1
Q
List 3 applications of cytogenetics
A
- Chromosomal abnormalities
- Microdeletions
- Cancer diagnostics
2
Q
Give an example of a metacentric chromosome
A
Chromosome 2
3
Q
Give an example of a submetacentric chromosome
A
Chromosome 18
4
Q
Give an example of an acrocentric chromosome
A
Chromosome 21
5
Q
Name two classes of chromosomal abnormalities
A
- Numerical abnormalities, e.g. Down syndrome
2. Structural abnormalities, e.g. Wolf Hirschhorn syndrome 4p-
6
Q
What chromosome abnormality is seen in Wolf Hirschhorn syndrome?
A
Del 4p16
7
Q
What disease are the following characteristics associated with:
- Wide spaced eyes
- Prominent nose
- Delayed growth and development
- Intellectual disability
- Seizures
A
Wolf Hirschhorn (del 4p16)
8
Q
What disease are the following characteristics associated with:
- Distinctive high-pitched cry that sounds like a cat
- Intellectual disability and delayed development
- Widely set eyes (hypertelorism), low-set ears, small jaw, rounded face
A
Cri du Chat (del 5p15)
9
Q
What disease are the following characteristics associated with:
- Underdeveloped chin, low-set ears, wide-set eyes, narrow groove in upper lip
- Variable clinically: Heart defects, poor immune system function
- ADHD
A
Di George Syndrome
10
Q
What chromosome abnormality is seen in Cri du Chat syndrome?
A
del 5p15
11
Q
What chromosome abnormality is seen in Di George syndrome?
A
del 22q11.2
12
Q
What is the most prevalent behaviour disorder seen in children with 22q11.2 deletion syndrome?
A
ADHD
It is seen in 30-50% of children
13
Q
What is the most common psychiatric disease that adults with 22q11.2 deletion syndrome develop?
A
1 in 4 develop schizophrenia
14
Q
What chromosome abnormality is seen in Angelman syndrome?
A
del 15q11-q13
15
Q
What chromosome abnormality is seen in Prader-Willi syndrome?
A
del 15q11-q13
16
Q
What type of chromosomal abnormality is seen in the Philadelphia chromosome?
A
Reciprocal translocation
46, XY, t(9:22)(q34.1;q11.2)
17
Q
What two chromosomes are implicated in the Philadelphia chromosome (bcr-abl)?
A
Chromosome 9 & 22
18
Q
What kind of chromosomes are involved in a Robertsonian translocation?
A
Translocation between two acrocentric chromosomes.
Balanced rearrangement.
19
Q
What is a carrier of a Robertsonian translocation at risk of when having a baby?
A
Aneuploid offspring
20
Q
Polyploidy is a change in chromosome number that is an ____ _____ of the haploid chromosome number
A
Polyploidy is a change in chromosome number that is an exact multiple of the haploid chromosome number
21
Q
What will triploid foetuses show in the womb?
A
Intrauterine growth retardation
22
Q
What causes aneuploidy?
A
Non-disjunction of homologous chromosomes at meiosis
23
Q
List 3 autosomal aneuploidy disorders
A
- Trisomy 21 (Down syndrome)
- Trisomy 18 (Edward syndrome)
- Trisomy 13 (Patau syndrome)
24
Q
What are 2 common features of autosomal trisomies?
A
- Intellectual disability
- Congenital abnormalities
25
What disease are the following characteristics associated with:
- Simian crease
- Flat facial profile
- Congenital heart defects
- Thick neck skin
Down syndrome
26
What is Down syndrome's most common karyotype?
47, XX, +21
27
If a parent has a child with Down syndrome, what is the recurrence risk for future pregnancies?
1%
28
Aside from aneuploidy, what other chromosomal abnormality accounts for 4% of down syndrome?
Robertsonian translocation.
Usually involves chromosome 14 or 21.
45, XY, t(14,21)
29
If two parents have a child with translocation Down syndrome, what is the recurrence risk in future pregnancies if the father is the carrier of the translocation?
2.5%
30
If two parents have a child with translocation Down syndrome, what is the recurrence risk in future pregnancies if the mother is the carrier of the translocation?
10%
31
What is the karyotype that accounts for 1% of down syndrome cases? (mosaic karyotype)
47, XY,+21/46, XY
32
What adulthood disease does Down syndrome confer a 100% risk of developing?
Early onset Alzheimer's Disease
33
What gene is implicated in both Down Syndrome and Alzheimer's Disease?
APP
34
Name two dosage sensitive genes
APP and DSCR1
35
What is the average incidence of Down syndrome?
1 in 650-700
36
The risk of Down Syndrome increases with....
The risk of Down Syndrome increases with age of the mother
37
When is Meiosis I completed?
Ovulation
38
In first trimester screening, what screening tests are done for Down Syndrome?
- Nuchal translucency thickness scan (NT)
| - Maternal serum markers
39
In second trimester screening, what screening tests are done for Down syndrome?
Anomaly scan and quad test - inhibin A
40
In prenatal diagnosis for Down Syndrome, what procedure is done in first trimester?
CVS
41
In prenatal diagnosis for Down Syndrome, what procedure is done in second trimester?
Amniocentesis
42
What is the sample used for analysis in Non invasive prenatal screening?
Cell free DNA (cfDNA) which includes foetal DNA.
| Blood can be taken at 9 weeks.
43
What is the incidence of Edward syndrome?
1 in 5000
44
What is the mortality of Edward syndrome in the first 2 years?
90% mortality
45
What disease are the following characteristics associated with:
- Prominent occiput
- Overlapping fingers
- Rocker bottomed feet
Edward syndrome (Trisomy 18)
46
What disease are the following characteristics associated with:
- Microphthalmia
- Cleft lip & palate
- Post axial polydactylyl
Patau Syndrome (Trisomy 13)
47
What % of infants with Patau syndrome survive past 1 year?
10%
48
Why are imbalances of sex chromosomes better tolerated than autosomal imbalances?
X chromosome inactivation
49
When does X chromosome lyonisation occur?
2 weeks after fertilisation
50
What is the dense mass of sex chromosome that arises from X chromosome lyonisation?
Barr body
51
How many Barr bodies does a normal female have?
1
52
How many Barr bodies does a normal male have?
None
53
What is another name for an inactive X chromosome?
Barr body
54
What is the karyotype for Turner syndrome?
45, X
55
What is the incidence of Turner syndrome?
1 in 2000
56
What chromosome disorder are the following characteristics associated with:
- Wedding neck
- Coarctation of aorta
- Infertility
- Broad chest and widely spaced nipples
Turner Syndrome
57
What are the clinical features of Turner syndrome due to?
Haploinsufficiency of certain genes on X chr e.g. SHOX
58
What treatment helps improve growth and breast development in Turner Syndrome?
Hormonal therapy
59
What is the incidence of Klinefelter syndrome?
1 in 1000
60
What chromosome disorder are the following characteristics associated with in a min:
- Infertility
- Tall stature
- Breast development
- High pitched voice
- Reduced body and facial hair
Klinefelter Syndrome
61
Name 4 types of common variants
- Nonsense
- Missense
- Frameshift
- Large deletion
62
Give an example of a disease that is affected by a missense point mutation
Sickle cell anaemia
63
Give an example of a disease that is affected by a nonsense point mutation
Beta thalassaemia
64
List the 3 stop codons
UAA
UAG
UGA
65
What specific frameshift deletion is a common cause of autosomal recessive congenital deafness?
35delG in connexin 26 gene
66
What is the most common mutation in cystic fibrosis?
del F508
| Phenylalanine at position 508
67
What are the consensus nucleotide sequences involved in splicing? (i.e. all introns start and end with these nucleotides)
Almost all introns start with GU and end with AG
68
What is the recurrence risk of autosomal dominant disorder?
50%
69
What complication is associated with familial hypercholesterolaemia?
Myocardial infarction
70
What receptor has an abnormality in familial hypercholesterolaemia?
LDL receptor defect causes increase levels of plasma cholesterol
71
What disorder are these clinical features associated with:
- formation of distinctive cholesterol deposits(xanthomas) in skin and tendons
- develop premature atherosclerosis leading to coronary heart disease
Familial hypercholesterolaemia
72
Name a disorder that arises from haploinsufficiency
Familial hypercholesterolaemia
73
What chromosome is the LDL receptor gene located on? (Familial hypercholesterolaemia)
Chromosome 19p
74
What do mutations in familial hypercholesterolaemia cause?
Mutations reduce number of functioning LDL receptors
75
Heterozygotes for mutant allele in familial hypercholesterolaemia have ____ fold increased plasma cholesterol levels, while homozygotes have _ fold increased levels.
Heterozygotes for mutant allele in familial hypercholesterolaemia have 2-3 fold increased plasma cholesterol levels, while homozygotes have 5 fold increased levels.
76
What treatment is used for familial hypercholesterolaemia?
- Statins
| - Gene therapy
77
What enzyme do statins inhibit for the treatment of familial hypercholesterolaemia?
HMG CoA reductase
78
What gene is mutated in Marfan syndrome, and what chromosome is it on?
FBN1 gene on chr 15
| encodes fibrillin-1 protein
79
What 3 body systems are defects found in in Marfan syndrome?
- Ocular
- Skeletal
- Cardiovascular
80
What term describes when a gene has effects on multiple aspects of physiology or anatomy?
Pleiotropy
81
What pattern of inheritance does Marfan syndrome follow?
Autosomal dominant
82
What disorder are the following clinical features associated with:
- Unusually tall stature, long limbs with long spidery fingers (arachnodactyly), scoliosis
- Dislocation of the lens
- Mitral valse prolapse
Marfan Syndrome
83
What is the main type of mutation found in Marfan syndrome?
Most mutations are missense which act in a dominant negative fashion
84
What pattern of inheritance does Achondroplasia follow?
Autosomal dominant
85
What disorder are the following clinical features associated with:
- Common cause of dwarfism
- Large head with prominent forehead, shortened limbs
- Severely dwarfed (adults ~ 4ft), normal IQ
- Respiratory problems can occur in infants and children due to narrowed nasal passage
Achondroplasia
86
What gene is mutated in Achondroplasia and what chromosome is it found on?
FGFR3 on chromosome 4p.
Majority of mutations are G to A transition.
87
Is the mutation of FGFR3 in Achondroplasia loss or gain of function?
Gain of function mutation - has implications for gene therapy
88
Name a disorder that has 100% penetrance
Neurofibromatosis type 1
89
What is the recurrence risk with autosomal recessive disorders?
25%
90
What pattern of inheritance do disorders affecting metabolic pathways usually have?
Autosomal recessive
91
Name 2 genes that may be mutated in Albinism
1. TYR
2. TYRP1
(chromosome 11p)
92
What do 10% of babies with cystic fibrosis present with at birth?
Meconium ileus
93
List 2 methods used for the diagnosis of cystic fibrosis
- Sweat test with increased Na+
| - Newborn screening program
94
What gene is mutated in cystic fibrosis and what chromosome position does it occupy?
CFTR (7q31.2)
95
What other receptor does CFTR work in conjunction with? (especially in the sweat gland epithelium)
ENaC
96
List 4 TYPES of mutations that may arise in cystic fibrosis
- Missense
- Nonsense
- Splicing
- Frameshift
97
What is the most common 3bp frame deletion in cystic fibrosis?
F508del
98
What is the R117H variant affected by?
Poly T tract in intron 8
99
Which T variant of R117H promotes exon 9 splicing?
5T variant promotes exon 9 splicing
100
List 2 treatments for cystic fibrosis
1. Antibiotics
2. Kalydeco
3. Physiotherapy
101
What is the complication of phenylketonuria if undiagnosed and untreated?
Develop hyperphenylalaninemia which impairs brain development
102
What gene is mutated in phenylketonuria?
PAH gene resulting in failure to convert phe to tyrosine
103
What test is performed at birth to screen for Phenylketonuria?
Guthrie test (heel prick test)
104
If a mother has phenylketonuria and takes excess phe during pregnancy, what does that excess phe act as on the foetus?
Excess phe acts as teratogen on developing foetus
105
Name two clinical presentations found among offspring of mothers with phenylketonuria who did not maintain diet during pregnancy?
1. Dysmorphic features
| 2. Microcephaly
106
What is the most common mutation in Hereditary Haemochromatosis?
C282Y in exon 4
107
List 2 disorders seen in travelling community
1. Galactosemia
| 2. Hurler syndrome
108
What term describes a person with the following:
"because X inactivation is random, carrier females have varying proportion of cells expressing mutant allele and hence can occasionally exhibit signs of disorder"
Manifesting heterozygote
109
What gender are X-linked disorders more commonly seen in?
Males.
X-linked rec diseases are transmitted by phenotypically normal heterozygous females to sons. But NO male to male transmission.
110
Name 2 common X-linked disorders.
1. Duchenne muscular dystrophy
| 2. Becker muscular dystrophy
111
What enzyme is increased in Duchenne muscular dystrophy?
Increased creatine kinase.
112
What gene is mutated in both Duchenne- and Becker Muscular Dystrophy, and what chromosome is it on?
Dystrophin gene at Xp21
113
What type of mutation is usually seen in Duchenne muscular dystrophy?
Frameshift
114
What molecular genetic tool is used for the initial genetic screening of Duchenne muscular dystrophy?
MPLA or multiplex PCR.
Followed up by full sequencing is MPLA negative.
115
Give 3 examples of mitochondrial disorders.
- Leigh syndrome
- MELAS
- MERRF
116
What does MELAS stand for? (Mitochondrial disorder)
Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes
117
When is the onset for MELAS syndrome?
Childhood
118
Is mitochondrial inheritance paternal or maternal inheritance?
Maternal inheritance
119
Name 4 complications in inheritance patterns1
1. Penetrance
2. Expressivity
3. Mosaicism
4. Anticipation
120
Name mutated genes that commonly show reduced penetrance
BrCa1 and BrCa2
121
Name a disease that shows variable expressivity.
Neurofibromatosis
122
What is one explanation of why parents who are apparently normal on genetic testing, can have more than one affected offspring with a dominant genetic disorder?
Germline mosaicism
123
What term describes the following:
"Tendency for some disorders to begin at an earlier age and with increased severity with successive generations eg Huntington’s Disease & Myotonic Dystrophy"
Anticipation
124
What is one possible explanation for genetic anticipation?
Unstable mutation - Expansion of repeated DNA sequences
125
In anticipation disorders, there is a correlation between number of repeats and _____ __ ________
In anticipation disorders, there is a correlation between number of repeats and severity of disease
126
In anticipation disorders, there is inverse correlation between number of repeats and ___ __ _____
In anticipation disorders, there is inverse correlation between number of repeats and age of onset.
127
What is the pattern of inheritance for Huntington disease?
Autosomal dominant
128
What disease are the following clinical presentations associated with:
- Movement disorder accompanied by behavioural changes including aggression, anxiety, apathy, depression and cognitive changes affecting memory, awareness and communication
Huntington Disease
129
Name one early stage, middle stage, and late stage motor change in Huntington Disease.
Early stage - Restlessness
Middle stage - Trouble with balance and walking
Late stage - Inability to walk
130
What is the penetrance of Huntington Disease?
100% penetrant but in age-dependent manner
131
What part of the brain is affected in Huntington Disease?
Caudate (Severe atrophy of caudate seen in HD)
132
What mutation repeat is seen in Huntington Disease?
CAG repeat in exon 1 of HTT gene on chr 4
133
What range of CAG repeats are necessary to show full penetrance of Huntington Disease?
40-120
134
What range of CAG repeats indicate someone is at increased risk of developing Huntington Disease?
36-39
135
What disease are the following clinical presentations associated with:
- Progressive weakness
- Cataracts
- Cardiomyopathy
- Testicular atrophy
- Frontal baldness in males
Myotonic dystrophy (DM1)
136
What two factors complicate the inheritance pattern of Myotonic Dystrophy (DM1)?
Variable expression & anticipation
137
Name one complication of congenital myotonic dystrophy
Neonatal respiratory distress
138
What nucleotide repeat is expanded in Myotonic Dystrophy (DM1)?
Mutation is expansion of CTG normally present in 3'UTR of DMPK gene
139
How does Myotonic Dystrophy (DM2) differ from DM1?
DM2 does not show congenital form
140
What nucleotide repeat is expanded in DM2 Myotonic Dystrophy?
CCTG expansion in ZNF9 gene
141
How does CTG expansion cause disease?
Causes abnormal splicing
142
What is the most common cause of inherited mental retardation?
Fragile X syndrome
143
Why is the inheritance pattern of fragile X syndrome considered atypical?
Inheritance pattern not fully recessive
144
What is the most single genetic cause of autism spectrum disorders?
Fragile X syndrome
145
What nucleotide repeat is expanded in Fragile X syndrome?
Mutation is expansion of CGG in the FMR-1 gene
| >200 copies in Fragile X syndrome
146
What is the repeat expansion in Fragile X associated with (molecularly)?
Repeat expansion is associated with Hypermethylation of DNA and gene silencing. Lack of FMR protein is responsible for signs of Fragile X.
147
What 2 clinical phenotypes are associated with premutation carriers of Fragile X syndrome?
1. Premature ovarian failure
| 2. FXTAS syndrome
148
What can PCR be used for?
- To detect the presence or absence of a sequence
| - To measure the size of a sequence
149
What molecular process does PCR imitate?
DNA replication
150
Name 4 components of PCR
1. DNA
2. Primer
3. Nucleotides
4. Taq polymerase
151
Name the 3 key steps in PCR and their temperatures
1. Denaturing DNA (95 C)
2. Annealing primers (55-60 C)
3. Extending DNA (72 C)
152
What machine does PCR take place in?
Thermocycler
153
List 4 applications of PCR
1. Genotyping
2. Drug discovery
3. Mutation screening
4. Pre-natal diagnosis
154
Name 2 applications of multiplex PCR (amplification of multiple targets in a single PCR experiment)
1. Pathogen detection
| 2. Exon deletion
155
What molecular genetic tool is used to diagnose deletion-type DMD?
Multiplex PCR
156
Name 2 limitations of end-point PCR (i.e. normal PCR)
1. Low sensitivity
| 2. Not very quantitative
157
What type of PCR allows for the quantitative analysis of gene expression?
Real-time PCR (qPCR)
158
What distinguishes the qPCR components from standard end-point PCR (i.e. normal PCR)?
The addition of a fluorescent label
159
What molecular genetic tool is described in the following statement:
"A method based on in vitro synthesis of DNA incorporating special chain terminating nucleotides - dideoxynucleoside triphosphates"
Dideoxy method of sequencing
160
What general term describes modern sequencing technologies?
Next Generation Sequencing (NGS)
161
Is Next Generation Sequencing targeted or not targeted?
Not targeted - they sequence everything in the sample
162
List 2 barriers for clinical implementation of NGS
1. Evidence for clinical utility
| 2. Data interpretation
163
What is the pathogenic mechanism behind Fragile X syndrome?
Loss of function due to blocked transcription
164
What is the pathogenic mechanism behind Fragile X associated tremor and ataxia (FXTAS)?
Gain of function by pathogenic RNA
165
What is the pathogenic mechanism behind Huntington Disease?
Gain of function of a protein
Genetics, Perinatal & Paediatrics
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