M2M Unit 2 Flashcards
(280 cards)
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"
2
Q
Patterns of Mendelian Inheritance- generic
A
genes come in pairs
(note x-linked and mito diseases)
genes’ alleles lead to observed phenotypes
3
Q
Law of Segregation
A
Alleles segregate at meiosis into the gametes
4
Q
Law of Independent Assortment
A
The segregation of each pair of alleles is independent
exception: genes close together are linked
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)
6
Q
Horizontal pattern of affected phenotype
A
tends to be autosomal recessive- more likely affected in siblings and not parents
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)
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
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
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
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
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)
13
Q
population genetics:
A
the study of allele frequencies and changes in allele frequencies in populations
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
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
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
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
18
Q
3 common human trisomies
A
trisomy 13, 18, 21
19
Q
clinical features of trisomy 13
A
Patau syndrome
characteristic faces
severe mental retardation
congenital malformations- holoprosencephaly, facial clefts, polydactyly, renal abnormalities
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
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
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
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)
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
25
SNP frequencies
average of 1 SNP every 1000 bp between any 2 randomly chosen genomes
99.9% identical and 3,000,000 differences
26
5 types of variations that occur between genomes:
- 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
27
Insertion-deletion polymorphisms:
minisatellites
microsatellites
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)
28
SNPs
frequency of 1 in ~1000 bp's
| PCR-detectable markers, easy to score, widely distributed
29
CNVs
variation in segments of genome to 200bp-20 Mbp's
can range from one additional copy to many
array comparative genomic hybridization (array CGH)
30
genome "structural" variation
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
31
```
characteristics of the genome:
gene-rich
gene-poor
stable
unstable
GC rich
AT rich
euchromatin
heterochromatin
```
```
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
```
32
completely sequenced human genome?
no completely sequenced and assembled human genome
| -sequencing focused on euchromatic regions: easiest to access and interpret; repeats are often difficult to decipher
33
gaps remaining in the euchromatic regions
341 gaps
1% of euchromatic genome
many contain segmental duplications that require more work and new methods
34
categories of genomic DNA sequences
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
35
2 types of repetitive DNAs
tandem repeats AKA satellite DNAs
dispersed repetitive elements
36
tandem repeats AKA satellite DNAs
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)
37
dispersed repetitive elements
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)
38
estimated number and types of human genes
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?)
39
gene families
genes with high sequence similarity;
perform similar functions
arise by gene duplication
40
gene duplication as an evolutionary mechanism
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
41
2 methods of current genome sequencing and "missing heritability" problem
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
42
genetic variability from meiosis
- 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
43
mitosis vs meiosis cell divisions
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
```
44
banding of karyotypes
giemsa- dye used to create banding patterns based on selective binding (G-banding)
ideogram- banding pattern depiction, w/ bands numbered prox-> distal from centromere
45
```
p and q
chromosome types:
metacentric
submetacentric
acrocentric
```
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
46
noting chromosome abnormality
general format:
total # of chromosomes,
gender chromosomes,
type of mut (loc of mut)
```
+ additional chromosome
del
inv
dup
ins
r (ring)
```
47
aneuploidy
loss/gain of selected chromosomes usually fatal)
often due to selective meiotic disjunction
specifically maternal meiosis 1
48
polyploidy
extra copies of all chromosomes (triploidy);
almost always fatal
complete meiotic disjunction
2 sperm + 1 egg, or a diploid sperm/egg
49
mosaicism
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
50
3 common trisomies
trisomy 13, 18, 21
51
Patau Syndrome
| AKA Trisomy 13
```
most clinically severe of trisomies
polydactylity
CNS abnormalities
omphalocele (GI organ herniation outside abdomen)
renal dysplasia
congenital heart disease
```
52
Edwards Syndrome
| AKA Trisomy 18
SGA
rocker bottom feet
clenched fists
congenital heart disease
hypertonicity (clenched hands, narrow hips)
severe CNS abnormalities, severe retardataion
53
Down Syndrome
| AKA Trisomy 21
```
most common survivable trisomy
congenital heart disease
hypotonia
GI abnormalities
early-onset Alzheimer's
```
54
2 common mech's of chromosomal structural rearrangements
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.
55
balanced vs unbalanced structural rearrangements
balanced- normal, but rearranged, complement of chromosomal material. often phenotypically neutral
no gain or loss
unbalanced- abnormal chromosome content. often phenotypically abnormal
56
3 types of balanced rearrangement
| alternate segregation
```
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
57
4 types of unbalanced rearrangement
| adjacent segregation
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
58
family risks with balanced translocations leading to unbalanced progeny
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
```
59
the most common contiguous gene syndroms in humans
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
60
define epigenetics and how modifications may affect gene expression
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
61
genetic imprinting and its molecular basis
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
62
3 rules for epigenetic DNA methylation
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)
63
genetic imprinting with Prader Willi Syndrome and Angelman Syndrome
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*
64
uniparental disomy with PW and Angelman Syndrome
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;
65
2 of the most common leukemia translocations
CML and APML
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
66
childhood B-cell leukemia
| AKA ALL
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
67
6 types of FISH probes
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"
68
FISH basic definition
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
69
chromosomal microarray analysis CMA roles and limits
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
70
lab test algorithm for children w/ learning disorders, developmental delays, autism, dysmorphic features, failure to thrive
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
71
Down Syndrome- 3 chromosomal abnormalities
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
72
testing for Down Syndrome
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
73
Down Syndrome Phenotype
```
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
```
74
Down Syndrome medical problems
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
75
Down Syndrome developmental and behavioral phenotype
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
76
Prader Willi Syndrome chromosome abnormalities
```
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
77
Diagnose PW
made with FISH or microarray
| methylationg tests on maternal and paternal alleles
78
imprinting regions and disorders on Chr 15
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
79
Prader Willi phenotype
infancy-
hypotonia and dysmorphic features, almond eyes, undescended testicles, light pigmentation, feeding issues
toddler- feeding problems reverse; persistent hunger
80
PW medical problems
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
81
PW developmental and behavioral phenotype
mild to mod dev delay leading to intellectual disabilities as adults
behavioral issues are common
82
other abnormalities associated with Chromosome 15 abnormalities
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?)
83
pharmacogenetics vs
| pharmacogenomics
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
84
pharmacodynamics vs pharmacokinetics
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
85
Phase 1 and Phase 2 in drug metabolism
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
86
central role of CYP450 enzyme sys in drug metabolism
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
87
substrates, inhibitors, and inducer of
| CYP450 gene CYP3A
sub- felodipine and cyclosporine
inhibitors- ketoconazole, grapefruit juice
inhibitor- rifampin
88
substrates and inhibitors of
| CYP450 gene CYP2D6
sub- tricyclic antidepressants and codeine
inhibitors- quinidine, fluxotine, paroxetine
89
substrate and dosing of CYP450 gene CYP2C9
sub- Warfarin
overdose- clotting
underdose- bleed out
start w/ 5mg/day and adjust
90
NAT gene substrate
isoniazid for tuberculosis
91
TMPT gene substrates and comments
sub- 6-mercaptopurine and 6-thioguanine
can kill a child w/ ALL
classic pharm mech that can be fatal if ignored
92
G6PD gene substrates, mech, and comments
sub- sulfonamide, dapsone
mech- x-linked enzyme
deficient individuals subject to hemolytic anemia after drug exposure
93
VKORC1 gene substrate, and comments
sub- Warfarin
blood thinner
prescribed to >20 mil patients annually
94
population genetics and relevance of "population field"
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
95
mutation rate for autosomal dominant- direct and indirect methods
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
96
how physicians managing genetic diseases could affect prevalence of genetic diseases
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
97
biological advantages of sexual reproduction
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
98
x chromosome inactivation and implications
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)
99
non-random X inactivation
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
100
genetic regulation of sexual differentiation-
| WT gene, SRY, MIF
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
101
true hermaphroditism vs. pseudohermaphroditism
true- 46XX /46XY
show ovaries, testes, partial uterus
pseudo- ambiguous external genitalia but normal ovaries or testes (NOT both)
102
sex reversals
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
103
45XO Turner Syndrome
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
104
47XXY Kleinfelter Syndrome
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
105
Androgen insensitivity
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)
106
clinical apporach to disorders of sexual differentiation
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
```
107
multifactorial inheritance
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
108
```
complex traits characteristics-
incomplete penetrance
variable expressivity
phenocopies
heterogeneity
```
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
109
heterogeneity
| allelic vs locus
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)
110
multifactorial inheritance disease examples
```
cystic fibrosis
Alzheimer's
some cancers
diabetes 1 and 2
inflammatory bowel disease
asthma
Schizophrenia
hypertension
cleft lip/palate
rheumatoid arthritis
```
111
strategies to determine importance of genetic vs non-genetic factors contributing to variations in complex traits
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)
112
heritability and difficulties w/ quantifying role of genetics in populations and individuals
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
113
rationale for finding disease genes
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
personalized medicine paradigm
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
genetic linkage study
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
genetic linkage studies- recombination
more recombination- genes are probably farther apart and not inherited together
117
genetic linkage studies- LOD
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
genetic linkage studies- centiMorgan
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
genetic association studies
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
case-control design for genetic association studies
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
genetic association studies- 2 fatal flaws
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
genome-wide association study (GWAS)
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
exome/genome sequencing study
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
types of genetic studies
genetic linkage
genetic association
genome-wide
exome/genome sequencing
125
3 most commonly used types of DNA polymorphisms as tools for finding genes
-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
Turner Syndrome clinical presentation
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
Turner syndrome challenges across lifespan
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
Turner syndrome and medical community pitfalls
secret keeping, difficulty communicating an infertility diagnosis, perceived negative experiences with physicians
129
common autosomal recesive characteristics
```
phenotype in homozygotes
equal across males/females
horizontal inheritance pattern
parents are affected or carriers
predisposition in certain populations
```
130
allelic heterogeneity
compound heterozygote
high-risk groups
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
phenylketoriuria (PKU)
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
PKU patient biochem deficiencies and appropriate treatments
>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
maternal PKU and treatment
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
PKU newborn screening procedures
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
alpha-1-antitrypsin deficiency (ATD)
inherited genetic disorder that causes defective alpha-1-antitripsin production, a protease inhibitor; suicide substrate of elastase
136
ATD clinical features and ecogenetics
late-onset and underdiagnosed; more common among Northern-Europeans
increased risk for dev emphysema and liver cirrhosis
smoking aggravates both problems
137
primary enzyme target of ATD
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
2 most common mutant alleles that cause ATD
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
Tay-Sach disease (T-S)
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
T-S biochem defects
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
Tay-Sachs vs
Sandhoff vs
AB variant of Tay-Sachs
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
T-S high risk groups and screening methods
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
different forms of Hb during development
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
erythrogenesis location during development
yolk sac to liver/spllen in utero, then bone marrow after birth
145
locus control region LCR
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
sickle cell anemia and
| Hemoglobin C mutations
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
sickle cell DNA diagnosis
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
6 possible genotypes of alpha-globin locus (due to 4 copies of alpha)
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
```
beta thalassemia-
thalassemia major
thalassemia minor
B0
B+
trait
```
simple vs complex
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
Hereditary Persistence of Fetal Hemoglobin HPFH and
| 2 known mutations
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
Thalassemia- qualitative changes in global chains
```
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
Thalassemia- quantitative distribution
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
geographic distribution of common Hb variants
SE Asia
Africa
West Pacific
East Mediterranean
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
autosomal dominant
characteristics
problems
```
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
genocopy vs phenocopy
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
Acondroplasia
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
Marfan Syndrome
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
neurofibromatosis-1
```
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
tuberous sclerosis
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
osteogenesis imperfecta type 1
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
retinoblastoma
autosomal dominant
malignant tumor of retina
RB1 gene on Chr 13
90% penetrance
162
trinucelotide disorders
slipped mispairing
anticipation
parental transmission bias
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
how trinucleotide repeat disorders expand-
replication
repair
recombination
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
mytonic dystrophy type 1
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
polyglutamine-containing proteins and trinucleotide repeat disorders
occur in Huntington's from CAG-repeats
| cause trouble- aggregate w/ each other in beta-sheets and alter a lot of transcriptional regulators
166
Huntington's Disease
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
x-linked pedigree
x-linked recessive vs
x-linked dominant
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
5 x-linked recessive disorders
```
Lesch-Nyhan syndrome
duchenee muscular dystrophy
becker muscular dystrophy
DMD- associated CM
hemophilia A
```
169
Lesch-Nhyan syndrome
x-linked recessive
HPRT1 gene mutation- recycling of purines
cerebral palsy; cognitive behavior disturbances; overproduction of uric acid; self injury;
170
Dystrophinopathies
Duchenne MD
Becker MD
DMD-associated CM
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
hemophilia 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
3 X linked dominant disorders
Rickets
Fragile X Syndrome
Rett syndrome
173
Rickets-
x linked dominant
PHEX gene- regulates fibroblast growth factor; inhibits kidneys reabsorbing phsophate back into blood stream
hypophosphatemia
short stature; bone deformities;
174
Fragile X syndrome
```
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
Rett Syndrome
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
mitochondrial inheritance features
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
```
mitochondrial inheritance diseases
Leber's hereditary optic neuropathy
Kearns-Sayre Syndrome
MELAS
MERRF
```
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
4 main characteristics of epigenetic phenomena
- 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
Waddington's epigenetic landscape
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
3 examples of epigenetic phenomena
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
how DNA methylation is inherited through cell division
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
3 chem modifications to DNA or histones that can potentially be inherited
methylation
acetylation of histone tails
phsophorylation
restablishment- new histones need to become like the original ones
183
specific type of gene that can lead to cancer when aberrantly methylated with 5meC
5meC will silence Tumor Supressor Gene (TSG)
aging, environment, mutation, etc.
methylating a TSG will cause tumors to develop
184
4 major mech's of genetic mutations leading to disease and examples
- 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
loss of func protein examples
```
Duchenne MD;
alpha-thalassemia;
Turner Syndrome;
hereditary neuropathy w/ liability to pressure palsies (HNPP)- deletion of PMP22 gene
osteogenesis imperfecta type 1
```
186
gain of func protein examples- 2
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
acquisition of a novel protein function examples- 2
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
perturbed expression of a gene at wrong time/place
wrong time- heterochronic
wrong place- ectopic
alter regulatory regions of a gene
ex. Fetal Hb after birth
189
8 steps where mutations can disrupt normal protein production
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
genetic anticipation in tri/tetra-nucleotide repeat disorders
mech- expansion of noncoding repeats:
loss of func
novel property
expand exons
ex Fragile X
myotonic dystrophia
Huntington's Disease
191
2 definitions of a genetic test
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
order of DNA tests broad to specific
Chromosome analysis
microarray
FISH
DNA sequencing
193
chromosome analysis
looking at big picture differences in karyotype
| large deletions/dups; resolution is 3-5Mb
194
microarrary
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
FISH
| fluorescent in situ hybridization
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
DNA sequenicing
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
informative vs non-informative results
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
allelic heterogeneity vs genetic heterogeneity
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
ways genetic diseases can be managed, even if non-curable
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
genetic disorders treated on basis of ERT/ protein replacement therapy
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
3 gene therapy methods
retroviral
adenoviral
non-viral
202
retroviral gene therapy
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
adenoviral gene therapy
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
non-viral gene therapy
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
present day goals of genetic counseling
comprehend medical facts
understand conditions' heridatries
understand options for dealing with recurrence risks
adjust to condition
206
indications for genetic counseling
```
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
genetic counseling code of ethics
respect for patient autonomy
beneficence (personal well-being is promoted)
nonmalificence (do no harm)
justice (incl. equity w/ provision of equal care)
208
reproductive options
```
have a child traditionally
no children
adoption
prenatal diagnosis
sperm/egg donors
in-vitro fertilization w/ surrogate
pre-implantation genetic diagnosis
sperm sortin
```
209
achrondroplasia
```
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
nonsyndromic deafness
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
Fragile X syndrome
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
5-alpha reductase deficiency
46 XY
body can't convert testosterone to dihydrotestosterone
phenotype- undervirilized male with increased virilization at puberty
213
SRY gene disorders
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
Denys-Drash and Frasier Syndrome
46 XY sex reversal
mutation in WT1 gene (transcription factor for SRY gene)
chronic kidney disease
215
Congenital adrenal hyperplasia
46 XX ambiguous genitalia
21-hyrdoxylase deficiency
salt wasting
216
triple X syndrome
```
47 XXX
may have tall stature
increased risk of learning, speech, motor, problems
seizures
kidney abnormalities
```
217
Jacobs Syndrome
47 XYY
tall stature
learning, speech, dev, behavioral and emotional problems, autism spectrum
218
male embryology
```
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
female embryology
```
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
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?
methylation studies on Chromosome 15q11-q13
221
15 y/o girl evaluated for autism and seizures. normal face, normal body habitus
which genetic abnormality?
maternally inherited interstitial duplication on Chromosome 15(q11-q13)
222
5 y/o girl with classic Duchenne MD, an x-linked recessive disorder
what explains this?
x linked testicular feminization
223
what is true of X-chromosome inactivation
non-random x inactivation is seen in balanced and unbalanced x-autosome translocations
224
karyotype most likely to yield a live birth
47 XX + 21
```
not:
69 XXX
47 XX + 3
46 XY -11 +22
46 YY
```
225
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?
46 XX
226
which single mutation is least likely to result in an individual expressing a genetic disease?
when the gen product is a typical enzyme in a biosynthetic pathway, like phenylalanine hydroxylase
227
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
germline mosaicism
228
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?
17%
229
what is a major limitation of chromosomal microarray testing vs chromosome (cytogenic) analysis
CMA testing can't detect balanced translocations
230
codeine question...
caucasian mother (+/-) and caucasian father (dup/ )
231
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?
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
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?
50%
233
which disease is caused by a mutation that leads to heterochronic protein expression?
hereditary persistence of fetal hemoglobin
234
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?
defective in post-translational modification
235
couple comes for preconception counseling. both 44 y/o. which disorder is most associated w/ paternal age effect?
achrondroplasia
236
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?
wild type/ wild type
237
what explains role of evolutionary change (deletions/dups to generate diversity) on separation of species?
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
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?
45 XX, rob(13; 14)(q10; q10)
239
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?
del 22q11.2
240
2 unrelated boys have abnormal methylation patterns for 15q11-q13, consistent w/ imprinting disorder. which matches w/ pictures?
large boy has likely required a feeding tube at some point in his life
241
what about PKU is correct/incorrect?
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
healthy couple risk for having a SC baby? (wife's bro has SC) disease freq 1/4000
1-2%
243
which best describes frequency of occurence of a med problem in DS?
thyroid disease 25%
244
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?
C- post translational modification
245
where on the figure is the abnormal CAG repeat, leading to toxic gain of fun protein defect for Huntington disease?
C- at the exon
246
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
locus heterogeneity
247
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
polymerase chain reaction amplification of the 5 exons of EBP followed by direct DNA sequencing of each exon
248
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?
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
which statement is correct about therapeutic approaches to metabolic diseases?
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
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
1 in 500
251
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?
genome wide association studies
252
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?
germline mosaicism
253
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
Yp: autosomal translocation
254
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?
genital abnormalities ranging from ambiguous to normal male may occur
255
Major flaws in case-control allelic association studies that frequently lead to false-positive “genetic
association” include all of the following EXCEPT
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
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?
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
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?
The degree of similarity in environmental factors among the two twins is the same for identical
and fraternal twins
258
Which characteristic of epigenetic phenomena is most important when considering a potential for
therapeutics?
they are erasable
259
Hydrops fetalis (4 alpha Hb gene deletions) is
incompatible with life
260
which is at greatest risk for being affected w/ pyloric stenosis
The son of a couple who already have a daughter with pyloric stenosis.
261
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?
both chromosomes came from mother
262
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?
x linked recessive
263
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?
triplet repeat expansion
264
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?
60%
265
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?
1/400
266
The elements of genetic counseling delivered by providers include all of the following EXCEPT
recommendation of specific reproductive options
267
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?
1/72
268
which is a cause of SC?
missense mutation in the coding region of beta globin gene
269
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?
tetramer of 4 gamma-subunits
270
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
deletion of a locus subject to imprinting from a paternal chromosome
271
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?
The retina would be hypo-pigmented, being approximately 50% pigmented as compared to the
normal eye.
272
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?
karyotype for the husband
273
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?
heterozygous advantage
274
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 PCR of exon 10 (contains the delta F508 mutation) followed by DNA sequencing
275
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?
1/3
276
Angelman syndrome can be caused by all of the following EXCEPT
partial deletion of paternal chromosome 15
277
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?
multifactorial inheritance
278
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?
acrocentric
279
which is most likely to be phenotypically normal?
person w/ karyotype 45 XX rob(21; 21)
280
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?
45 X
