MCQ 3 Flashcards
1
Q
What causes Deletion Syndromes?
A
- usually an error in crossover in meiosis
- unbalanced exchange of genes
- one chromosome with duplication; other with deletion
2
Q
What type of chrome disorder presents with Turner Syndrome?
A
Sex chromosome aneuploidy disorder. Patient has an abnormal number of sex chromosomes
3
Q
Describe pt population of Turner syndrome?
A
Female with missing X chromosome (XO)
4
Q
How is Turner Syndrome diagnosed?
A
Karyotype Test
5
Q
What causes Turner Syndrome?
A
Caused by sperm lacking X chromosome
6
Q
Describe mosaic Turner syndrome
A
- Often milder
- some cells have 45 X, but other cells have 46 XX
7
Q
What causes mosaic Turner Syndrome?
A
Mitotic nondisjunction during post-zygotic cell division
8
Q
20% of pts w/ Miller-Dieker Syndrome inherit the _______ from a parent who carries__________
A
deletion / a balanced chromosomal rearrangement
9
Q
Describe the etiology of Miller-Dieker Syndrome
A
contiguous gene deletion syndrome caused by heterozygous deletion of 17p13.3
10
Q
mechanism responsible for microdeletions
A
recombination at segmental duplication
11
Q
normal couple has recurrent spontaneous miscarriages. what is the most common cause? What testing will confirm?
A
balanced translocation / standard karyotyping
12
Q
What is the most likely cause of partial deletion and partial duplication involving the same chromosome?
A
parental chromosomal abnormalities most likely caused pericentric inversion
13
Q
Where does the Robertsonian translocation usually occur?
A
between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosome 14 or 22)
14
Q
-Onset at neonatal to adulthood
-Progressive pulmonary disease
-Exocrine pancreatic insufficiency
-Obstructive azoospermia
-Elevated sweat chloride
concentration
-Growth failure
-Meconium ileus
A
Cystic Fibrosis
15
Q
Mutation of cystic fibrosis?
A
CFTR Mutation
16
Q
Sickle cell disease pathogenesis
A
-Hemoglobin is composed of four subunits, two α subunits encoded by HBA on chromosome 16 and two β subunits encoded by the HBB gene on chromosome 11 -The Glu6val mutation in β-globin decreases the solubility of deoxygenated hemoglobin and causes it to form a gelatinous network of stiff fibrous polymers that distort the red blood cell, giving it a sickle shape Glutamate to valine mutation causing sickled RBCs
17
Q
Sickle cell disease phenotype
A
- Onset at childhood
- Anemia
- Infarction
- Asplenia
18
Q
Sickle Cell
Disease inheritance
A
autosomal recessive
19
Q
Beta-globin
Glu6Val
Mutation
A
Sickle Cell
Disease
20
Q
Turner syndrome pathogenesis
A
Without a second X chromosome, oocytes in fetuses and neonates with TS degenerate, and their ovaries atrophy into streaks of fibrous tissue. Oocytes can develop but cannot be maintained
21
Q
Turner
Syndrome phenotype
A
- Prenatal onset
- Short stature
- Ovarian dysgenesis
- Sexual immaturity
22
Q
Female
Monosomy X
A
Turner
Syndrome
23
Q
Sex
Development
Disorder (46,
XX Male) pathogenesis
A
-SRY is a DNA-binding protein that alters chromatin structure by bending DNA altering gene expression -SRY is necessary for the formation of male genitalia and the absence forms female genitalia SRY in females causing male genitalia
24
Q
Sex
Development
Disorder (46,
XX Male) phenotype
A
-Prenatal onset
-Sterility
-Reduced secondary sexual features
-Unambiguous genitalia mismatched
to chromosomal sex
25
Sex
Development
Disorder (46,
XX Male)
y-linked or chromosomal
26
SRY
| Translocation
Sex
Development
Disorder (46,
XX Male)
27
Absence of
paternally derived
15q11-
q13
Prader-Willi
| Syndrome
28
Prader-Willi
| Syndrome inheritance
Chromosomal deletion, uniparental
| disomy
29
Prader-Willi
| Syndrome phenotype
- Onset at infancy
- Infantile feeding difficulties
- Childhood hyperphagia and obesity
- Hypotonia
- Cognitive impairment
- Short stature
- Dysmorphism
30
Prader-Willi
| Syndrome pathology
```
-Deletion of 15q11-q13 during
male meiosis gives rise to children
with PWS because children formed
from a sperm carrying the deletion
will be missing genes that are active
only on the paternally derived
15q11-q13.
-The mechanism underlying this
recurrent deletion is illegitimate
recombination between low-copy
repeat sequences flanking the
```
31
Miller-Dieker
| Syndrome pathology
```
More than 50 genes have been
mapped within the MDS deletion
region in 17p13.3, but only the
LIS1 gene (MIM 601545) has
been associated with a specific
phenotypic feature of MDS;
heterozygosity for a LIS1
mutation causes lissencephaly
MDS deletion and LIS1 mutation
```
32
Miller-Dieker
| Syndrome phenotype
- Prenatal onset
- Lissencephaly type 1 or type 2
- Facial dysmorphism
- Severe global intellectual disability
- Seizures
- Early death
33
17p13.3
Heterozygous
Deletion
Miller-Dieker
| Syndrome
34
autism pathology
```
-16p11.2 microdeletion is one of
many microdeletion/
microduplications that recur due to
low-copy repeat sequences (LCRs)
with high sequence homology
flanking the deleted or duplicated
DNA
Microdeletions causing
developmental/intellectual
disability
```
35
Autism phenotype
```
-Onset at birth or first 6 months of
life
-Intellectual disability to normal
intelligence
-Impaired social and communication
skills or frank autism spectrum
disorder
-Minor dysmorphic features
```
36
Autism inheritance
autosomal dominant or de novo
37
16p11.2
Deletion
Syndrome
Autism
38
Xeroderma
| Pigmentosum pathogenesis
```
-Caused by mutations affecting the global
genome repair subpathway of nucleotide
excision repair or by mutations affecting postreplication
repair
-Loss of caretaker function required for
maintenance of genome integrity causing
oncogenic mutations
Cancer risk from error with nucleotide
excision repair
```
39
Xeroderma
| Pigmentosum phenotype
- Onset at childhood
- UV light sensitivity
- Skin cancer
- Neurological dysfunction
40
Xeroderma
| Pigmentosum Inheritance
autosomal recessive
41
Xeroderma
| Pigmentosum phenotype
- Onset at childhood
- UV light sensitivity
- Skin cancer
- Neurological dysfunction
42
Defect of
Nucleotide
Excision Repair
Xeroderma
| Pigmentosum
43
Thrombophilia pathogenesis
-The coagulation system maintains a delicate
balance of clot formation and inhibition;
however, venous thrombi arise if coagulation
overwhelms the anticoagulant and fibrinolytic
systems
-Impaired Factor V function to accelerate the
conversion of prothrombin to thrombin
-PROC mutation impairing Protein C function
(inactivates Factor V)
Coagulation impaired by errors with
Factor V and PROC function with Protein
C
44
Thrombophilia phenotype
- Onset at adulthood
| - Deep venous thrombosis
45
Thrombophilia inheritance
autosomal dominant
46
FV and PROC
| Mutations
Thrombophilia
47
Retinoblastoma pathogenesis
-The retinoblastoma protein (Rb) is a tumor
suppressor that plays an important role in regulating the progression of proliferating
cells through the cell cycle and the exit of
differentiating cells from the cell cycle.
-Retinoblastoma-associated RB1 mutations
occur throughout the coding region and
promoter of the gene
Issue with tumor repressor
48
Retinoblastoma phenotype
- Onset at childhood
- Leukocoria
- Strabismus
- Visual deterioration
- Conjunctivitis
49
Retinoblastoma inheritance
autosomal dominant
50
RB1 Mutation
Retinoblastoma
51
Neurofibromatosis 1 pathogenesis
-NF1 is a large gene (350 kb and 60 exons)
that encodes neurofibromin, a protein widely
expressed in almost all tissues but most
abundantly in the brain, spinal cord, and
peripheral nervous system.
-The clinical manifestations result from a
loss of function of the gene product; 80% of
the mutations cause protein truncation.
Issue with neurofibromin
52
Neurofibromatosis 1 phenotype
- Prenatal onset to late childhood
- Cafe au lait spots
- Axillary and inguinal freckling
- Cutaneous neurofibromas
- Lisch nodules
- Plexiform neurofibromas
- Optic glioma
- Specific osseous lesions
53
Neurofibromatosis 1 inheritance
autosomal dominant
54
NF1 Mutation
Neurofibromatosis 1
55
Myoclonic Epilepsy
with Ragged-Red
Fibers pathogenesis
- In MERRF, the activities of complexes I
and IV are usually most severely reduced.
-The tRNAs mutations associated with
MERRF reduce the amount of charged tRNA
lys in the mitochondria by 50% to 60% and
thereby decrease the efficiency of translation
so that at each lysine codon, there is a 26%
chance of termination.
-Because complexes I and IV have the most
components synthesized within the
mitochondria, they are most severely
affected.
Issue with translation at lysine codon
56
Myoclonic Epilepsy
with Ragged-Red
Fibers phenotype
```
-Onset at childhood through
adulthood
-Myopathy
-Dementia
-Myoclonic seizures
-Ataxia
-Deafness
```
57
Myoclonic Epilepsy
with Ragged-Red
Fibers inheritance
matrilineal, mitochondrial
58
Mitochondrial
tRNA lys
Mutation
Myoclonic Epilepsy
with Ragged-Red
Fibers
59
Marfan Syndrome pathogenesis
-FBN1 encodes fibrillin 1, an extracellular
matrix glycoprotein with wide distribution. -
Fibrillin 1 polymerizes to form microfibrils in
both elastic and nonelastic tissues, such as the
aortic adventitia, ciliary zonules, and skin.
-Mutations affect fibrillin 1 synthesis,
processing, secretion, polymerization, or
stability
Problem with fibrillin
60
Marfan Syndrome phenotype
- Onset at early childhood
- Disproportionately tall stature
- Skeletal anomalies
- Ectopia lentis
- Mitral valve prolapse
- Aortic dilatation and rupture
- Spontaneous pneumothorax
- Lumbosacral dural ectasia
61
Marfan Syndrome inheritance
autosomal dominant
62
FBN1 Mutation
Marfan Syndrome
63
MCAD Deficiency pathogenesis
```
-MCAD deficiency is caused by homozygous
or compound heterozygous mutations in
ACADM. The point mutation c.985A>G,
which causes an amino acid change from
lysine to glutamate at residue 304
(Lys304Glu) of the mature MCAD protein, is
found in approximately 70% of mutant alleles
of clinically ascertained patients, but
neonatal screening shows over 90 different
loss-of-function mutations to date.
Change from lysine to glutamate in MCAD
protein
```
64
MCAD Deficiency phenotype
- Onset between 3 and 24 months
- Hypoketotic hypoglycemia
- Vomiting
- Lethargy
- Hepatic encephalopathy
65
MCAD Deficiency inheritance
autosomal recessive
66
ACADM
| Mutation
MCAD Deficiency
67
Lynch Syndrome pathogenesis
```
-In most colorectal cancers, including in
familial adenomatous polyposis, the tumor
karyotype becomes progressively more
aneuploid
-Approximately 70% of Lynch syndrome
families with carcinomas exhibiting MSI
have germline mutations in one of four
DNA mismatch repair genes: MSH2,
MSH6, MLH1, or PMS2
Causes tumors and cancer
```
68
Lynch Syndrome inheritance
Autosomal dominant
69
Lynch Syndrome phenotype
- Onset at middle adulthood
- Colorectal cancer
- Multiple primary cancers
70
DNA Mismatch
Repair Gene
Mutations
Lynch Syndrome
71
Long QT Syndrome inheritance
Autosomal dominant
| or recessive
72
Long QT Syndrome pathogenesis
-Caused by repolarization defects in cardiac
cells
-Most cases of LQT syndrome are caused
by loss-of-function mutations in genes
that encode subunits or regulatory proteins
for potassium channels
Problem with repolarization (K+ channels)
73
Long QT Syndrome phenotype
```
-QTc prolongation (>470 msec in
males, >480 msec in females)
-Tachyarrhythmias
-Syncopal episodes
-Sudden death
```
74
Cardiac Ion
Channel Gene
Mutations
Long QT Syndrome
75
Pathogenesis of Hypertrophic
| Cardiomyopathy
Approximately 60% of adult and pediatric patients with a family history of HCM will have a sarcomere mutation identified. In contrast, only approximately 30% of patients without a family history will have positive results, often due to sporadic or
de novo mutations
76
Phenotype of Hypertrophic
| Cardiomyopathy
```
-Onset at adolescence and early
adulthood (age 12 to 21 years)-Left ventricular hypertrophy
-Myocardial crypts or scarring
-Elongated mitral leaflets
-Diastolic dysfunction
-Heart failure
-Sudden death
```
77
Cardiac
| Sarcomere Gene mutation
Hypertrophic
| Cardiomyopathy
78
Pathogenesis of Hereditary Hemochromatosis
-Mutant HFE interferes with hepcidin
signaling, which results in the stimulation of
enterocytes and macrophages to release iron.
The body, therefore, continues to absorb and
recycle iron, despite an iron-overloaded
condition.
Iron overload
79
Phenotype of Hereditary
| Hemochromatosis
```
-Onset at 40-60 years in males and
after menopause in females
-Fatigue, impotence,
hyperpigmentation (bronzing),
diabetes, cirrhosis, cardiomyopathy
-Elevated serum transferrin iron
saturation
-Elevated serum ferritin level
```
80
HFE Mutation
Hereditary
| Hemochromatosis
81
Pathogenesis of Fragile X Syndrome
```
-The FMR1 gene product, FMRP, is
expressed in many cell types but most
abundantly in neurons. The FMRP protein
may chaperone a subclass of mRNAs from
the nucleus to the translational machinery
-More than 99% of FMR1 mutations are
expansions of a (CGG)n repeat sequence in
the 5′ untranslated region of the gene
Problem with FMRP in neurons
```
82
phenotype of Fragile X Syndrome
- Onset at childhood
- Intellectual disability
- Dysmorphic facies
- Male postpubertal macroorchidism
83
FMR1 Mutation
Fragile X Syndrome
84
Pathogenesis of Familial
| Hypercholesterolemia
```
-The LDL receptor, a transmembrane
glycoprotein predominantly expressed in the
liver and adrenal cortex, plays a key role in
cholesterol homeostasis. It binds
apolipoprotein B-100, the sole protein of
LDL, and apolipoprotein E
-Mutations associated with FH occur
throughout LDLR; 2% to 10% are large
insertions, deletions, or rearrangements
mediated by recombination between Alu
repeats within LDLR
Impacts cholesterol homeostasis
```
85
Phenotype of Familial
| Hypercholesterolemia
```
-Onset for heterozygote: early to
middle adulthood
-Onset for homozygote: childhood
-Hypercholesterolemia
-Atherosclerosis
-Xanthomas
-Arcus corneae
```
86
Inheritance of Familial
| Hypercholesterolemia
Autosomal
| Dominant
87
Low-density
lipoprotein
(LDLR) Mutation
Familial
| Hypercholesterolemia
88
Pathogenesis of Duchenne Muscular
| Dystrophy (DMD)
```
DMD encodes dystrophin, an intracellular
protein that is expressed predominantly in
smooth, skeletal, and cardiac muscle as
well as in some brain neurons
-DMD mutations that cause DMD include
large deletions (60% to 65%), large
duplications (5% to 10%), and small
deletions, insertions, or nucleotide changes
(25% to 30%)
Problem with dystrophin in muscle and
neurons
```
89
Phenotype of Duchenne Muscular
| Dystrophy (DMD)
- Onset at childhood
- Muscle weakness
- Calf pseudohypertrophy
- Mild intellectual compromise
- Elevate serum creatine kinase level
90
Inheritance of Duchenne Muscular
| Dystrophy (DMD)
X-linked
91
Dystrophin
| [DMD] Mutation
Duchenne Muscular
| Dystrophy (DMD)
92
Inheritance of cystic fibrosis?
Autosomal recessive
93
Inheritance of Deafness
Autosomal dominant
| and recessive
94
Pathogenesis of Deafness
```
The GJB2 gene encodes connexin 26,
one of a family of proteins that form gap
junctions
-Connexin 26 is highly expressed in the
cochlea, the inner ear organ that
transduces sound waves to electrical
impulses
Impacts gap junctions in ear
```
95
Deafness
| (nonsyndromic) phenotype
-Congenital deafness in the
recessive form
-Progressive childhood deafness in
the dominant form
96
GJB2 Mutation
Deafness
| nonsyndromic
97
Pathogenesis of cystic fibrosis
Dysfunction of CFTR can affect many
different organs, particularly those that
secrete mucus, including the upper and
lower respiratory tracts, pancreas, biliary
system, male genitalia, intestine, and sweat
glands
Impacts mucus secretion
98
Autosomal recessive
99
What is the inheritance type?
100
What is the inheritance type?
101
What is the inheritance type?
102
What is the inheritance type?
103
What is the inheritance type?
104
What is the inheritance type?
105
What is the inheritance type?
106
What is the inheritance type?
107
What is the inheritance type?
108
What is the inheritance type?
109
What is the inheritance type?
110
What is the inheritance type?
111
What is the inheritance type?
112
Difference between x-dominant and x-recessive?
X-dominant all females will be affected. In recessive females will not be affected.
113
What is variable expressivity?
Variety of expression of one disease within a family.
114
Autosomal dominant with reduced penetrance
115
Autosomal recessive
116
X-linked dominant
117
Germline mosaicism: Germline mosaicism means that some sperm or eggs have a gene mutation that may not be present in other tissues of the body
118
Autosomal dominant with imprinting
119
Digenic: disorder determined by the additive effect of the genotypes at two or more genes from the same parent
120
Imprinting
In image all of the sons are passing it down. the affected daughter does not pass it down. Only one parent can pass it down. Father and mother would not both pass it down.
121
How would you rule out a X-linked disorder?
If a father passes down the disease to their son.
122
Genetic anticipation
A phenomenon in which the signs and symptoms of some genetic conditions tend to become more severe and/or appear at an earlier age as the disorder is passed from one generation to the next.
