Genetics Flashcards
(106 cards)
1
Q
What proportion of newborns do congenital defects affect
A
1 in 50
2
Q
What are the 2 broad types of congenital defect
A
Single and multiple
3
Q
What is malformation and give an example
A
Single congenital defect
Morphological defect of an organ due to abnormal development e.g. cleft lip, atrial septal defect
4
Q
What is disruption and give an example
A
Single congenital defect
Morphological defect of an organ from intrinsic breakdown or interference with a normal process e.g. amniotic band
5
Q
What is deformation and give an example
A
Single congenital defect
Abnormal form shape or position due to mechanical factors e.g. club foot
6
Q
What is dysplasia and give an example
A
Single congenital defect
Abnormal organisation of cells into tissue and its morphologic results e.g. thanatophoric dysplasia
7
Q
What is a sequence
A
Multiple congenital defects
Pattern of abnormalities derived form a single known or preserved prior anomaly e.g. Potters sequence
8
Q
What is a syndrome
A
Multiple congenital defect
Multiple anomalies thought to be pathogenically related that is not a sequence e.g. Downs
9
Q
What is an association
A
Multiple congenital defects
Non-random occurrence in 2 or more individuals of multiple abnormalities e.g. VATER association
10
Q
Describe the packaging of DNA
A
DNA
Gene
Chromosome
Genome
11
Q
What is the normal human karyotype
A
22 chromosomes and 1 sex chromosome (haploid) from 1 parents
12
Q
What is nomenclature of chromosomes based on
A
bands
long arm= P
short arm = Q
13
Q
What are the possible structural abnormalities of chromosomes
A
duplication inversion deletion ring - telomeres translocation - Transfer of genetic material from one chromosome to another
14
Q
Describe Robertsonian translocation
A
The short arms (q) are lost while the long arms are combined
These become fused and therefore do not separate during division
If there is a balance, it is unlikely that there will be an abnormal phenotype
If unbalanced, disruption of a gene may occur or a fusion product
15
Q
Give the possible consequences of robertsonian translocation on reproduction with a normal cell
A
normal
monosomy (lethal)
trisomy
16
Q
Which monosomy abnormality is not lethal
A
Turner’s
17
Q
Define aneuploidy
A
Loss or gain of 1 or more chromosome
18
Q
Describe the different types of numerical abnormalities in chromosome
A
monosomy - loss of 1 chromosome
disomy - normal
trisomy - gain of 1 chromosome
tetrasomy - gain of 2 chromosome
19
Q
Give 3 examples of trisomy
A
Downs - 21
Edwards - 18
Patau - 13
20
Q
What is the most common form of trisomy
A
Chromosome 16
Lethal and leads to miscarriage
21
Q
Describe the features of trisomy 21
A
hypotonia lethargy excess nuchal skin Cranofacial features Sandal gap Single palmar crease Septal and heart defects
22
Q
What are the causes of trisomy 21
A
Non-disjunction in meiosis 1 where homologous chromosomes fail to separate
Translocation
Mosaicism
23
Q
What is mosaicism caused by
A
mitotic non-disjunction
Children are less severely affected
24
Q
Define dosage compensation
A
ensures equivalent gene expression in both sexes
Inactivation of an X chromosome in females (lyonisation)
25
What is Turner's syndrome and its features
monosomy X
Loss of the X or Y in paternal meiosis
Webbed neck, low ears, normal intelligence
26
What is Klinefelter's syndrome
47 XXY
X from either parent
Phenotypically male, learning disability, taller, learning disability, infertility
27
Identify the symbols used in pedigree charts for proposiatus, X-linked carrier, unspecified sex, abortion, unidentical twins and identical twins
```
arrow = proposiatus (first)
solid with an outline = X-linked carrier
diamond = unspecified sex
little circle = abortion of still birth
diagonal lines = unidentical twins
diagonal twins + horizontal = identical twins
```
28
Describe the inheritance patterns for an autosomal dominant disease
```
Only 1 copy is needed to be presented in the phenotype
At least one parent is affected
M or F
Vertical transmission
Age of onset decreases further down
```
29
Describe Huntington's disease
Autosomal dominant disease
Motor, cognitive and psychiatric disfunction
Caused by CAG repeats
The greater the no. of CAG, the more severe
30
Describe the inheritance patterns for an autosomal recessive disease
Both alleles must abnormal to be presented in the phenotype
No affected parents
M or F
Usually very little family history
31
Describe cystic fibrosis
Autosomal recessive disease
Thick mucous produced in the lungs
breathing problems, infectious, blocks the pancreas
CTFR gene incorrectly folded
32
Describe the inheritance patterns for a X-linked recessive disease
No affected parents
Only M affected
Transmitted by F carriers
33
Describe haemophilia
X-linked recessive disease
Blood clotting disorder
Easy bruising and bleeding
Types A and B
34
Give an example of how the same gene can have different mutations
The CFTR gene mutating can cause cystic fibrosis or CAVD
35
Give an example of how mutations in different genes can cause the same disease
Mutations in genes A and B can both cause haemophilia
36
Give an example of how different genes and inheritance can cause the same disease
AD and AR will cause epidermis bullosa
37
Define Mendelian inheritance
Individuals inherit and transmit to their offspring one out of the 2 alleles present in homologous chromosomes
38
Define polymorphism
Mutation present in >1% of the population which may contribute to complex disease
39
What are the types of point mutation
missense (1 amino acid for another)
| nonsense (stop codon for an AA)
40
Define incomplete inheritance
Symptoms are not always present in an individual with a disease-causing mutation
41
Define variable expressivity
Disease severity may vary between individuals with the same disease-causing mutation
42
Define phenocopy
Having the same disease but with a different underlying cause
43
Define epistasis
Interaction between disease gene mutations and other modifier genes which can affect genotype
44
What are dominant conditions usually caused by and how may this be resolved
mutations that result in the presence of a toxic protein
| Switch off the gene or neutralise the produced protein
45
What are recessive conditions usually caused by and how may they be resolved
Mutations that lead to the absence of a functional protein
| Restore tha activity of the missing protein
46
What are co-dominat conditions usually caused by and how may they be resolved
Both the mutated and normal genes are apparent
| Switch off the abnormal gene of neutralise the protein
47
What is the epigenome
Transcriptome
Surrounds the genome
Non-mendelian inheritance
48
What is imprinting
Involves DNA methylation. The genome carries an imprint of the parental origin.
75 genes are affected
The DNA sequence remains normal while function changes
Reflects that parental origin of chromosomes is important
49
What is methylation
Methyl groups are attached to the 5 position of the pyrimidine ring cytosine on DNA
Decreases gene expression as it blocks transcription factors
50
Describe Prader-Willis syndrome
Loss of function of the paternal chromosome
| Critical region is deleted OR 2 maternal copies are inherited (uniparental isodomy)
51
What are the symptoms of Prader-Willis syndrome
```
Hyperphagia (overeating with loss of regulatory process)
Obesity
Mental retardation
Hypotonia (reduced muscle tension)
short
Infertile
```
52
Describe Angelman syndrome
Loss of function of the maternal chromosome
| Imprinting defects OR UB3A mutations
53
How is Prader-Willis syndrome treated
Diet restriction
Exercise for muscle
Growth hormones
Hormone replacement
54
What is the karyotype of the mitochondria
36 genes
| 2-10 copies are circular genomes
55
Describe mitochondrial inheritance
Only inherited through females
| The sperm lose their mitochondria as they meet the egg
56
What is heteroplasmy
Mixture of mitochondria with some containing mutant DNA while others are maternal
57
Give some examples of mitochondrial diseases
```
MELAS
LHON
MERRF
DEAF
NARP
```
58
Describe MELAS
Mitochondrial myopathy Encephalopathy Lactic Acidosis and Stroke
Progressive neurodegenerative disorder
The muscle and brain have lots of mitochondria so they are heavily affected
59
What are the symptoms of MELAS
muscle weakness
episodic seizures
stroke-like episodes
vomiting
60
Describe LHON
Leber's hereditary Optic Neuropathy
| More common in males
61
What are the symptoms of LHON
Bilateral vision (loss of central vision)
Optic atrophy
Blindness
62
What are the emerging therapies for LHON
3 parent babies
| donor gives an empty egg cell
63
What is the newborn screening programme in the UK
Physical exam
Hearing test
Blood spot (Guthric acid) - sickle cell, cystic fibrosis, PKU(9 in total)
64
Describe PKU and its symptoms and treatment
```
Phenylketonuria
Deficiency of phenyladenine hydroxylase
Severe retardation
Eczema
Blonde hair and blue eyes
Reduced melanin
Remove phenylalanine from the diet
```
65
Describe MCAD deficiency and its treatment
Medium chain Acyl coA dehydrogenase deficiency
Common disorder of fatty acid oxidation
Sudden death
Beta oxidation cannot occur so fasting an hypoglycaemia is dangerous
adjust caloric intake and avoid fasting
66
Compare somatic to germline mutations
somatic - occurs in a single body cell and cannot be inherited
gremlin - occurs in the gametes and can be inherited
67
Give examples of types of mutations
```
Aneuploidy
Translocation
chromosome:
Macro-deletions
Macro-insertions
gene:
Large insertion
Large or deletions
```
Point mutation
68
What are the hallmarks of cancer
```
Dysregulated growth
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
Invasion/ metastasis
Genome instability and mutation (disordered growth, disordered death, disordered behaviour)
```
69
Explain what a polyclonal disease is
Cancer is polyclonal
| Many clones of varied genetically distinct cells
70
Compare driver to passenger mutation
driver - The 1st key mutation
Can cause a normal cell to become a cancer cell
passenger - mutations that don't contribute to the development of cancer but have occurred during cancer growth
71
What are the 2 main classes of cancer causing genes
proto-oncogenes
| tumour suppressors
72
What is Knudson's 2 hit hypothesis
Most TS genes require damage to both alleles to make the cell cancerous
Hit 1 reduces transcript/protein levels but there is no phenotypic affect
hit 2 causes a total loss of transcription (usually a deletion) and causes malignant potential
73
Give an example of Knudson's two hit hypothesis in practice
Retinoblastoma
When TF E2F is bound it is not functional
Mutated RB does not bind
RB phosphorylated by cyclin CDK, releasing E2F
Genes transcribed to cause pro-growth signals
Familial - child born with 1 mutation, second is somatic
Sporadic - one somatic mutation acquired, second somatic mutation in the same cell
74
What is an SNP
Single nucleotide polymorphism where the base on the genes of different chromosomes are different
DNA cannot be sequenced without an SNP
75
How can SNPs be used to guess the cause of disease
1st hit = SNP
2nd hit = Large deletion
If there is not SNP then it is likely there was a large deletion
76
What percentage of breast cancers are caused by germline mutation and of what genes
2.4%
BRCA1 or BRCA2
BRCA2 predisposes to breast cancer in men
77
Describe breast cancer as mutations
Hit 1 is inherited
hit 2 may not always occur
BRCA genes are TS genes that repair DNA by homologous recombination which cannot happen with mutation
78
Which defects in cell division or DNA repair influence the risk of familial colorectal cancer
Familial adenomatous polyposis
| Lynch syndrome
79
Describe familial adenomatous polyposis
Thousands of intestinal polyps which contribute risk to colorectal cancer
Caused by the APC gene on chromosome 6
Autosomal dominant
80
Describe HNPCC
hereditary non polyposis colorectal cancer
Most common inherited form
mutation of MLH1 or MSH2 (DNA repair genes)
81
Describe oncogenes and tumour suppressors
Proto-oncogenes promote growth and proliferation in cells and those that are in overdrive are oncogenes.
Signalling cascades and mitogenic pathway activation
TS genes regulate cell division, DNA damage, apoptosis and DNA repair
mutations cause loss of function and faulty cell division
82
Describe chronic myeloid leukaemia
Clonal myeloproliferative disorder => overproduction of mature granulocytes
Middle ages/elderly
3 phases: chronic (benign), accelerated (omnious), blast crisis (acute leukaemic, invariably fatal)
Philadelphia chromosome is found in >90% produces a new tyrosine kinase
83
What are the indications of testing
```
Nuchal scan
Mid-trimester
Previous pregnancies with DS or CF
Parents are carriers of chromosome rearrangement or genetic condition
FH of genetic condition
```
84
Describe the nuchal scan
Looks at the thickness of the fluid at the back of the fetal neck
> 3mm indicates a chromosomal abnormality
Not a diagnostic test
Could be Down's, Edwards, Patau or cardiac
85
What is the combined test for Down's
Combined test =levels of the hormone free beta-hCG +protein PAPP-A
High hCG and Low levels of PAPP-A.
86
Describe the mid-trimester scan
20 weeks
dates the pregnancy
Diagnose miscarriage or fatal anomalies
87
What are the reproductive options available
Planning prenatal testing
Facilitating decision making
Seeing patients in clinic following diagnosis in utero
Arrange termination if necessary
Discuss recurrence risks and plans for future pregnancies
Taking into account: previous experiences, family situation, personal beliefs, psychosocial situation, miscarriage risk with genetic risk
88
What types of scanning are done in pre-natal testing
ultrasound - early scan, nuchal, anomalies in hands, feet, face, lip
MRI at 20 weeks
89
Describe non-invasive pre-natal testing
Maternal serum screening = testing serum markers in the blood for trisomy 21 or 18 + nuchal measurement
cell-free fetal DNA = analysing DNA fragments in the maternal plasma during pregnancy. baby at 9 weeks. Only 10-20% from the placenta
ultrasound
90
What are the disadvantages of non-invasive testing
Both not as useful for multiple pregnancies
| non-invasive is harder with a greater BMI
91
Describe Amniocentesis
Invasive
16 weeks onwards
Sample the amniotic fluid which contains fetal cells
1% miscarriage risk, infection, Rh sensitisation
92
Define heritability
The study of genetic contribution to increased risk of disease
Studies usually use mono and dizygotic twins
93
Why may estimates on heritability vary
different populations
different ages
baseline risk of disease in population
sampling variance
94
What is GWAS
genome wide association studies that studies SNPs
95
What is the copy number variant
Repeated code
Deletions, duplications, insertions that increase polygenic disease risk
Found in obeisty
96
What are the types of obesity
Monogenic - dominant or recessive single gene disorder
Common - general population
Syndromic - e.g. Prader Willis
97
What is leptin
Hormone made by adipocytes inwards white adipose tissue which circulates in proportion to the amount of adipose tissue
Inhibits appetite via the hypothalamus
High with high fat
98
What are the symptoms of monogenic leptin deficiency
```
hunger
obesity
no puberty
poor growth
Low thyroid
```
99
Give examples of genes that cause single gene obesity
```
MC4R = dominant
PCSK1 = recessive
POMC = recessive
MRAP2 = recessive
```
100
How is obesity clinically management
Lifelong prevention
Lifestyle measures
Medication
bariatric (weight loss) surgery
101
How is obesity diagnosed
PCR for diagnosis
Pre-implantation diagnosis for IVF embryos
Mitochondrial transfer (3 parent babies)
102
What is Sanger sequencing
Amplifying the region of interest with nucleoside terminators
Genetic sequence of the region of interest
103
What is Next generation sequence
Fragmentation, sequencing and mapping of reads
| sequence of the genome/transcriptome
104
What are the advantages and disadvantages of Sanger sequencing
quick
gives sequence
cannot multiplex
Limited to 2000bp
105
What are the advantages and disadvantages of next generations sequencing
Massively multiplex
Multiple different libraries
```
Cost
Time
Read-depth
Data overload
Library bias
```
106
Describe chorionic villus sampling
```
Invasive
11-14 weeks
1-2% miscarriage risk
Sample of chorionic villi part of developing placenta (same DNA as the foetus)
Ealier result than amniocentesis
```
