Genen Flashcards
1
Q
Who is the Proband?
A
the person who brings the family to the attention of the genetics clinic
2
Q
Who is the Consultand?
A
the person sitting in front of you asking for genetic advice
3
Q
Vertical pattern of inheritance
A
feature in which multiple generations are affected
This is dominant inheritance – you only need one faulty gene to get the disease
4
Q
Horizontal inheritance
A
People in a single generation are affected (sibship)
This is recessive inheritance – you need two faulty genes to get the disease
NB: vertical always takes precedence over horizontal
5
Q
Knight’s move inheritance
A
two males are affected through an unaffected
female
This is characteristic of an x-linked recessive disorder (the female has an additional
unaffected X chromosome which ‘protects’ her)
6
Q
What is the inheritence of Achondroplasia?
A
Autosomal dominant
Causes short stature due to shortening of the limbs (short-limb dwarfism)
Shows complete penetrance
7
Q
What is the inheritence of Albinism?
A
Autosomal recessive
8
Q
Autosomal Dominant Inheritance
A
The genes for these traits are on the autosomes.
you need only one mutant gene to express the trait.
heterozygote and homozygote for the mutation show the same phenotype.
9
Q
What are the features on a pedigree that suggest dominant inheritance?
A
1) vertical pattern of inheritance, affects every generation
2) both males and females affected
3) male to male transmission
Variable expression and complete/incomplete penetrance are possible
10
Q
Variable expressivity
A
quantitative and qualitative differences in phenotype between individuals having the same allele or genotype.
I.e. not everyone affected, even in the same family (who are assumed to have
the same mutation) has exactly the same phenotype as they can be affected to different extents by the same gene.
severity, frequency of ‘attacks’ and age of onset can all vary.
11
Q
What causes Variable expressivity?
A
Environmental factors causing an epigenetic effect (switching on or off of genes)
MODIFIER GENES: alter expression of a human gene at anotherlocusthat in turn
causes agenetic disease
If the trait is X linked, there can be variation due to the differences in the pattern of X inactivation
12
Q
Incomplete penetrance
A
Refers to the fact that you can inherit a mutation, e.g. BRCA, but not express the phenotype
i.e. the phenotype can skip a generation
Many autosomal dominant disorders show incomplete penetrance
13
Q
Obligate heterozygotes
A
individuals in the direct line of descent of an affected parent who have
affected children.
I.e. they must be carriers of the trait
14
Q
GONADAL MOSAICISM
A
Gonadal mosaicism = a type of genetic mosaicism where more than one set of genetic information is found
specifically within the gamete cells.
When present in the gonads, offspring can inherit the mutation (will affect 100% of child’s cells)
15
Q
Genetic mosaicism
A
Genetic mosaicism indicates that a person is composed of more than one genotype
develops when a genetic mutation occurs after fertilization, and results in an individual possessing both a mutated cell line and a normal cell line
16
Q
Autosomal recessive conditions
A
for someone to be affected they must have inherited two faulty copies of the gene
Parents are assumed to be carriers
17
Q
What are the characteristic traits of an autosomal recessive inheritance pattern?
A
1) horizontal pattern of inheritance
2) both sexes can be affected
3) parents are usually both carriers but unaffected
4) the probability of a normal sibling being a carrier is 2/3
5) if the trait is rare, there may be consanguinity
AR conditions are usually fully penetrant
18
Q
What is the probability of a normal sibling of an affect child with an AR condition being a carrier?
A
2/3
19
Q
What is the recurrence risk for each sibling of an affected person with an AR condition?
A
1/4 (25%)
20
Q
Name 3 AR conditions
A
- sickle cell disease
- cystic fibrosis
- phenylketonuria (PKU)
- spinal muscular atrophy (SMA)
- congenital adrenal hyperplasia
21
Q
Compound heterozygotes
A
have two different mutations in the same gene, causing a mutation in each allele
22
Q
Sex linked inheritance
A
refers to traits controlled by genes on the X or Y chromosome.
23
Q
Transmission of x-linked recessive disorders to offspring
A
1) XR traits show no male to male transmission since their sons receive their Y and not their X.
2) Unaffected males do not transmit the phenotype.
3) All daughters of an affected male are heterozygous carriers since they get their father’s X
chromosome with the mutant allele.
4) knights move pedigree pattern
4) males affected more than females
24
Q
What is the genotype of the daughter of a man affected by an x-linked recessive disorder?
A
All daughters of an affected male are heterozygous carriers since they get their father’s X chromosome with the mutant allele.
25
What is the genotype of the son of a man affected by an x-linked recessive disorder?
XR traits show no male to male transmission since their sons receive their Y and not their X.
26
What is a manifesting carrier?
Females may be mildly affected x-linked recessive disorders as a result of to skewed x-inactivation (uneven inactivation of the x-chromosome)
27
What is the inheritance pattern of Duchenne Muscular Dystrophy?
X-linked recessive
~ 2/3 cases are inherited from a person's mother
~1/3 cases are due to a new mutation
28
What is the risk of the son of a female carrier of an x-linked recessive disorder being affected?
Sons of female carriers have a 50% risk of being affected
father passes on Y chromosome, mother can pass on either the normal
X chromosome or the faulty X chromosome
29
What is the risk of the daughter of a female carrier of an x-linked recessive disorder being affected?
Females are usually only carriers
Daughters of a female carrier have a 50% chance of being a carrier
30
What are the expected genotype proportions of the offspring of a male with an X-linked recessive condition?
No sons are affected – passes on Y chromosome
all daughters are carriers
31
X-Linked Dominant Inheritance
When the disorder nearly always manifests in heterozygous females
Females tend to be affected twice as often as males and an affected female will transmit the phenotype
to 50% of her children independent of their sex.
No male to male transmission.
32
Name 3 conditions that show X-Linked Dominant Inheritance
vitamin D resistant rickets
Incontinentia pigmenti (has male lethality)
Rett syndrome (male lethality - usually)
33
What is the risk of the daughter of a female affected by an x-linked dominant disorder being affected?
50% chance of passing on the gene
Sons and daughters at equal risk
34
What is the risk of the son of a female affected by an x-linked dominant disorder being affected?
50% chance of passing on the gene
Sons and daughters at equal risk
35
What is the risk of the daughter of a male affected by an x-linked dominant disorder being affected?
All daughters will be affected
36
What is the risk of the son of a male affected by an x-linked dominant disorder being affected?
No sons will be affected
37
Which one of the following is common for X-linked recessive inheritance:
* Severely affected females
* Parental consanguinity
* Daughters are carriers if their father is affected
* Equal sex ratio for affected individuals
* Affected boys with an affected father
Daughters are carriers if their father is affected
38
What is Genetic “anticipation”?
Increasing severity and earlier age of onset of a condition in successive generations
39
Which conditions show genetic anticipation?
Huntington disease (HD),
Fragile X syndrome,
Myotonic dystrophy
40
what is Pseudo-dominant inheritance?
If an autosomal recessive condition has a very high carrier frequency or consanguinity – it appears like an autosomal dominant condition
i.e. the inheritance of a recessive trait mimics a dominant pattern
41
Which condition shows Pseudo-dominant inheritance?
Gilbert syndrome - carrier frequency is approximately 50%
42
What is the pattern of mitochondrial inheritance?
inherited only from the mother, but to variable extents
43
hypertelorism
abnormally increased distance the orbits (eyes)
44
Examples of dysmorphic features
Head - micro/macrocephaly
Eyes - abnormal Palpebral fissures
Ears - low set, rotated anteriorly or posteriorly
Philtrum - smooth in FAS
Skin – Lumps, abnormal pigmentation
Hands and feet - Palmar creases
Fingers and toes – Polydactyly/syndactyly
45
Pre-implantation Genetic Diagnosis
1-2 cells removed for testing at 3 days of development, when the embryo contains only 6-10 cells
analysis by PCR or FISH
Embryo sexing for X-linked recessive disorders possible by FISH
46
Pre-implantation Genetic Diagnosis advantages
Permits implantation of unaffected embryos
Termination of pregnancy then unnecessary
47
Pre-implantation Genetic Diagnosis disadvantages
Possible long waiting list
Not available to all women
Difficult with multiple visits and procedures
“Take home baby rate” usually <50% per cycle
48
Main principles of a screening programme
```
Clearly defined disorder
Appreciable frequency
Advantage to early diagnosis
Few false positives (specificity)
Few false negatives (sensitivity)
Benefits outweigh the costs
```
49
False negative
missed true case (negative result on screening test)
50
False positive
positive on screening but negative on diagnostic test
51
Sensitivity
How good is the test at correctly identifying people who do have the condition?
i.e. of all the people who have the condition, how many get a positive test on the screening
test?
52
Specificity
How good is the test at identifying people who don’t have the disease?
i.e. How good is this test at ruling out the disease when it’s not present
53
PRENATAL SCREENING TESTS
Down syndrome
Two methods, which can be used in combination with each other:
1) Serum screening
Maternal blood biochemical markers
Blood sample taken from the mother between 10 - 14 weeks of pregnancy
Serum screen measures free beta-hCG and pregnancy-associated plasma protein A (PAPP-A)
2) Ultrasound screening (nuchal translucency)
Carried out between 11 -14 weeks
Foetal nuchal translucency (FNT) screening uses ultrasound to measure the size of the nuchal pad at
the nape of the foetal neck.
nuchal translucency increases in Down syndrome
54
Guthrie test
NEONATAL SCREENING TEST
Screens for 9 conditions, including PKU, CF, sickle cell disease and congenital hypothyroidism
55
Who is Sickle Cell and Thalassaemia (SCT) screening offered to?
all pregnant women
fathers-to-be, where antenatal screening shows the mother is a genetic carrier
all newborn babies,
56
Chorionic villus sampling
GENETIC DIAGNOSTIC TEST
o Weeks 10-12
o Up to 1/50 chance of miscarriage
o Result in <1 week
57
Amniocentesis
GENETIC DIAGNOSTIC TEST
o Weeks 16-18
o Up to 1/100 miscarriage rate
o Result in 1-2 weeks
58
Array comparative genomic hybridization
technique for detection of chromosomal copy
number changes on a genome wide and high-resolution scale.
compares foetal DNA with normal DNA
checks for excess of any part of any chromosome
59
non-invasive prenatal diagnosis (NIPD)
sample of blood taken from the mother. Detects free foetal DNA in the maternal serum
Can be used for achondroplasia and for foetal sex determination
60
What is Heteroplasmy?
the presence of more than one type of organellar genome (mitochondrial DNA
or plastid DNA) within a cell/individual.
I.e. A cell can have some mitochondria that have a mutation in the mtDNA and some that do not. This is termed heteroplasmy.
61
Threshold effect
Mitochondrial disease may become clinically apparent once the number of affected
mitochondria reaches a certain level; the "threshold expression."
62
Huntington Disease
- inheritance
- onset
- mutation
- symptoms
- autosomal dominance with genetic anticipation (especially when passed on by the father)
- onset typically in adulthood between 30 and 50
- unstable length mutation in gene (huntingtin, HTT)
Repeat of CAG codon
- symptoms = progressive choreas, dementia and psychiatric symptoms
63
How many CAG repeats cause the varied presentations in Huntington's disease?
* up to 35 repeats = unaffected
* 36-39 = incomplete penetrance (may or may not get HD)
* >40 = Huntington’s
64
How do CAG repeats lead to HD?
* CAG repeat unit within the coding sequence encodes a polyglutamine tract
* expansion of the tract causes insoluble protein aggregates and neurotoxicity
65
Myotonic dystrophy
- inheritance
- mutation
- symptoms
Autosomal dominant with genetic anticipation
Adult onset disease.
unstable length mutation of a CTG repeat
in the 3’ untranslated region of the DMPK gene. causes RNA splicing abnormalities for several genes because the abnormal region binds to a protein binding factor needed for splicing.
Symptoms:
o progressive muscle weakness in early adulthood
o myotonia - inability to relax voluntary muscle after vigorous effort.
o cataracts
66
A man has been diagnosed as having myotonic dystrophy (DM), an adult onset disease for which there is no cure. He wishes to know if his healthy 5-year-old son is later going to develop DM.
Can parent request genetic test for child?
No - they will have to wait until the child is able to decide for themselves.
Parents can only request for their child to be testing if it has a specific benefit such as in cystic fibrosis, when they can test for the specific phenotype to determine which medication will work best.
67
Cystic Fibrosis
- inheritance
- mutation
- symptoms
Autosomal recessive
CFTR mutations causes defective chloride ion channel. Leads to increased thickness of secretions as the ion channel does not function properly. Phenylalanine deletion is most common
Causes:
• recurrent lung infections
• exocrine pancreatic insufficiency (85-90% of cases) due to blockage by secretions
68
How is Cystic Fibrosis diagnosed?
screening of newborns by immunoreactive trypsin (IRT) level
confirmation by DNA testing (for CF mutations) and/or sweat testing (for increased chloride concentration)
69
Name 4 conditions that show genetic anticipation
1) huntington's disease
2) myotonic dystrophy
3) Fragile X syndrome
4) spinocerebellar ataxia
70
Name 3 x-linked recessive conditions
1) duchenne uscular dystrophy
2) Becker's muscular dystrophy
3) Fragile X syndrome
71
NF-1
- inheritance
- mutation
- symptoms
Autosomal dominant
mutation of a gene on chromosome 17
that is responsible for production of
the protein neurofibromin --> abnormal neurofibromin production
```
Symptoms
café au lait macules
neurofibromas
short stature
macrocephaly
```
Incomplete penetrance
72
Duchenne muscular Dystrophy
- inheritance
- mutation
- symptoms
X-linked recessive
DMD Gene: Out of frame mutation -removal of TCAC, 4 nucleotides
Causes Abnormal dystrophin
production
Symptoms
progressive muscle degeneration and weakness
Onset by ~3 years, wheelchair by ~12
Boys with DMD will have massively increased levels of serum CK from birth
73
Becker's muscular dystrophy
- inheritance
- mutation
- symptoms
X-linked recessive
DMD Gene: In-frame mutation - TTC codon is removed
Causes Abnormal dystrophin
production
Symptoms = milder phenotype of DMD
Onset by ~11 years
74
Fragile X syndrome
- inheritance
- mutation
- symptoms
X-linked recessive + genetic anticipation
Repeats in 5’ UTR of FMR1 gene. The repeat causes hypermethylation of DNA & repression transcription of genes
leads to silencing of the FMR1 gene and
a lack of its product
most common inherited cause of significant learning disability
75
Edward syndrome
Trisomy 18
Much more severe than trisomy 21
* small chin
* clenched hands with overlapping fingers
* malformations of heart, kidney & other organs
• If babies survive first year, generally have profound learning disabilities
76
Patau syndrome
```
Trisomy 13
• Congenital heart disease is usual
• About 50% die within 1 month
• like in Edward syndrome, approximately only 10% survive 1st year,
generally with profound LD
```
* cleft lip & palate
* Microphthalmia
* abnormal ears
* clenched fists
* post-axial polydactyly – (extra little finger)
77
Unbalanced translocation
A portion of a chromosome becomes deleted and rejoins at a different
point of the same chromosome or with a different chromosome
78
Balanced carriers
male or female who has all the chromosomes (normal total amount of chromosomal material), but part of one chromosome has swapped with part of another chromosome
Child can inherit an unbalanced set of chromosomes because they inherit one of these abnormal chromosomes and not the other
May account for multiple miscarriages or stillbirths within a family
79
Non-disjunction
Failure of a pair of homologous chromosomes or sister chromatids to separate during meiosis I
and II respectively
Most error results from non-disjunction during meiosis
80
What is an enhancer?
```
a short (50–1500 bp) region of DNA that can be bound by proteins
(transcription factors) to increase the likelihood that transcription of a particular gene will occur.
```
may be missing in some developmental disorders
81
What abnormalities can you look for with DNA-based detection methods?
1. Detection of point mutations
2. Detection of sub-microscopic duplications and deletions
3. detection of aneuploidies
82
aneuploidies vs polyploidies
Aneuploidy - whereby there is an abnormal number of chromosomes, e.g. Trisomy 18
polyploidy – abnormal number of chromosomes but total chromosome number is a multiple of 23, e.g. triploidy
83
How can you detect of point mutations?
1) DNA sequencing
- Sanger - looks at one gene at a time
- next generation sequencing - looks at all genes at once
2) Allele-specific (ARMS) PCR
84
How can you detect of point mutations if you don't know where the point mutation is?
DNA sequencing:
- Sanger
- next generation sequencing
85
How can you detect of point mutations if you know where the point mutation is?
Allele-specific (ARMS) PCR can be used for specific known point mutations (primer has to be designed specifically)
86
What methods are used for detection of sub-microscopic duplications and deletions?
1) MLPA (PCR-based):
o Used to look for deletions between 500-2000 nucleotides in size
2) Array comparative genomic hybridisation (aCGH)
o A way of looking across all of the chromosomes all at once
87
What methods are used for detection of aneuploidies?
Quantitative fluorescent PCR (QF-PCR)
Use DNA markers on chromosomes 13, 18 and 21 to give PCR peaks
2 signals = indicates 2 chromosomes, ok
3 signals = indicates extra chromosome
Remember: quantitative because aneuploidies have a different number
88
What are the available Chromosome-based analysis methods?
Karyotyping - evaluates the number and structure of a person's chromosomes in order to detect abnormalities
FISH (Fluorescence In-Situ Hybridisation) - Used to look for particular parts of a chromosome. Not as precise as other techniques.
Can be used to look for a deletion of 1-2 million nucleotides
89
What methods would you use for Whole chromosome analysis?
karyotyping
QF-PCR
90
What methods would you use for detecting Sub-microscopic deletions/duplications (<5Mb)?
o FISH (Fluorescence In-Situ Hybridisation)
o MLPA (if you know the position)
o aCGH (if position not known)
91
What methods would you use for detecting Point mutations?
o DNA sequencing
o ARMS
92
Missense substitution vs nonsense substitution
Missense substitution – changes one amino acid into another one
nonsense substitution: a point mutation in a sequence of DNA that results in a
premature stop codon
93
Would two different gene mutations located on the same copy of a gene be enough to cause an AR disorder?
No
Both copies of the gene would need to be mutated for the disease to be caused.
Having just two different gene mutations on the same copy of a gene could still leave the other allele (gene copy) unaffected and functional.
Note that an individual with two different gene mutations on different copies of the same gene is called "compound heterozygous"
94
Could a female be affected by an XR disorder if she had a mutation on both of her X chromosomes?
Yes
Alternatively, she could be affected by also having Turner syndrome (XO)
If that single X chromosome contained a mutation then she could be as
severely affected as an affected male.
95
A boy has CF. What is the approximate chance of his mother’s brother being a carrier?
50%
CF is autosomal recessive therefore both of his parents must be carriers. This means that one of his mother’s parents are carriers.
Therefore, the uncle would have had 50/50 chance of inheriting the
mutation from the carrier grandparent.
96
A 12 year old boy has CF. What is the approximate chance that his healthy older sister is a carrier?
Age is significant as this is a childhood onset disease and she clearly does not have it
you need to remove the carrier phenotype out of the equation, so there are only 3 options left
The options left are:
o Carrier
o Carrier
o Unaffected
Therefore, the chance of her being a carrier is 2/3 = 67%
97
What is MLPA most commonly used to detect?
Looking for a sub-microscopic deletion of a gene
e.g. single nucleotide substitution in an unknown position in a gene
98
clinical features and inheritance of MYH polyposis
Autosomal recessive (not autosomal dominant!)
People with this condition have fewer polyps than those with the classic type of FAP
o 15-200 polyps
o like a mild (“attenuated”) form of FAP, but this is a different disorder
Caused by mutation in DNA repair gene MYH
o Normal function: base excision repair (BER) gene – DNA glycosylase
high risk of carcinoma
2 yearly colonoscopy
99
Li Fraumeni syndrome
```
Rare Autosomal Dominant cancer predisposition syndrome
o Breast cancer
o Brain tumours
o Sarcoma
o Leukaemia
o Adrenocortical carcinoma
```
Mutations in master control gene, TP53
100
```
The presence of male breast cancer in a family with other breast cancers, suggests which one of these
genes may be mutated?
1) MLH1
2) MSH2
3) MSH6
4) BRCA1
5) BRCA2
```
BRCA2
101
Which one of the following is not a tumour suppressor gene?
1) MSH2
2) MLH1
3) BRCA2
4) RET
5) APC
RET - proto-oncogene, encodes a receptor tyrosine kinase
102
Which one of the following is true for proto-oncogenes?
1) They include MSH2
2) They are only expressed in malignant tissues
3) Their tumorigenic activity requires the loss or mutation of both copies of the gene
4) They participate in the normal cellular response to growth factors
5) They inactivate oncogenes
They participate in the normal cellular response to growth factors
103
clinical features and inheritance of familial adenomatous polyposis (FAP)
autosomal dominant inherited condition
numerous adenomatous polyps form mainly
in the epithelium of the large intestine.
Polyps start out benign, but malignant transformation into colon cancer occurs when they are left untreated
Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) seen in 80%
o Black spots seen on the retina
o Caused by proliferation of cells due to gene mutations
APC gene - chromosome 5 (tumour suppressor gene)
Annual bowel screening from age 11 for individuals with the mutation
104
clinical features and inheritance of HNPCC/Lynch syndrome
autosomal dominant
high risk of colon cancer
Usually only a few polyps (less than 10)
Risk of getting other types of cancer:
o particularly endometrial cancer in females
o Stomach
o Ovary
inheritance of mutation in mismatch repair (MMR) system genes
o Complex of proteins that are important for accurate DNA replication
o if this system doesn’t work, mutations accumulate
105
Genes causing HNPCC
```
All code for proteins that are involved in mismatch repair.
MLH1
MSH2
MSH6
PMS2
```
