust to condition

206
Q

indications for genetic counseling

A 
previous child w/ congenital abnormalities
family history
consanguinity
teratogen exposure
repeated pregnancy losses/infertility
newly diagnosed genetic condition
positive newborn screen follow-ups
risk assessments
drug metabolism
direct to consumer results
207
Q

genetic counseling code of ethics

A

respect for patient autonomy
beneficence (personal well-being is promoted)
nonmalificence (do no harm)
justice (incl. equity w/ provision of equal care)

208
Q

reproductive options

A 
have a child traditionally
no children
adoption
prenatal diagnosis
sperm/egg donors
in-vitro fertilization w/ surrogate
pre-implantation genetic diagnosis
sperm sortin
209
Q

achrondroplasia

A 
FGFR3 gain of func mutation
autosomal dominant- 
80% denovo mutation
exclusively from paternal germline
inhibits chrondrocyte proliferation in growth plate
rhizomellic short stature
megalencephaly
brainstem/spinalcod compression
trident hand

use DNA sequencing for FGFR3 mutation

210
Q

nonsyndromic deafness

A

GJB2 mutation
autosomal dominant and recessive
codes for connexin26 to form gap junctions
loss of cochlear func

nonsyndromic-
recessive- congenital deafness
dominant- progressive childhood deafness

syndromic- incl sys’s outside of just ears

measure otoacoustic emissions w/ automated ABR to detect brain response to sound

211
Q

Fragile X syndrome

A

FMR1 mutation
x-linked
produces FMRP
triplet repeat expansion in 5’ UTR; leads to hypermethylation in region and promoter

use microarray analysis; thyroid func test; DNA analysis for Fragile X

212
Q

5-alpha reductase deficiency

A

46 XY
body can’t convert testosterone to dihydrotestosterone
phenotype- undervirilized male with increased virilization at puberty

213
Q

SRY gene disorders

A

46 XY or 46 XX when SRY is transponsed onto an X chromosome

deletion of SRY results in normal phenotypic female

addition of SRY to XX results in male

mutations in SRY result in decreased/absent Anti Mullerian Hormone

214
Q

Denys-Drash and Frasier Syndrome

A

46 XY sex reversal
mutation in WT1 gene (transcription factor for SRY gene)
chronic kidney disease

215
Q

Congenital adrenal hyperplasia

A

46 XX ambiguous genitalia
21-hyrdoxylase deficiency

salt wasting

216
Q

triple X syndrome

A 
47 XXX
may have tall stature
increased risk of learning, speech, motor, problems
seizures
kidney abnormalities
217
Q

Jacobs Syndrome

A

47 XYY
tall stature
learning, speech, dev, behavioral and emotional problems, autism spectrum

218
Q

male embryology

A 
SRY gene on Y
Wolffian duct
genital ridge turns into sertoli and leydig cells
sertoli- AMH 
leydig- testosterone
SRY and SOX9
FGF9
SF1/NR5A1
219
Q

female embryology

A 
absence of SRY gene
Mullerian ducts
WNT4 protein (inhibited by SOX9 in males) signals to form ovaries
DHH gene- ups WNT4 and downs SOX9
RSPO1 gene- WNT4 pathway coactivator
220
Q

young obese girl
dec fetal movements
severe hypotonia for 1st yr, strabismus, mild intellectual disability
gained weight at 3, obsessed w/ food
which test is the best chance of confirming diagnosis?

A

methylation studies on Chromosome 15q11-q13

221
Q

15 y/o girl evaluated for autism and seizures. normal face, normal body habitus
which genetic abnormality?

A

maternally inherited interstitial duplication on Chromosome 15(q11-q13)

222
Q

5 y/o girl with classic Duchenne MD, an x-linked recessive disorder
what explains this?

A

x linked testicular feminization

223
Q

what is true of X-chromosome inactivation

A

non-random x inactivation is seen in balanced and unbalanced x-autosome translocations

224
Q

karyotype most likely to yield a live birth

A

47 XX + 21

not:
69 XXX
47 XX + 3
46 XY -11 +22
46 YY
225
Q

pregnant 45 y/o woman w/ abnormal fetal US- fetus w/ congenital heart disease, nuchal fold thickening, shortened long bones, and duodenal atresia. Diagnostic chromosomal abnormality of fetus. What’s the most likely karyotype of the mother?

A

46 XX

226
Q

which single mutation is least likely to result in an individual expressing a genetic disease?

A

when the gen product is a typical enzyme in a biosynthetic pathway, like phenylalanine hydroxylase

227
Q

family w/ 4 children has boy and girl w/ achondroplasia, an autosomal dominant short-limb dwarfism w/ high penetrance. 5 generation pedigree shows no signs of disease. this occurance is best explained by

A

germline mosaicism

228
Q

pregnant woman assess risk for having a 2nd child with Duchenne MD. No family history of DMD, what is the best estimate of their risk that the fetus will have DMD?

A

17%

229
Q

what is a major limitation of chromosomal microarray testing vs chromosome (cytogenic) analysis

A

CMA testing can’t detect balanced translocations

230
Q

codeine question…

A

caucasian mother (+/-) and caucasian father (dup/ )

231
Q

researcher studying new drug RT458 to treat bp. 2 SNPs in p450 gene hypothesized to be important in drug level variation. what is best experiment method?

A

expose 3 different strains of transgenic mice to 5 mg/kg RT458 for 3 days and serially measure blood levels to observe variation in rise/fall over 7 days.

232
Q

family history of x-linked recessive hemophilia A in father.
genetic test is negative
Hemophilia A inversion present in 45% of cases
brother and sister each expecting a baby boy

what is the risk that the male offspring of the sister is affected w/ Hemophilia A?

A

50%

233
Q

which disease is caused by a mutation that leads to heterochronic protein expression?

A

hereditary persistence of fetal hemoglobin

234
Q

Laminopathies- dominant genetic disease due to mutation in LMNA gene encoding lamin A and C proteins. Different mutations in LMNA can lead to a variety of clinically distinct disorders including skeletal myopathies, dilated cardiomyopathy, lipodystrophy, mandibuloacral dysplasia and progeria. Progeria has a cytosine–> thymine that alters RNA splicing, removes 150 nucleotides, and deletes 50 AAs in lamin A protein.
which step in protein production is the progeria defect most likely causing the disease?

A

defective in post-translational modification

235
Q

couple comes for preconception counseling. both 44 y/o. which disorder is most associated w/ paternal age effect?

A

achrondroplasia

236
Q

non-syndromic deafness mutations- one in caucasians, and one common in Chinese. white and chinese couple have family history, and are carriers of different deletions. . what is possible genotype for hearing son?

A

wild type/ wild type

237
Q

what explains role of evolutionary change (deletions/dups to generate diversity) on separation of species?

A

duplication of a gene frees up one copy of the gene to vary and evolve while the other one continues to carry out a critical function

238
Q

34 y/o woman w/ family history of mom having miscarriage w/ trisomy 13 fetus and others
which genetic result indicates she has a high risk for abnormal children?

A

45 XX, rob(13; 14)(q10; q10)

239
Q

5 y/o boy w/ congenital and dev problems- cleft palate, dysmorphic features, interrupted aortic arch, absent parathyroid glands, mild intellectual delays
which most likely explains this?

A

del 22q11.2

240
Q

2 unrelated boys have abnormal methylation patterns for 15q11-q13, consistent w/ imprinting disorder. which matches w/ pictures?

A

large boy has likely required a feeding tube at some point in his life

241
Q

what about PKU is correct/incorrect?

A

incorrect- both PKU patients w/ phenylalanine hydroxylase defect and cofactor deficiencies respond well to low-F diets

correct-
PKU sensitivity test is influenced by age
most PKU cases have defective F hydroxylase, but a few have BH4 syn problems
women w/ PKU should have low-F diets during pregnancy to prevent maternal PKU
gene encoding PAH has high allelic heterogeneity; most pops are compd heterozygotes

242
Q

healthy couple risk for having a SC baby? (wife’s bro has SC) disease freq 1/4000

A

1-2%

243
Q

which best describes frequency of occurence of a med problem in DS?

A

thyroid disease 25%

244
Q

l-cell disease failure to add a P group in lysosomal enzymes, required to target to lysosomes
which step in figure is major defect occurring?

A

C- post translational modification

245
Q

where on the figure is the abnormal CAG repeat, leading to toxic gain of fun protein defect for Huntington disease?

A

C- at the exon

246
Q

individuals who carry a mutation in any one of 3 different genes are at increased risk of early onset Alzheimer disease compared to the general pop. this is an ex of

A

locus heterogeneity

247
Q

X-linked chondrodysplasia punctata is an X-linked dominant disorder characterized by growth deficiency,
abnormal facial features, tracheal calcifications, punctuate calcium stippling of the skeleton
(chondrodysplasia punctata), skin lesions, mental deficiency and high levels of serum
8-dehydrocholesterol. The majority of mutations in the disorder are novel missense or nonsense
mutations due to mutations of individual bases in the coding region (i.e. in the exons) of the EBP gene on
Xp11.23. A patient from a large family with X-linked chondrodysplasis punctata undergoes genetic testing
to confirm her suspected clinical diagnosis and for reproductive planning purposes. A testing approach
which is most likely to be successful in identifying the genetic mutation in this patient is

A

polymerase chain reaction amplification of the 5 exons of EBP followed by direct DNA sequencing of each exon

248
Q

The family below is affected with Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig disease). The
condition is autosomal dominant, adult-onset, and manifests incomplete penetrance. Genetic
heterogeneity is present as more than one genetic locus has been linked to the disease. 20% of cases
are due to mutations in the SOD1 gene. Individual III:2 (arrow) is tested for SOD1 mutations by DNA
sequencing of the SOD1 exons and his results are normal (no mutation detected). Which of the following
statements is true?

A

Unaffected individual II:13 (dashed arrow, right) should be tested next. If she has an SOD1 gene
mutation then III:2’s test result would be informative, predicting no increased risk of ALS for III:2.

249
Q

which statement is correct about therapeutic approaches to metabolic diseases?

A

Most newborn babies are screened for several metabolic disorders in the first few days of life to
identify babies who have early or preclinical metabolic disorders, allowing for the institution of
therapies before significant morbidity has occurred

250
Q

Familial hypercholesterolemia, due to mutations in the LDL receptor gene (LDLR), leads to moderately
(250-450 mg/dl) and very high cholesterol (>500 mg/dl) levels in heterozygous and homozygous
mutations carriers, respectively. The prevalence of homozygous mutation carriers in the general
population is 1 in a million. The prevalence of heterozygous mutation carriers is estimated as

A

1 in 500

251
Q

Which of the following approaches have been highly successful when applied to discovery of genes
involved in susceptibility to common “complex” diseases such as type 1 diabetes, asthma, coronary
artery disease, and many others?

A

genome wide association studies

252
Q

A family with four children had two children (son and daughter) both affected with osteogenesis
imperfecta II, a severe autosomal dominant condition with high penetrance. The parents have no sign of
osteogeneis imperfecta and the family history taken over four generations is negative for any other
affected individuals. The presence of two affected children in this family is best explained by?

A

germline mosaicism

253
Q

A newborn infant with normal male genitalia including palpable testes has a 46, XX karyotype. The most
likely explanation for this apparent sex reversal is

A

Yp: autosomal translocation

254
Q

The karyotype from a genetic amniocentesis for advanced maternal age is found to be mosaic 45, X; 46,
XY. Which of the following is appropriate counseling for the parents?

A

genital abnormalities ranging from ambiguous to normal male may occur

255
Q

Major flaws in case-control allelic association studies that frequently lead to false-positive “genetic
association” include all of the following EXCEPT

A

insufficient sample size to permit detection of weak associations

incl:
inadequate ethnic matching between case versus control populations.
B. unrecognized population “stratification” due to occult ethnic diversity.
C. failure to correct for multiple testing.
E. selective reporting of positive associations.

256
Q

This infant delivered at 34 weeks gestation had disproportionate growth. Her head was proportionately
much larger than her body and limbs. Her tibia were angulated and had anterior over riding dermal
dysplasia. She had significant tracheomalacia that required intubation and ventilation. A karyotype was
obtained and was reported to be 46, XY. What is the most likely explanation for this infant’s phenotype?

A

The infant has sex reversal due to a heterozygous mutation in the SOX9 gene that regulates both
SRY expression and differentiation cartilage and bone.

257
Q

Studies that compare the concordance rate in identical (monozygotic) vs. fraternal (dizygotic) twins to
estimate the relative contribution of genetics and environment to disease risk rely on which one of the
following assumptions?

A

The degree of similarity in environmental factors among the two twins is the same for identical
and fraternal twins

258
Q

Which characteristic of epigenetic phenomena is most important when considering a potential for
therapeutics?

A

they are erasable

259
Q

Hydrops fetalis (4 alpha Hb gene deletions) is

A

incompatible with life

260
Q

which is at greatest risk for being affected w/ pyloric stenosis

A

The son of a couple who already have a daughter with pyloric stenosis.

261
Q

An obese child with cognitive disabilities is suspected to have Prader-Willi syndrome (PWS). A Southern
blot is performed using a RFLP (restriction fragment length polymorphism) assay specific to the 15
chromosome to determine the origin of the patient’s chromosome 15s. The results are shown in the
Figure. (Mom and child look identical)
Based on the information from the RFLP, what is the origin of the child’s two number 15 chromosomes?

A

both chromosomes came from mother

262
Q

Lesch-Nyhan syndrome is caused by a lack of the enzyme hypoxanthine phosphoribosyl transferase.
The pedigree shows a large family with three members affected with the disease. Which is the most likely
inheritance pattern shown in this pedigree?

A

x linked recessive

263
Q

A 28 year old male is seen for early dementia. His father and paternal uncle suffer from similar symptoms
although their symptoms did not develop until they were 48 years old and 42 years old respectively. A
region for the candidate gene at 4p16 was amplified from several family members, and analyzed by gel
electrophoresis (Southern blot) with the following results. Which of the following types of mutations is
most likely causing the disease?

A

triplet repeat expansion

264
Q

A man is affected with an X linked dominant disorder which has a penetrance of 60%. His wife is
homozygous normal at this locus. What is the probability that his first daughter will be affected?

A

60%

265
Q

Hereditary hemochromatosis is an autosomal recessive disorder in which there is increased intestinal
iron absorption leading to iron overload. If the frequency of the mutant allele (C282Y) is 1/20, what is the
prevalence of individuals who are homozgyous for the mutant disease alleles in the population?

A

1/400

266
Q

The elements of genetic counseling delivered by providers include all of the following EXCEPT

A

recommendation of specific reproductive options

267
Q

An African American couple comes to the clinic for counseling because the husband’s brother is affected
with sickle cell anemia. Neither the husband nor wife is are anemic. The population carrier rate for
heterozygotes in the African American community is approximately 1 in 12. What is the risk that this
couple will have a child with sickle cell anemia?

A

1/72

268
Q

which is a cause of SC?

A

missense mutation in the coding region of beta globin gene

269
Q

Which of the following is the major abnormal form of hemoglobin seen in a fetus with hydrops fetalis with
Hb Barts, the severe form of alpha thalassemia?

A

tetramer of 4 gamma-subunits

270
Q

An 8-year-old obese boy has an eating disorder, behavioral problems, hypogonadism and mild mental
retardation. He is found to have a rare maternal uniparental disomy of chromosome 15. The principle
mechanism for most cases of this disease are due to

A

deletion of a locus subject to imprinting from a paternal chromosome

271
Q

X-linked ocular albinism only involves the eyes. The retina of affected individuals is depigmented and
hence the choroidal vessels stand out. This condition is associated with decreased vision, commonly in
the 20/70 to 20/200 range, and nystagmus. (Nystagmus means the rapid repetitive oscillations of the
eyeballs) Which of the following would best describe the retina of a female ‘carrier’ of this trait?

A

The retina would be hypo-pigmented, being approximately 50% pigmented as compared to the
normal eye.

272
Q

After 5 years of trying to have a child and a recent spontaneous abortion, a couple presents for primary
infertility counseling. Currently, the husband is 30 years old and his wife is 28 years old. During the
interview, the husband reveals that his mother also had several spontaneous abortions, and gave birth to
a child with Trisomy 21 when she was 25 years old. Which of the following tests is likely to establish the
cause of their infertility?

A

karyotype for the husband

273
Q

Sickle Cell anemia is a potentially lethal genetic disease that severely limits the ability of the red blood
cells to carry oxygen. However, in areas where malaria due to Plasmodium falciparum is prevalent, the
sickle cell allele is maintained because individuals who are heterozygous for the sickle-cell trait are
resistant to malaria. This situation illustrates which of the following concepts?

A

heterozygous advantage

274
Q

A 21-year-old woman has a brother with cystic fibrosis who is homozygous for the delta F508 mutation.
The most appropriate method to assess her carrier status is

A

a PCR of exon 10 (contains the delta F508 mutation) followed by DNA sequencing

275
Q

Albinism is an autosomal recessive disorder caused by a lack the enzyme tyrosinase. A man whose
brother is an albino, marries a woman who is an albino. What is the probability that their first child will be
an albino?

A

1/3

276
Q

Angelman syndrome can be caused by all of the following EXCEPT

A

partial deletion of paternal chromosome 15

277
Q

A medical student took a year off to perform research. For her project, she decided to investigate the
possibility of a genetic contribution to schizophrenia. Published data that had been collected from families
affected with schizophrenia and some similarly aged population controls demonstrated that siblings of
patients with schizophrenia were found to have schizophrenia 25% of the time while the siblings of
control patients had schizophrenia only 2% of the time. She then attended schizophrenia clinic for one
year, where she was able to recruit 50 pairs of monozygotic twins and 50 pairs of dizygotic twins where
at least one of the twins had schizophrenia. She found that 69% of monozygotic twins displayed
concordance, while 14% of dizygotic twins were concordant for schizophrenia. Which of the following
mode of inheritance BEST describes the inheritance of schizophrenia in these populations?

A

multifactorial inheritance

278
Q

Which of the following types of chromosomes is most likely to be involved in a Robertsonian translocation
resulting in the loss of the p-arm in a clinically normal individual?

A

acrocentric

279
Q

which is most likely to be phenotypically normal?

A

person w/ karyotype 45 XX rob(21; 21)

280
Q

Karyotype analysis is performed on a nine year old boy with mild intellectual disability, but an otherwise
normal physical exam. Which of the following karyotypes is LEAST likely to be detected upon
chromosome analysis of this patient?

A

45 X

M2M (4 decks)

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