Categories of Genetic Disease Flashcards
(151 cards)
1
Q
Using a triangle model, how can the aetiology of diseases be described?
A
100% environmental
Single gene
Polygenic
The overall balance of genetic and environmental determinants can be represented by a point somewhere on the triangle
2
Q
What are the 5 categories of genetic disease?
A
- multifactorial
- single gene
- chromosomal
- mitochondrial
- somatic mutations (cancer)
3
Q
What is the cause of a multifactorial genetic disorder?
A
Likely to be associated with the effects of multiple genes in combination with lifestyle and environmental factors
4
Q
Where does a somatic mutation occur and how is it passed on?
A
Any cell in the body other than a germ cell
The genetic alteration is passed on the the progeny of the mutated cell during cell division
5
Q
What is penetrance?
A
The extent to which a particular gene is expressed in the phenotype
6
Q
How does penetrance relate to symptoms of a genetic disorder?
A
Penetrance refers to the proportion of individuals with a particular mutation that exhibit signs and symptoms of the genetic disorder
7
Q
What type of features are exhibited by someone with reduced penetrance?
A
They have a mutation but do not develop the features of the disorder
8
Q
What type of disorder is fully penetrant?
A
Single gene (Mendelian)
other genes and environmental factors have no effect
9
Q
How is a person’s susceptibility to disease determined?
A
Low-penetrance genes all play a small part, along with other genetic and environmental factors to determine susceptibility
10
Q
What type of condition is multiple sclerosis and what does this mean in terms of penetrance?
A
multifactorial
each individual genetic factor that is involved in determining susceptibility has a very low penetrance
11
Q
How does a single gene disorder arise?
What % of liveborns exhibit this kind of disorder?
A
mutation in a single gene (monogenic) often causes a loss of function of the gene
1%
12
Q
What is Mendelian inheritance?
A
A gene will show segregation of two alleles from a hybrid individual
Different characteristics result from different alleles for a single gene
13
Q
How do single gene disorders show Mendelian inheritance?
A
They have dominant and recessive pedigree patterns
14
Q
What type of structures do single gene disorders usually affect?
A
structural proteins, enzymes, receptors and transcription factors
15
Q
How are multifactorial disorders brought about?
A
They are associated with the effects of multiple genes (polygenic) rather than a single gene
16
Q
How is susceptibility to disease determined in a multifactorial disorder?
A
by the genetic predisposition combined with the environmental influence
17
Q
What structures do multifactorial disorders affect?
A
They will only affect one organ system
18
Q
What % of liveborns have a chromosomal disorder?
A
0.6%
More common in spontaneous abortions
19
Q
How many genes are involved in a chromosomal disorder and what structures do they affect?
A
Thousands of genes involved
Multiple organ systems are affected at multiple stages in gestation
20
Q
What does a chromosomal imbalance cause?
A
An alteration in gene dosage
21
Q
What is gene dosage?
A
The number of copies of a particular gene present in the genome
22
Q
How are chromosomal disorders often caused?
A
Usually de novo mutations
23
Q
What is a de novo mutation?
A
A genetic alteration present for the first time in one family member as a result of a mutation in a germ cell from one of the parents
24
Q
What is a more rare way for chromosomal disorders to be caused?
A
Chromosomal mutations, like translocations, can be inherited
25
What is a chromosome made up of?
DNA tightly coiled around histone proteins
26
What are the 2 arms of the chromosome?
The short arm is the p arm
The long arm is the q arm
27
What are the 2 types of chromatin that make up the chromosome?
Heterochromatin
Euchromatin
28
What is heterochromatin?
It contains DNA that is more condensed and does not have much transcriptional activity
29
What is euchromatin?
Contains DNA that is less condensed and contains the active genes
30
What are the roles of the telomeres?
Prevent end-to-end fusion of chromosomes
Prevent degradation by exonucleases
Needed for chromosomal replication
31
What is the centromere?
A specialised DNA sequence of a chromosome that links a pair of sister chromatids
32
What is a 'syndrome'?
A syndrome refers to a collection of features
33
What are the typical features of Down's Syndrome?
1. round face
2. protruding tongue
3. upslanting palpebral fissures
4. epicanthic folds
5. developmental delay
6. mild to moderate intellectual disability
34
What is Down's syndrome caused by?
trisomy of chromosome 21
This is the presence of ALL or PART OF a third copy of cs21
35
What is a karyotype?
It shows the number and appearance of chromosomes in the nucleus of a eukaryotic cell
It shows all the pairs of chromosomes and their order
36
What are the 5 ultrasound features of Down's syndrome?
1. short femurs
2. nuchal translucency
3. echogenic bowel
4. choroid plexus cyst
5. sandal gap
37
What is nuchal translucency?
the appearance of fluid under the skin behind the foetal neck due to limited lymphatic drainage
38
What is echogenic bowel?
foetal bowel is brighter than expected
39
What is choroid plexus cyst?
small fluid-filled structure within the choroid of the lateral ventricles of the foetal brain
40
What is a sandal gap?
expanded first interspace of the feet
41
What are the 3 different patterns of chromosomes that can cause Down's syndrom?
1. three separate copies of chromosome 21
2. extra copy of chromosome 21 due to Robertsonian translocation
3. mosaicism with normal and trisomy 21 cell lines
42
What % of people have trisomy 21 as a cause of Down's syndrome?
95%
43
What % of people have Robertsonian translocation as a cause of Down's syndrome?
4%
44
How does the Robertsonian translocation arise?
The participating chromosomes break at their centromeres
The long arms fuse to form a single, large chromosome with a single centromere
45
How is the Robertsonian translocation inherited?
It can be de novo and occur at the time of conception
It can also be inherited from a parent
46
In someone with Down's syndrome due to a Robertsonian translocation, how many copies of ch21 do they have?
3 copies of the LONG ARM of ch21
The effects are the same as when someone has 3 copies of the entire ch21
47
What % of people have Down's syndrome due to mosaicism?
1%
48
What is mosaicism?
It is being composed of cells of two genetically different types
Different cells in the same individual have different numbers or arrangements of chromosomes
49
What do the cells look like in someone with Down's syndrome due to mosaicism?
Some cells will have 2 copies of ch21, but some cells will have 3 copies
50
How do the features of mosaic Down's syndrome differ?
the features are milder due to the presence of normal cells
51
When does mosaic Down's syndrome occur?
The process occurs postzygotically
52
What causes Edwards syndrome and how many people does it affect?
trisomy of chromosome 18
occurs in 1 in 3000 births
53
What are the symptoms of Edwards syndrome?
multiple malformations, notably to the heart and kidneys
clenched hands with overlapping fingers
54
What causes Patau syndrome and how many people does it affect?
trisomy of chromosome 13
occurs in 1 in 5000 births
55
What are the symptoms of Patau syndrome?
It particularly affects midline structures:
1. incomplete lobation of the brain
2. cleft lip
3. congenital heart disease
56
What is the prognosis like for Edwards and Patau syndrome?
Very poor prognosis
Majority of babies die a few weeks after birth
If they do survive, they have severe mental retardation
57
How is Klinefelter syndrome caused?
What is its alternative name?
47,XXY
it is the set of symptoms that results from two or more X chromosomes in males
58
How many people does Klinefelter syndrome affect?
1 in 850 males
59
What do sufferers of Klinefelter syndrome often look like?
tall with a thin build and disproportionately long arms and legs
60
How does Klinefelter syndrome cause infertility?
Atrophic (decreased size) testes do not produce sperm
61
What occurs during puberty in sufferers of Klinefelter syndrome?
Poorly developed SSCs due to lack of testosterone
Gynecomastia occurs in late puberty
62
What is gynecomastia?
enlargement of the male breast gland due to a hormonal imbalance
63
What are the other symptoms of Klinefelter syndrome?
osteoporosis
hypogonadism
64
What is azoospermia?
The semen contains no sperm
65
What is oligospermia?
the deficiency of sperm cells in the semen leading to low sperm count
66
What is Turner syndrome?
What is its alternative name?
45, X
occurs when females only have one normal X chromosome, rather than 2
67
How many people are affected by Turner syndrome?
1 in 3000 females
99% are lost spontaneously in pregnancy
68
What do sufferers of Turner syndrome often look like?
Short stature becomes evident around age 5, with a wide carrying angle of the arms
Low hairline
Narrow hip development
Shield-shaped chest
Hyperconvex nails
69
What do 20% of patients with Turner syndrome also experience?
congenital heart disease due to coarctation of the aorta
70
What is the main symptom of Turner syndrome?
Primary amenorrhoea
The ovaries involute before birth (premature ovarian failure)
71
What are numerical chromosome abnormalities?
The gain or loss of complete chromosomes
72
What is non-disjunction?
Failure of homologous chromosomes or sister chromatids to separate properly during cell division
73
When does non-disjunction usually occur?
In the germ cells during meiosis
74
What happens if non-disjunction occurs in somatic cells?
Leads to mosaicism
75
What are autosomal monosomies?
A monosomic cell has only one copy of a particular chromosome
76
What happens to a foetus with an autosomal monosomy?
They abort spontaneously during early pregnancy
Autosomal monosomies are not compatible with life
77
What is significant about sex chromosome anomalies?
Lead to fewer serious effects
78
What is a microdeletion?
The loss of a chromosomal region
The loss is too small to be observed microscopically by high resolution karyotyping
79
What is microdeletion syndrome?
A syndrome caused by a chromosomal deletion smaller than 5 million base pairs (5 Mb) spanning several genes
80
What causes DiGeorge syndrome?
deletion of a small segment of chromosome 22
81
What is the proper way to describe DiGeorge syndrome?
22q11.2 deletion syndrome
82
What are the physical features of someone with DiGeorge syndrome?
small mouth
prominent nose
thymic aplasia
cleft palate
83
What are the symptoms of DiGeorge syndrome?
```
congenital heart problems
specific facial features
frequent infections
developmental delay
learning problems
```
84
What causes Williams syndrome?
microdeletion of genetic material (26-28 genes) from a specific region of chromosome 7
the deletion occurs in the sperm or oocyte at the time of conception
85
What particularly accounts for many of the physical features of Williams syndrome?
deletion of the elastin gene
86
What is the proper way to describe Williams syndrome?
7q11.23 microdeletion that affects the long arm of chromosome 7
87
What are the physical features of a patient with Williams syndrome?
```
bright eyes
stellate irises
wide mouth
upturned nose
long philtrum
flattened nasal bridge
```
88
What are the symptoms of Williams syndrome?
heart defects including heart murmurs and supravalvular aortic stenosis
overly sociable
89
What does FISH stand for?
fluorescence in situ hybridisation
90
What is FISH used for?
It is used to detect the presence or absence of specific DNA sequences on chromosomes
91
What is used as the probe and the target in FISH?
The probe sequence is a piece of cloned DNA labelled with a fluorescent marker
The target DNA is chromosomes on a glass slide
The probe DNA is complementary to the target DNA
92
What is the first stage in FISH?
Target and probe sequences are denatured with heat or chemicals
This allows new hydrogen bonds to form between the target and the probe
93
What is the second stage in FISH?
The probe and the target DNA are mixed together
The probe will hybridise to its complementary sequence on the chromosome
94
How is the site of hybridisation detected in FISH?
Through fluorescence of the probe strand
95
What is the alternative name for Prader-Willi syndrome?
15q13 microdeletion
96
What are the symptoms of Prader-Willi syndrome in new-borns?
1. weak muscles
2. poor feeding
3. slow development
97
What are the symptoms of Prader-Willi syndrome in childhood?
The child is constantly hungry, which leads to obesity and type 2 diabetes
98
What causes Prader-Willi syndrome?
A deletion in the paternal chromosome 15 or by maternal uniparental disomy
99
What is uniparental disomy?
2 copies of chromosomes come from the same parent
100
What are the other symptoms of Prader-Willi syndrome?
1. hypogonadism
2. development and cognitive delays
3. short stature
4. behavioural and psychiatric disturbances
5. marked skill in completing jigsaws
101
What is the alternative name for cat-eye syndrome?
22pter-22q11
the 22 inverted duplication
102
What causes cat-eye syndrome?
The short (p) arm and a small region of the long arm of chromosome 22 are present 4 times, rather than twice
This is a partial tetrasomy
103
What are the symptoms of cat-eye syndrome?
1. iris coloboma
2. anal atresia
3. ear tags/ear pits
4. heart defects
5. kidney malformations
104
According to Mendelian genetics, how do dominant disorders present?
Heterozygotes with one copy of the altered gene are affected
105
According to Mendelian genetics, how do recessive disorders present?
Homozygotes with two copies of the altered gene are affected
106
According to Mendelian genetics, how do X-linked disorders present?
Males with one copy of the altered gene on the X-chromosome are affected
107
What is the relationship between single gene disorders and relatives?
Single gene disorders pose high risks to relatives
108
What is Huntingdon disease?
A progressive brain disorder that causes uncontrolled movements, emotional problems and the loss of thinking ability
109
How is Huntingdon disease contracted?
It is an inherited condition that damages nerve cells in the brain
110
What is the mutation that causes Huntingdon disease?
Autosomal dominant mutation in either of an individual's two copies of the Huntingtin gene
111
What does the Huntingtin gene code for?
The Huntingtin protein
112
What causes an abnormal Huntingtin protein?
Expansion of CAG triplet repeats in the Huntingtin gene
The abnormal protein gradually damages cells in the brain
113
What is familial hypercholesterolaemia?
Cholesterol deposits in patients who are heterozygous for familial hypercholesterolaemia
114
What causes familial hypercholesterolaemia?
Inherited disorder caused by a defect on chromosome 19
This means the body is unable to remove LDL cholesterol from the blood
115
What does familial hypercholesterolaemia cause?
1. tendon xanthomata
| 2. corneal arcus
116
What is tendon xanthomata?
Skin lesions caused by cholesterol deposits in tendons
117
What is corneal arcus?
Greyish/yellowish opaque ring around the peripheral cornea caused by cholesterol deposits
118
What is the major problem associated with familial hypercholesterolaemia?
High risk of cardiovascular disease
119
What organs are affected by cystic fibrosis?
Mainly the lungs
Also the pancreas, liver, kidneys and intestine
120
What are the long-term issues associated with cystic fibrosis?
1. breathing difficulties
| 2. coughing up mucus asa result of frequent lung infections
121
What causes cystic fibrosis?
A defect in the CFTR gene that codes for chloride ion channels
The CFTR protein controls the movement of salt and water in and out of cells
122
What does a faulty CFTR protein cause?
Thick, sticky mucus and salty sweat
123
What type of disease is cysticc fibrosis?
Autosomal recessive
Sufferers must have 2 copies of the faulty CFTR gene
If they have one faulty gene, they are carriers
124
What is Duchenne muscular dystrophy?
Progressive muscle degeneration and weakness that usually only affects boys
125
Why does Duchenne muscular dystrophy usually only affect boys?
It is an X-linked recessive condition
Females with a single copy of the defective gene may show mild symptoms
126
What causes Duchenne muscular dystrophy?
The absence of dystrophin
This is a protein that helps to keep muscle cells intact
Absence of dystrophin leads to disorganisation of muscle cells and invasion by fibrous tissue
127
When is the onset of symptoms in Duchenne muscular dystrophy?
Early childhood, usually between the age of 3 and 5
128
What is Gower's manoeuvre?
Boys with Duchenne muscular dystrophy stand up by bracing their arms against their legs as their proximal muscles are weak
129
Where are mitochondria inherited from?
Exclusively from the mother
Mitochondria in the sperm are destroyed by the egg after fertilisation
130
What does mitochondrial DNA encode?
13 of the proteins used within the mitochondria
All other mitochondrial proteins are encoded by DNA in the nucleus of the cell
131
How do genetic alterations occur in mitochondrial DNA?
Can occur in individual genes or as rearrangements of the DNA within its circular structure
132
What is the result of genetic alterations in mitochondrial DNA?
The cells have a mixture of normal and altered mtDNA
This is heteroplasmy
133
How are the offspring of a male and female with mtDNA alterations likely to be affected?
All of the offspring of an affected woman would inherit the condition
An affected male does not pass on his mitochondria, so his offspring are not affected
134
What is Leber hereditary optic neuropathy?
Inherited form of vision loss that begins in the teens or twenties
135
What is the first symptom of Leber hereditary optic neuropathy?
Blurring and clouding of vision in one or both eyes
136
What happens over time in Leber hereditary optic neuropathy?
Vision worsens with severe loss of sharpness and colour vision
137
What causes Leber hereditary optic neuropathy?
Vision loss results from death of cells in the optic nerve
It is caused by mutations in mitochondrial DNA
138
What happens in genomic imprinting?
For most genes, 2 functioning copies are inherited, 1 from each parent
With imprinted genes, only one working copy is inherited and the other copy is epigenetically silenced
139
How are imprinted genes silenced?
Through the addition of methyl groups to the DNA during egg or sperm formation
140
How are imprinted genes expressed?
Gene expression occurs from only one allele rather than 2
141
How are imprinted genes maintained?
Epigenetic marks are imprinted in the germline of the parents and are maintained through mitotic cell divisions in the somatic cells
142
How are imprinted genes important in normal development?
Appropriate imprinting of certain genes is important for normal development
143
What are the characteristics of a genetic disorder?
1. rare
2. genetics are simple
3. unifactorial
4. high recurrence rate
144
What are the characteristics of an environmental disorder?
1. common
2. complex genetics
3. multifactorial
4. low recurrence rate
145
What % of cancers are sporadic?
75-80%
146
What happens in a sporadic cancer?
Both alleles of a gene become inactivated in a particular somatic cell
This leads to loss of control of cell growth and unchecked cell proliferation
147
What % of cancers are familial?
10-20%
148
How are familial cancer syndromes inherited?
Dominantly inherited
The altered allele is inherited so resides in all body cells containing genetic material
149
How does the cancer begin in a familial cancer syndrome?
When the second allele of the gene pair becomes inactivated in a particular somatic cell, this leads to loss of control of cell growth and unchecked cell proliferation
150
How is multifactorial inheritance controlled?
It is polygenic as it is controlled by many genes with small additive effects
Also influenced by the environment
151
What is significant about multifactorial inheritance?
It only affects one organ system
