Unit II Flashcards
(272 cards)
1
Q
What is important about meiotic prophase I?
A
Reciprocal recombination occurs here
2
Q
What are bivalents?
A
Maternal and paternal homologs of
each chromosome become paired or synapsed along their entire lengths, forming
structures known as “bivalents”.
3
Q
What is the synaptonemal complex?
A
a proteinaceous structure which promotes inter-homolog interactions.
4
Q
Define chiasmata
A
attachments or crossovers
5
Q
Which step of meiosis is most error prone?
A
Meiosis I during chromosome nondisjunction
6
Q
What is the proband?
A
The affected individual through whom a family with a genetic disorder is ascertained
7
Q
What is the consultand?
A
The individual (not necessarily affected) who presents for genetic evaluation and through whom a family with an inherited disorder comes to attention.
8
Q
Define consanguinity
A
identifies cases of genetic relatedness between individuals descended from at least one common ancestor.
9
Q
Define Phenotype
A
The observable expression (of a genotype) as a morphological, clinical, cellular, or biochemical trait
10
Q
Define Genotype
A
The set of alleles that make up his or her genetic constitution
11
Q
Mendelian Inheritance
A
disorders that are due to the predominant effects of a single mutant gene
12
Q
Mendel’s First Law
A
The Law of Segregation
13
Q
What is the law of segregation?
A
At meiosis, alleles separate from each other such that each gamete receives one copy from each allele pair
14
Q
What is Mendel’s Second Law?
A
That Law of Independent Assortment
15
Q
What is the Law of Independent Assortment?
A
At meiosis, the segregation of each PAIR of alleles is independent.
16
Q
Define Codominant
A
If both traits (alleles) are expressed in the heterozygous state
17
Q
Define Semi- Dominant or incomplete dominant
A
The heterozygous phenotype is intermediate between the two phenotype. A degree of both phenotypes combined.
18
Q
Define hemizygous?
A
A chromosome in a diploid organism is hemizygous when only one copy is present.
19
Q
Define Expressivity
A
The degree to which a trait is expressed in an individual (is a measure of
severity). Expressivity is analogous to a light dimmer (the light is ‘on’ but the brightness
(expressivity) exists along a spectrum (of severity)). The variation in phenotype is
explained (in part) by sex influence, environmental factors, stochastic effects, and
modifier genes.
20
Q
Sex Influence
A
Phenotypic expression in some conditions is
dependent on the individual’s sex (e.g. gout is more common in males than
premenopausal females)
21
Q
Sex limitation
A
occurs if only one sex can express a phenotype
e.g. unicornuate uterus
22
Q
Environmental factors
A
Some environmental factors can affect the expression of
Mendelian diseases. The disease may only manifest in individuals if particular
environmental factors are present.
Example: In acute intermittent porphyria, episodes of
abdominal pain and psychiatric illness are dependent on exposures (alcohol,
medications).
23
Q
Stochastic Effects
A
Stochastic (random) effects can influence the expression of
phenotypes. This concept pays homage to the fact that some phenotypes may be
influenced by chance events/processes absent any obvious genetic/environmental factor.
24
Q
Modifier genes
A
Genetic factors outside of the genetic locus causing a disease can be
important for the expression of Mendelian diseases.
25
Phenocopies
Diseases (traits) that are due to non-genetic factors.
Example: A thyroid
cancer due to radiation exposure cannot always be distinguished from a thyroid cancer
due to mutations in RET gene.
26
Pleiotropy
Used to describe multiple different phenotypic effects due to mutation(s) in a
single gene. Often used, when the phenotypes are seemingly unrelated and/or in
multiple different tissues.
Example: Neurofibromatosis Type I leads to: café au lait spots
(skin), neurofibromas (peripheral nervous tissue), hammartomas in the eyes (ocular),
abnormal freckling (skin again), and learning difficulties (central nervous system).
27
Penetrance
The fraction of individuals with a trait (disease) genotype who show
manifestations of the disease.
Penetrance is analogous to a light switch (can be ‘on’ or ‘off’).
28
How frequently is a SNP likely to occur between two individuals?
1 in every 1000 bp
29
Name a chromosome that is gene rich?
Chromosome 19
30
Name a chromosome that is gene poor?
Chromosome 13, 18, 21
31
Is most of the genome stable or unstable?
stable
32
Percentage of genome that is GC rich?
38%
33
Percentage of genome that is AT rich?
54%
34
What percent of genome is protein coding?
1.5%
35
What percent of the genome is represented by genes?
20-25%
36
percent of genome that is repeptitive dna?
40-50%
37
alpha satellite repeats
171 bp repeat unit near the centromere.
may be important to chromosome segregation in mitosis and meiosis.
38
Alu family
example of DISPERSED DNA repeats about 300 bp in length.
500,000 copies in the genome
retrotransposition can cause insertional inactivation of genes via non-allelic homologous recombination
39
L1 family
An example of DISPERSED DNA repeats about 6 kb in length
100,000 copies in the genome
can lead to disease via non-allelic homologous recombination
40
Microsatellites
2-4 bp nucleotide repeats
5x10^4 per genome
aka short tandem repeat polymorphism
Useful in DNA fingerprinting
41
Minisatellites
tandem repeats about 10-100 bp
aka variable nucleotide tandem repeats.
useful in DNA fingerprinting
42
Gene Families
Gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions
43
Copy number variation
primary type of structural variation
may cover 12% of genome
involved in rapid & recent evolutionary changes
Link between evolutionary adaptive copy number increasing and increase in human disease. EX: 1q21
44
When does the synaptonemal complex disassemble?
At the end of prophase I
45
Define metacentric
the centromere is located in the middle of the chromosome,
| such that the two chromosome arms are approximately equal in length.
46
Submetacentric
the centromere is slightly removed from the center
47
Acrocentric
the centromere is near one end of the chromosome
48
heterochromatic regions are right with what nucleotides?
AT
49
Euchromatin is __ rich?
GC
50
G banding uses what type of dye?
Giemsa
51
G banding stains what structures?
heterochromatic/ AT regions which are typically gene poor
52
Aneuploidy
the condition in which cells contain an abnormal chromosome number
53
Monosomy
the condition in which a cell lacks one copy of a chromosome
54
trisomy
the situation in which an extra copy of an entire chromosome is
present in the cell.
55
Most common cause of down syndrome?
nondisjunction during maternal meiosis I
56
Tolerated Aneuploidy conceptions?
45 X, trisomy 16, 21, and 22
57
Tolerated Live Birth Aneuploidy
Trisomy 13, 18 or 21
Gain of X and Y chromosome
Loss of X or Y chromosome
58
List the characteristics of Down Syndrom
Trisomy 21
```
Short stature
Hypotonia
Moderate intellectual disability
Cardiac anomalies / congenital heart defect
leukemia in infancy
early onset Alzheimers
hearing loss
```
59
Trisomy 18
```
Edwards syndrom
small for gestational age
small head
clenched fingers
rocker bottom feet
```
60
Most common chromosomal abnormality in spontaneous abortions?
Turner Syndrome (loss of X chromosome)
61
Phenotype of Turner Syndrome
(loss of x chromosome)
```
short stature
webbed neck
edema of hands and feet
broad shield like neck
gonadal dysgenesis
renal and cardiovascular anomalies
```
62
Klienfelter syndrome
male with extra X chromsome
XXY
63
Mosaicism
Mosaicism is defined as the presence of at least two genetically different cells in a
tissue that is derived from a single zygote.
EX: mosaicism turner syndrome has a chromosomal change in only SOME of their cells. Some cells have 46 chromosomes and others have 45
64
Trisomy 13
```
Patau Syndrome
Most clinically severe of the 3
CNS abnormalities
Omphalocele (herniation of GI organs outside abdomen)
Renal dysplasia
Congenital heart disease
```
65
Describe a paracentric inversions
inversion that occurs outside of the centromere. During meiosis, an inversion loop is required for the associated regions to align. If a crossover occurs WITHIN the loop, you end up with a chromosome that has two centromeres (dicentric) and one WITHOUT a centromere (acentric)
= infertility
66
Describe a pericentric inversion
inversion that occurs within the centromere. During meiosis, an inversion loop is required for the associated regions to align. If cross over occurs WITHIN the loop, you end up with a chromosome that is unbalanced with both having some duplications and some deletions.
67
What is a Reciprocal Translocation?
results from the breakage and rejoining of non-homologous
chromosomes, with a reciprocal exchange of the broken segments.
creates quadrivalent so all four chromosomes can align
68
What is a Robertsonian Translocation?
the fusion of two acrocentric chromosomes within their
| centromeric regions, resulting in the loss of both short arms (containing rDNA repeats).
69
What type of rearrangement is a Robertsonian translocation?
A BALANCED ONE.
It does result in a reduction of chromosome however the loss of ribosomal DNA is not considered deleterious
70
What is the outcome of a Robertsonian translocation
The carrier is phenotypically normal however the rearrangement may lead to unbalanced karyotypes in their offspring. Can lead to monosomies or trisomies in their offspring
71
What is an unbalanced rearrangment?
The chromosome set has additional or missing material
72
What are some of the outcomes of unbalanced rearrangement?
Duplication of genetic material can lead to partial trisomies.
Deletions of genetic material can lead to monosomies.
Phenotypically ABNORMAL
73
What are the two most common chromosomes involved in Robertsonian translocation?
Chromosomes 13 and 14.
Can occur in chromosome 21
74
Which chromosomes are acrocentric?
13, 14, 15, 21, and 22
75
Which acrocentric chromosomes are most commonly fused together?
13 and 14
14 and 21
76
What are the benign pericentric inversions?
9 qh, 16 qh, 1 qh, and Yqh
These are within the heterochromatic region
Does NOT result in spontaneous abortions, infertility, or recombinant offspring
77
What is the risk of a balanced translocation carrier having an unbalanced progeny?
0-30%
maternal carriers are morel likely to have a progeny with a phenotype
78
Incidence of Inversion structural rearrangements?
1%
79
What percentage of meiotic recombinations for inversion carriers lead to a normal progeny or balanced progeny?
50%
80
Numerical abnormalities vs. structural abnormalities?
Numerical abnormalities are more common than structural abnormalities
81
Define Epigenetic
Mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence
EX: post-translational modifications of histones and DNA methylation.
82
Name a couple of proteins that recognize methylated DNA and play a role in gene silencing
HDAC
| MeCP2
83
Where does methylation of DNA take place?
CpG islands
84
What is the function of DNA methylation?
Usually gene silencer BUT in some cases acts as a gene activator!
85
What is genetic imprinting?
Sex-Dependent epigenetic modulation of regulatory regions such as promoter sequences
86
What percent of the human genome is imprinted?
Less than 10%
87
What enzyme is responsible for the propagation of methylated marks?
Maintenance methyltransferase
88
Describe Epigenetic Reprogramming
In primordial germ cells demethylation occurs. If you produce oocytes, the specific corresponding region is methylated. If you produce sperm, then the male corresponding region is methylated.
Somehow the cell KNOWS. So that you pass on the correct methylation pattern to your progeny.
89
What causes Prader Willi Syndrome?
Deletion of paternal 15q 11- 13
90
What percentage of Prader Willi Syndrome is due to deletion of paternal chromsome 15?
70%
91
What percentage of PWS is caused by maternal uniparental disomy?
28%
92
Percent of PWS caused by imprinting centre mutation on paternal allele?
93
What is the major cause of Angelman Syndrome?
Deletion of maternal chromosome 15 q 11- 13
94
What percent of Angel Syndrome is caused by deletion of maternal chromosome 15?
70%
95
What percent of AS is caused by paternal uniparental disomy?
4%
96
What percent of AS is caused by imprinting center mutation on maternal allele?
8%
97
What percet of AS is caused by mutation of UBE3A on maternal allele?
8%
98
Which cells undergo universal demethylations?
Primordial cells
99
What is the outcome of maternal uniparental disomy of chromosome 15?
Prader Willi Syndrome
100
What is the outcome of paternal uniparental disomy of chromsome 15?
Angelman syndrome
101
What leads to the deletion of PWS And AS genes?
misalignment and homologous recombination
102
Significance of gene HERC2
generates repeats that flank the 15q 11 -13 region on chromosome 15
103
Prader-Willi Syndromes
short stature
excessive eating
hypogonadism
some degree of intellectual disability
104
Angelman Syndrome
Severe intellectual disability
Spasticity
Seizures
Short stature
105
Cancer Cytogenetics is important for what two diseases?
Leukemia and lymphomas
106
What test is used for the diagnosis of children with developmental delays?
Chromosomal Microarray (CMA) AKA Array CGH
107
What two tests do you use to investigate leukemia and lymphoma?
Chromosome analysis and FISH
108
Name the specimens used in cancer diagnostics
```
Bone Marrow
Unstimulated Blood
Lymph node tissue
Solid tumor tissue
Cerebrospinal fluid
```
109
What are the uses of FISH?
INITIAL differential diagnosis
| monitor treatments or disease progression
110
Auer Rod
Suggests Myelogenous Leukemia
111
What are some of the key differences of MicroArray vs. regular Cytogenetics techniques?
Chromosomal Microarray detects gains and losses ONLY
It uses interphase DNA instead of mitotic cells
Analyzes ALL CELLS
Technology Dependent
Detects runs of homozygosity
112
What is the threshold for CMA detecting runs of homozygosit
can evaluate greater than or equal to 5 Mb with a 10 Mb threshold
113
Limitation of CMA
Cannot detect very low level mosaicism, heterodisomy, or balanced chromosome rearrangement
114
Protocol for child with developmental delays
1. If deletion or duplication is detected by CMA consult Database of Genomic Variance
2. Parental FISH studies will be offered to determine if this finding is a rare,
normal, familial variant.
4. If a deletion or duplication is found in one or both parents, other family
members may be tested by FISH. Often extensive consultation between
the clinical geneticist, genetic counselors and cytogeneticist are required.
5. If the deletion or duplication is not found in either parent, and it is not found in
the genomic variants Database, further data-base mining, literature
searches are performed. Often a gene or genes mapped in the region of
deletion or duplication reveals a syndromic association.
115
Pharmacogenetics
Variable response due to individual genes
116
Pharmacogenomics
Variable response due to multiple loci across the genome
117
Pharmacokinetics
the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites
"What the body does to the drug"
118
Pharmacodynamics
The differences in the way the body responds to the drug.
"What the drug does to the body"
119
Phase I drug metabolism
the introduction of a more polar group to a compound that allows a side group to be more readily attached
The hydroxyl group attached in phase I
provides a site for a sugar or acetyl group to be attached to the drug to detoxify it and make it much easier to excrete in what is referred to as phase II of drug metabolism
120
Mutation that causes cytochrome P450 to have no activity
splicing or frameshift mutations
121
Mutation that causes REDUCED activity in cytochrome P450
missense mutation
122
Where are are the gene products of CYP450 most active?
Mostly in the liver.
Also, intestinal epithelium
123
What are the three main families of the CYP450 gene?
CYP1, CYP2, CYP3
124
Significance of CYP3A4
takes part in metabolism of 40% of all drugs
125
Drugs that CYP3A metabolizes
Felodipine (CA channel blocker that can be used for hypertension) and Cyclosporine (immunosuppressant)
126
CYP3A inhibitors
grapefruit juice and ketoconazole (an antifungal agent)
need to reduce drug dosage so that patient does not suffer from drug toxicity
127
CYP3A inducers
rifampicin.
Need to increase drug dosage
128
important difference of CYP2D6 gene?
It ACTIVATES codeine into morphine
129
Drugs that the NAT gene metabolizes?
Isonizad for tuberculosis
130
Drug that the TMPT gene metabolizes?
6-mercaptopurine and 6-thioguanine
131
clinical relevance of the TMPT gene?
6-mercaptopurine is a drug used to treat ALL but in .5% of children the TPMT activity is so low (due to a mutation) that drug toxicity can occur and the child will die. Only 10% of standard drug dose is needed for these children.
TPMT is an enzyme transcribed from the TMPT gene and detoxifies the 6-mercaptopurine drug.
132
What drugs does the VKORC gene metabolize/
Warfarin which is a blood thinner that is always started at 5 mg/day and then adjusted from there
133
Define Heritability of a trait
The proportion of total variance in a trait the at is due to variation in genes
134
Heterogeneity in Cystic Fibrosis
Different alleles at same location can cause CF
135
Heterogeneity in Alzheimers
Alleles at different location or Loci can cause AD
136
Example of diesease that demonstrate multifactorial inheritance
```
Some cancers
diabetes I and II
Alzheimers
Inflammatory bowel disease
Asthma
Schizophrenia
Hypertension
Cleft lip / palate
Rheumatoid arthritis
```
137
Odds ratio
Risk of disease if carrying a given gene variant/ risk of disease if not carrying a given gene variant
138
How do we find diseases today?
Start with disease --> MAP genome --> find gene --> figure out its functio
139
Linkage Diequilibrium tends to occur within..
haplotype blocks because they are so close together that recombination does not typically occur
140
Candidate Gene DNA sequencing
Hypothesis driven
"I think this disease is caused by this gene"
Leads to FALSE POSITIVES 97% of the time
141
What are the two fatal flaws in Gene-by-Gene Case control design?
Stratification - no such thing as a homozygous population
Publication bias - the only studies that get published are the ones with positive confirming results
142
Describe what a Genetic Linkage Study is
Using patterns of inheritance to guess whats going on in a rare disorder
143
When should you use Genetic Linkage Study?
For UNCOMMON Mendelian traits
144
Define CentiMorgan
unit of genetic distance/recombination
145
LOD
"Log of Odds"
statistical measure of likelihood that loci are linked together given the inheritance/disease pattern
146
Level of LOD that confirms loci are linked?
>3
147
Name the hypothesis-free approach to finding a disease,
Genetic Linkage
| Genome-Wide Association Study
148
Describe Genome Wide Association Study (GWAS)
Tests ALL parts of the genome simultaneously between individuals for patterns of SNPs associated with diseases
149
Pros of GWAS
can accurately measure and correct for population stratification
You know the number of tests performed genome-wide (don't care about other studies)
150
When is GWAS most useful?
For COMMON alleles with small to moderate effect size
Can discover NEW genes as well
151
Benefits of Exome/Genome Sequencing
You sequence the coding region oof the genome and can combine result with other affected family members to narrow down the cause of disease.
Will eventually be replaced BY GENOME SEQUENCING
152
Cons of Exon/Genome Sequencing
Data interpretation can be difficult due to Variant of Unkown Significance.
Creates a lot of "noise"
153
What are the most commonly used types of DNA polymorphisms for finding genes?
1. Microsatellites
2. Single-Nucleotide-Polymorphisms (SNPs)
3. Copy-Number-Variants (CNVs)
154
What is allelic heterogeneity?
The existance of multiple mutant alleles of a single gene
155
Define compound heterozygote?
One who carries two different mutant alleles of the same gene
156
Phenylketonuria phenotypes
```
High phenylalanine level in the blood
hyperactivity
epilepsy
mental disability
microcephaly
```
157
What type of disorder is Phenylketonuria?
Autosomal Recessive
158
Biochemical cause of Phenylketonuria?
mutation in PAH that encodes phenylalanine hydroxylase (PAH) in 98% of case.
PAH converts phenylalanine to tyrosine
159
Biochemical cause of Phenylketonuria in 1-2% of cases
Defects in the PAH cofactor BH4 that disrupts production of tyrosine, dopamine, and serotonin
160
Where is the PAH gene located?
12q22-24
161
What type of heterozygote are PKU patients?
compound heterozygotes
162
How to manage PKU in patients?
Low phenylalanine diet.
Phenylalanine is an essential amino acid so you need some
163
Describe maternal PKU
Not dictated by the child's gene. Mom who is not on a restricted diet will lead to an increase in F in the maternal circulation leading to MISCARRIAGE and DEVELOPMENTAL ABNORMALITIES
164
Timing for newborn PKU screening
newborn won't have elevated F because mom's enzyme was working. Need to wait a couple days after birth to compare.
165
How to test of newborn PKU?
Mass spectroscopy
166
Guthrie test
The old way to test for PKU.
thienalalnin inhibits growth of bacteria. This can be inhibited by high level of phenylalanine causing bacteria to grow = + test
167
Clinical features of alpha 1-antitrypsin deficiency (ATD)
emphysema (shortness of breath)
increased risk for liver cirrhosis
LATE ONSET
168
Population most affected by ATD?
Northern Europeans
169
Biochemical defect in ATD?
Deficiency in protease inhibitor alpha1-antitrypsin (SERPINA1, AAT) which inhibits elastase
170
Function of elastase
breaks down elastin in CT
171
Function of Z allele in ATD
Glu342Lys and the Z allele protein is not folded properly and accumulates in liver cells leading to liver damage
ZZ genotype = 15% normal alpha1-antitrypsin function
172
Function of S alleles in ATD
Glu264Val makes unstable SERPINA1 protein
| 50-60% of normal SERPINA1 level
173
What environmental factor aggravates ATD?
smoking
174
Treatment for ATD
intravenous infusion and aerosol inhalation of SERPINA1
175
Tay-Sachs Disease Phenotype
progressive destruction of the central nervous system
neurological deterioration 3-6 months
Die by 2-4 years
176
First signs of Tay-Sachs Disease?
muscle weakness and startle response at sudden sound
177
Who is at most risk for Tay-Sachs disease?
Ashkenazi Jews
178
Biochemical defect in Tay-Sachs disease?
Inability to degrade GM2 ganglioside which leads to a build up within lysosomes in neurons found in the CNS
Defective Hexoaminidase A enzyme
179
What gene causes Tay-Sachs?
HEXA
180
What mutation causes Sanhoff Disease?
HEXB gene and affects HexA and HexB enzyme activity
181
AB variant Tay Sachs disease
rare form that does not affect Hex A or Hex B activity. Instead mutation on the GM2 activator protein which leads to build up of GM2 ganglioside
182
What is Turner's Syndrome?
Sex chromosome disorder. Women missing an X chromosome 45X
183
Turner Syndrom CVS abnormalities
aortic coarctation
bicuspid aortic valve
systemic hypertension
conduction difficulties
184
Turner Syndrome Abnormalities of the eye
inner epicanthal folds
ptosis (drooping of the eye)
Blue Sclera
185
Turner syndrome abnormalities of Skeletal System
Short 4th metacarpal
| short stature
186
Turner syndrome abnormalities of the Neck
Web neck
low hairline
cystic hygroma
187
Turner syndrome learning abnormalities
difficulty in math
visual spatial skills
low non-verbal skills
188
Turner syndrome abnormalities of chest
widely spaced nipples
189
Trisomy 21
95% of patients with Down Syndrome
| due to nondisjunction in maternal meiosis I
190
Unbalanced Translocation Trisomy 21
3-4% of patients with Down Syndrome
| Due to a Robertsonian Translocation leading to the fusion of chromosome 21 and 14
191
Mosaic Trisomy 21
1-2% of patients with Down syndrome
mixture of normal and abnormal cells
milder symptoms
192
DS phenotypes
```
upslanting palpebral fissure
epicanthal folds
midfacial hypoplasia
small ears
large appearing tongue
low muscle tone
```
193
CVS problems with DS
```
congenital heart disease
atrioventricular canal (hole between all four heart chambers)
```
194
GI problems with DS
esophageal atresia - leads to blind pouch rather than stomach
195
What is the significance of polyhydramnios
Child is unable to swallow amniotic fluid
196
What chromosome defect causes Prader-Willi?
15q11-13
197
Chorionic villus sampling
a prenatal test that is used to detect birth defects, genetic diseases, and other problems during pregnancy. Sample taken from the placenta where it attaches to the wall of the uterus.
198
What test is used to test DS?
FISH
199
What test is used to test for Prader Willi?
FISH or microarray
| II. Methylation testing
200
Physical features Prader Willi?
hypotonia
undescended testes
lighter pigmentation
feeding issues
201
Toddler Prader Willi features?
Increase appetite
| persistant hunger
202
Eye medical problems with Prader Willi
strabismus - lazy eye
| nystagmus - jiggly eye
203
Developmental abnormalities Prader Willi
mild-moderate developmental delays
| behavioral issues
204
What chromosomal abnormalities are linked to autism?
IDIC 15
| Maternally inherited interstitial duplication
205
What is the Cause of Kleinfelter Disease?
47 XXY
206
Kleinfelter behavioral childhood presentation
childhood- learning disability
delayed speech and language
tendency to be quiet
207
Kleinfelter phenotype
```
tall stature
small testes
reduced facial hair
infertility
hypospadia - urethra is underside of penis
gynecomastia - enlarged breasts in males
```
208
What is the genomic abnormality Jacobs Syndrome
47 XYY
209
Signs of Jacob's disease
```
learning disabilities
speech delays
developmental delays
behavioral and emotional difficulties
autism spectrum
tall stature
```
210
Signs of Triple X syndrome
```
learning disabilities
delayed speech
delayed motor
seizure
kidney abnormalities
```
211
5 alpha reductase deficiency
can't convert testosterone to dihydrotestosterone
under virilized male then increased during puberty
212
Gene involved in Digeorge Syndrome?
22q11.2
213
Presentation of Digeorge Syndrome?
Cleft lip / palate
congenital heart disoders
Thymus defect
parathyroid defect
214
What percentage of babies with Down syndrome also have congenital heart defects?
40-50%
215
If a pregnant 40-year-old woman presents to your office at 16 weeks of gestation, what standard test are you likely to perform to rule out Down syndrome?
amniocentesis and FISH
216
What is the Karyotype for Patau syndrome?
Trisomy 13
217
How are imprinting patterns maintained in offspring?
Maintenance methylation
218
Prader-Willi and Angelman's syndromes result from genetic aberrations to the same region of chromosome 15. Which of the following correctly explains why the resulting phenotypes differ from each other?
Phenotype depends on whether the mutation is maternal or paternal in origin.
Their effects are dependent on sex-specific methylation patterns that silence the only good copy of a gene.
219
essential characteristic for normal epigenetic marking to be successful?
1. Modification must be established in gametes
2. Must be stably maintained after fertilization
3. Must be reversible so appropriate sex-specific imprint is passed on
220
What is the purpose of a whole chromosome paint using FISH?
identification of markers and translocations
221
What is the recurrence risk for DS?
1/100 (1%) plus maternal age risk
222
Single Palmer crease and wide space between 1st and 2nd toe are phenotypes of what disease?
Down Syndrome
223
Define Pseudogene
They are non-functional genes that can be synthesized through reverse transcription
224
What is the karyotype for Edward's syndrome?
Trisomy 18
225
What are the phenotypes associated with Edward's syndrome?
```
small for gestational age
microcephaly
clenched hands/overlapping fingers
Rocker bottom feet
Heart/brain abnormalities
90% perinatal lethality
```
226
What are the phenotypes associated with Patau syndrome?
```
Characteristic facies
severe intellectual disabilities
Congenital malformations (fusion of brain lobes, facial clefts, polydactyly, renal defects)
```
227
Describe the alpha cluster in the alpha globin gene
zeta - alpha 2 - alpha 1 on CHROMOSOME 16
228
Describe the beta cluster
epsilon - gammaG - gammaA - delta - beta on CHROMOSOME 11
229
HBA
Majority of hemoglobin made up of alpha2 and beta2
230
Hb Gower I
zeta2 and epsilon2
231
Hb Gower 2
alpha 2 and epsilon2
232
Hb Portland
zeta2 gamma 2
233
Globin Switching part I
turn off zeta and epsilon, turn on alpha and gamma during early embryogenesis
234
Globin Switching part II
turn off gamma and turn on delta and beta at time of birth
235
HBF
Fetal Hemoglobin alpha2-gamma2
Has higher affinity for O2 at low pO2 than HbA
236
Hispanic Thalassemia
Caused by the deletion of the Locus Control Region (LCR) on the beta like cluster
237
Example of Qualitative Hemoglobinpathies
Hb^Kemsey (binds oxygen too tight)
| Hb^Kansas (bind too weak)
238
HBSS
mutation glutamate --> valine at codon 6
Hemoglobin is now 80% less soluble when not bound to O1 and polymerizes into long fibers
239
HbCC
Milder form of hemolytic anemia
mutation glutamate --> lysine at codon #6
forms crystals
240
Sickle Cell trait
HbS trait
heterozygous HbS/HbA
clinically normal except when under severe low pO2
241
Restriction enzyme used to distinguish sickle cell from wild type?
MstII
cannot distinguish Hemoglobin C disease!
242
Hb Kempsey leads to
Over production of blood cells - Polycythemia
243
Hb Kansas
Cyanosis
244
alpha thalassemia
caused by deletion of one or both copies of the alpha-globin gene in the alpha cluster.
gamma and beta globin now in excess
245
alpha thalassemeias most common in Southeast asia
Hydrops Fetalis - - / - - ton of gamma 4
HbH disease a - / - - beta 4
mild anemia aa / - - alpha thalassemia - 1 trait
246
alpha thalassemias most common in Africa, Mediterranean, and Asia
mild anemia a - / a - alpha thalassemia - 2 trait
247
alpha thalassemeias most common in Southeast asia
Hydrops Fetalis - - / - - ton of gamma 4
HbH disease a - / - - beta 4
mild anemia aa / - - alpha thalassemia - 1 trait
248
alpha thalassemias most common in Africa, Mediterranean, and Asia
mild anemia a - / a - alpha thalassemia - 2 trait
249
As an adult how much HbA2 do you have?
250
What gene is mutated in Achondroplasia?
Fibroblast Growth Factor Receptor 3
| FGFR3
251
Molecular basis of Achondroplasia?
Chromosome 4p16.3 nucleotide 1138
missense mutation Gly380Arg
Mutation increases the activity of the protein interfering with skeletal development
252
Mutation rate for Achondroplasia?
80%
253
Gonadal/germline mosaicism
The likely explanation of the rare situations where a person without a dominant condition can have two children with the same autosomal dominant condition
254
What is Retinoblastoma?
Malignant tumor of the retina
255
What is Neurofibromatosis Type 1
Mutation in the NF1 gene in Chromosome 17q11.2
Loss of function of a tumor suppressor gene NF1
256
Neurofibromatosis phenotype?
6 or more café-au-lait spots
2 or more neurofibromas
1 plexiform neurofibroma
2 or more Lisch Nodules
257
What is Neurofibromatosis Type 1
Mutation in the NF1 gene in Chromosome 17q11.2
Loss of function of a tumor suppressor gene NF1
258
Neurofibromatosis mutation rate?
50%
259
Osteogenesis Imperfecta Type 1 clinical manifestation
Multiple fractures
Mild short stature
Adult onset hearing loss
Blue sclera
260
Mutation that causes Osteogenesis Imperfecta Type 1
Collagen type 1 alpha 1 COL1A1 on Chromosome 7q21.3
Reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half
261
What is Marfan's Disease?
Systemic disorder of connective tissue, musculoskeletal and cardiovascular problems.
Aortic Root enlargement seen!
262
Things to look for to diagnose Marfan's Disease?
Thumb and wrist sign
scoliosis
ectopia lentis
pectus excavatum
263
What is the mutation involved in Marfan's Disease?
Fibrillin gene FBN1 on Chromosome 15q21.1
264
What causes Huntington's disease?
CAG repeats >39
265
Clinical manifestations of Huntington's Disease
Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances
Age of onset 35-44
Death approximately 15 years after onset
266
Clinical manifestations of Huntington's Disease
Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances
Age of onset 35-44
Death approximately 15 years after onset
267
What causes early Huntingtons onset?
Paternal transmission
268
Clinical manifestations of Myotonic Dystrophy Type 1
```
Adult onset muscular dystrophy
Progressive muscle wasting and weakness
Myotonia
Cataracts
Cardiac conduction defects
```
269
What causes Myotonic Dystrophy Type 1?
CTG repeat >50
| Myotonic dystrophy protein kinase (DMPK) gene on Chromosome 19q13.3
270
How is Myotonic Dystrophy Type 1 transmitted?
Maternally!
271
What type of inheritance do metabolic diseases have?
Typically autosomal recessive
ex: PKU and Gaucher's disease
272
Important use of DNA sequencing?
Ideal for looking at the sequence of a known disease gene
Can detect NOVEL mutations
