1
Q
What are the four classified genetic disorder categories
A
- Mendelian disorders
- Multifactorial disorders
- Chromosomal (cytogenetic) disorders
- Single-gene disorders with non-classic inheritance
2
Q
Define penetrance
A
The amount of people that carry an autosomal dominant gene and expressing the trait.
Penetrance refers to the probability of a gene or trait being expressed.
e.g 50% penetrance means that 50% of people who carry the gene also express the trait
3
Q
Define variable expressivity
A
Variability in the effect caused by the mutation
(e.g manifestations of neurofibromatosis type 1 ranges from macules on skint to tumours)
4
Q
Define co-dominance
A
full expression of both alleles of a given gene pair in a heterozygote e.g HLA
5
Q
Define polymorphism
A
Multiple allelic forms of a single gene
Each varient confers increased disease risk, no single gene is necessary or sufficient to produce disease
6
Q
Define pleiotropism
A
multiple end effects of a single mutant gene
e.g sickle cell disease - can cause haemolysis, bone necrosis)
7
Q
Define genetic heterogeneity
A
Multiple different mutations resulting in the same outcome
8
Q
In what way ways can our genetic code mutate (list 4)
A
Point mutations in coding sequences
Mutations in non-coding regions
Deletions and insertions
Trinucleotide repeat mutations
9
Q
What do point mutations usually result in
A
An abnormally short protein chain
10
Q
What causes familial hypercholesterolemia, how is it inhereted
A
mutation in the gene for a membrane receptor (chromosome 19)
Autosomal dominant
11
Q
How are mutations in structural genes normally transmitted
A
Autosomal dominant
12
Q
Characteristic features of autosomal dominant disorders (4)
A
- in many patients, structural proteins, rather than enzymes, are affected, so it’s a problem of STRUCTURE
- Age of onset usually delayed, clinical features variable, so high variable expressibility, low penetrance
- Affects both men & women, and both can transmit to their kids
- Risk to child of affected person is 50%
13
Q
Examples of autosomal dominant disorders (10)
A
- CNS
- neurofibromatosis
- Huntington’s disease - Urinary
- polycystic kidney disease - GIT
- Familial polyposis coli - Skeletal
- Marfan’s syndrome
- Elhers-Danlos syndrome
- osteogenesis imperfecta - Metabolic
- familial hypercholesterolemia - blood
- von Willebrand disease
- hereditary spherocytosis
14
Q
Examples of autosomal recessive disorders (11)
A
Metabolic
- cystic fibrosis, - phenylketonuria
- alpha1-antitrypsin deficiency
- Storage problems
- Wilson disease,
- Haemochromatosis
- Glycogen storage disease
- lysosomal storage disease - endo
- congenital adrenal hyperplasia - blood
- thalassemias
- sickle cell anaemia - CNS
- Friedreich ataxia
- spinal muscular atrophy
15
Q
Characteristics of autosomal recessive disorders
A
- in many patients, enzyme proteins, rather than structural proteins, are affected, So the problem is now FUNCTION
- age of onset usually at birth or early in life, clinical features more uniform, so low variable expressibility, high penetrance (complete penetrance is common)
Points to note
- Affected person usually has unaffected parents, these parents are usually carriers, so usually appear normal
- all children of affected parent will be carriers
- the birth of an affected child is usually the first indication of the disease in a family
- both the parents have transmitted the disease
- affects either sex
- 25% risk if a prior child is affected
- 2/3 of healthy offspring will be carriers
16
Q
A sickle cell trait heterozygote will have what
A
- An abnormal Hb
- Mild likelihood of vascular occlusions
17
Q
Key characteristics of X linked recessive disorders
A
- affects almost exclusively males
- affected males born to unaffected parents, mother is asymptomatic carrier
- females may be affected if father is affected and mother is carrier, or if X-inactivation if female is skewed
- no male-to-male transmission
18
Q
Key characteristics of X linked dominant disorders
A
- affects either sex
- females often more mildly and more variably affected (males hemizygous, females heterozygous)
- child of affected female has a 50% risk, regardless of sex
- for affected male, all his daughters will be affected, but non of his sons will
19
Q
Examples of X linked recessive disorders
A
Skeletal
- Duchenne muscular dystrophy
Blood
- haemophilia A and B, chronic granulomatous disease
G6P dehydrogenase deficiency
Immune
- agammaglobulinemia
Metabolic
- diabetes insipidus
CNS
- fragile X syndrome
20
Q
Clinical expression of a female who is heterozygous for a recessive x linked disorder
A
The disorder may be partially expressed
21
Q
Is an extra X chromosome more or less harmful than the possession of an extra autosomal chromosome and why
A
The possession of an X chromosome in excess of the normal complement is less harmful than the possession of an extra autosome BECAUSE
Only one X chromosome in a cell is functional
22
Q
Inheritance patterns of multifactorial inheritance
A
- Mutations may be present in more than one gene
- The risk of recurrence in subsequent pregnancies is less than 10%
- Identical twins will show 20-40% concordance
4.The risk of recurrence of the disorder in first degree relatives is 2-7%
23
Q
Characteristics suggesting a disorder is inherited as a multifactorial trait
A
- The disease occurs more frequently in the children of an affected person than among the grandchildren
- The risk of developing the disease is greater if both parents are affected than if only one parent is affected
- The disease occurs more frequently in women than in men
24
Q
Malignant conditions usually associated with chromosomal translocation include
A
- chronic myeloid leukemia
- Burkitt’s lymphoma
25
Outline chromosomal number changes in cytogenic disorder
- Monosomy
- Trisomy
- Mosaicism > a/w a group of cells, some with which is normal, others express extra or missing chromosomes
26
5 abnormal structures of chromosomes
May be caused by alterations in the number or in the structure of chromosomes.
Deletion
- Loss of a segment of a chromosome
Translocation
- Transfer of a segment of one chromosome to another two types...
1. Balanced reciprocal
- Exchange of chromosomal material between two chromosomes with no net gain or loss of genetic material
2. Robertsonian fusion
- Reciprocal translocation between two acrocentric chromosomes involving the short arm of one and the long arm of another. Leads to the formation of one abnormally large and one extremely small chromosome.
Iso-chromosome
- One arm is lost (short or long) and the remaining arm is duplicated.
- i.e chromosome with two short or two long arms
Inversion
- Rearrangement associated with two breaks in a chromosome followed by inversion and reincorporation of the broken segment
Ring chromosome
- deletion affecting both ends, followed by fusion of the damaged ends
27
Are chromosomal/karyotype abnormalities implicated in neoplasms and if so why.
Karyotype/chromosomal abnormalities are thought to be a primary event in development of many human neoplasms
BECAUSE
In certain types of human neoplasia, karyotype abnormality is non-random and common in that tumour type
28
What are the most common types of non-random structural abnormalities in tumour cells.
1. balanced translocations
2. chromosomal deletions, and
3. cytogenetic manifestations of gene amplification
29
What is aneuploidy
- It refers to a chromosome number different from the normal or euploid number
- Aneuploid cells may have more or fewer chromosomes than normal
30
Common disorders associated with aneuploidy
- Most patients with Down syndrome
- All trisomy syndrome
- Turner’s syndrome
- Poly-X females
31
How can Aneuploidy be detected
- May be detected by karyotyping
- In tumour cells may be detected by flow cytometry
32
What are 2 usual cause of aneuploidy
Non-disjunction
- Occurs during gametogenesis results in the formation of gamete with one less chromosome and one extra chromosome
- Failure of homologous chromosomes to separate in anaphase 1 (both get pulled to one side)
- Failure of sister chromatids to separate at meiosis II
- Gives rise to nullisomic and disomic gametes
Anaphase lag
- Homologoous chromosome in meosis or chromatid in mitosis is left behind.
- i.e chromosomes successfully seperate during anaphase but one spindle fibre lags behind leaving a chromsome in the cytoplasm not the nucleus so it gets destroyed.
- The result is one normal gamete/cell and one gamete/ cell with monosomy.
33
Are all cells in the body affected by aneuploidy
Meiotic non-disjunction means an aneuploid
###
34
Examples of trisomies and monosomy
Trisomies only survival for
> Sex chromosomes: XXY, XYY, XXXY, etc...
> 21 (down syndrome) 1/700 live births
> 13 (Patau syndrome) 1/5000 live births
> 18 (Edwards syndrome) 1/3000 live births
Monosomy X only
> Turner’s syndrome
35
What are complex multigenic disorders
Caused by an interplay of variant forms of genes and environmental factors.
Genetic variants with at least 2 different alleles and an incidence in the population >1% are called polymorphisms.
Occurs when several polymorphisms are present
Small effect and low penetrance
Not all polymorphisms are equally important - e.g 20-30 genes are implicated in T1DM, only 6-7 are important.
36
What are 2 distincttive features of mitochondrial disorders
- Matrilineal inheritance
- Heteroplasmy (some mitochondria acquire duplications, deletions etc and others don't. Leads to variation in expression of mutations in various genomes in the mitochondria).
37
What tissues are affected by mitochondrial diosders
Neural
Muscular
38
Inheritance pattern of mitochondrial disorders
Mostly autosomal recessive (in paediatrics)
Around 25% obey mitochondrial inheritance
- Both sexes affected
- Transmission only by females (mitochondria are maternally derived only)
- No transmission by males
39
What is incomplete penetrance
- An individual carrying mutation who does not express the phenotype
- A feature of dominantly inherited disorders
40
What is variable expressivity
- Variation between affected individuals in clinical manifestation
- Most common in dominant disorders
41
What are genes composed of
Exons: Specify the amino acids in the protein chain and also contain untranslated regulatory regions
Introns: Seperate exons
Promoters: Direct transcription
42
Where can mutations occur
Exons
- After the coding sequence (missense - incorrect amino acid = malfunctioning protein)
- Insert a truncating codon (nonsense stop codon added)
- After spllicing (splice site mutation)
- Cause a frameshift ( insertion or deletion of nucleotide bases in numbers that are not multiples of three)
Introns
Promoters
Enhancers
43
What chromosomes contain redundant DNA on their short arms
13,14,15, 21,22
44
Is familial polyposis coli x linked
No
45
Sensitive technique for HIV detection
PCR
46
What does FISH enhance and what can it indentify
1. enhances karyotyping
2. can identify intragene deletion
47
What can the southern blot analysis detect and what does the technique involve
1. involves separation of DNA sequences according to size
2. may be used to detect abnormalities due to point mutations
48
Genetic abnormality associated with Angelman syndrome
Genomic imprinting
49
Genetic abnormality associated with CF
Deletion
50
Genetic abnormality associated with Osteogenesis imperfecta
Gonadal moscism
51
Genetic abnormality associated with Beta thalassemia
Deletions
52
Genetic abnormality associated with Fragile X
Triple repeat mutation
53
4 categories of single gene disorders that dont follow non-classic inheritance
These are classified into 4 categories
1. Triplet repeat mutations Fragile X syndrome
2. mutations in mitochondrial genes
Leber hereditary optic neuropathy
3. genomic imprinting Prader-Willi and Angelman syndromes
4. Gonadal Mosaicism
54
What causes Turners syndrome
Non-dysjunction (failure of chromosomes to seperate)
55
Does Turners exhibit mosacism
Yes
56
Is spontaneous abortion common in Turners syndrome
Yes, occurs in 99%
57
Clinical features of Turners syndrome
Neck skin folds
Lymphodema
short stature
amenorrhoea
broad chest
low hairline
increased carrying angle of arm
coarctation of aorta 20% " hypertension
IG and life span normal
58
Frequency of Turners
1:5000 female births
59
Most common Karyoptype of Klinefelters and other possible karyotypes
47,XXY is most common (80% of cases)
others are mosaics, e.g. 46,XY/47XXY
60
Clinical features of Klinefelters (7)
leading cause of male infertility
Eunuchoid body habitus
minimal or no mental retardation
failure of male secondary sexual characteristics
gynecomastia; female distribution of hair
atrophic testis with hyperplasia of Leydig cells
plasma follicle-stimulating hormone and estrogen levels elevated; testosterone levels low
61
Clinical features of Trisomy 21 (6)
flat facies with oblique palpebral fissures and epicanthic folds
severe mental retardation IQ <50
congenital heart malformation 40%, esp. septal defect! death during infancy, otherwise lifespan is not reduced
10 to 20 fold increased risk of developing acute leukemia
serious infection resulting from abnormal immune responses
premature Alzheimer’s disease in those who survive after 35 yrs
62
Is down syndrome associated with mosaiscm
Yes, in milder cases
63
Most common cause of trisomy 21
95% free trisomy 21 > 47,XY (or XX) + 21
Maternal non-disjunction
- meiosis I 65%
- meiosis II 23%
Paternal non-disjunction
- meiosis I 3%
- meiosis II 5%
64
Less common cause of trisomy 21
5% Translocation (Robertsonian)
- Long arm chromosome 21 to chromosome 22 or 14.
- I.e now have a chromosome with the long arm from 21 + the long arm from 14/22 (dicentric) and an accocentric chromosome i.e the short arm from each.
- This short arm doesn't contain much DNA, can't undergo mitosis so disappears.
- Results in people becoming balanced carriers, they contain the chromosome with the two long arms (45 total chromosomes) but they have a normal phenotype as the genetic info is complete.
- Problems arise at gametogenesis
- No maternal age effect
- Risk of recurrenece
65
What are the two types of point mutations in coding sequences
Missense mutation
- Single nucleotide substitution
- Results in a change of amino acid and therefore final protein product.
- Considered a conservative misense mutation if the new amino acid is not significantly different from the original (minimal or maybe no consequences)
- Non conservative mutation - amino acid substituion is a different size or charge = loss/gain/degradation of protein
Nonsense mutation
- Single nucleotide substitution results in formation of a stop codon. Leading to a protein that may be truncated/ lose activity.
66
What are mutations within non-coding regions of DNA
Point mutation in enhancer or promoter region which results in big alteration in the regulation of gene transcription.
67
What is a frameshift mutation
A mutation which results in the deletion or insertion of a nucleotide (i.e not substituted) - greater to or less than 3.
Leads to defective protein products, truncation or misense mutation.
68
alterations in protein coding genes other than mutations
e.g amplification, deletion or translocation
69
What are trinucelotide repeat mutations
Amplification of triple nucleotide sequence such as in Hungtintons or fragile X
70
Examples of enzyme defect dissease
alpha 1 antitrypsin
Albinism
Phenylketonuria
71
Gene affected in marfan syndrome
inheritance pattern
Autosomal dominant
Fibrillin 1 gene
= Defective microfibril assembly resulting in reduced elasticity
= Reduced sequestration of TGF-B (increased inflammation)
= ANGII blockers inhibit TGF-B activity
72
Diagnosis of Marfans
Ghent criteria
- Family history
- Fibrillin mutation
- Major involvement in 2/4 systems (CVS, skeletal, ocular, cutaneous) + minor involvement of 1
73
What is EDS
Group of disorders affecting collagen synthesis
6 different variations
most are autosomal dominant
74
List 2 other trisomys
Trisomy 13 - Patau Syndrome
Trisomy 18 - Edwards Syndrome
75
What is chromosome 22q11.2 deletion syndrome
Di George
T cell immunodeficiency and hypocalcemia (hypoparathyroidsim
76
What is a Barr body and what gene is responsible
Random inactivation of an X chromosome
XIST gene
77
What type of mutations causes B thalassemia
Nonsense mutation
78
What type of mutation causes CF
3 base deletion (therefore not a frameshift)
79
What type of mutation causes the O mutation in ABO
Single base deletion
80
What type of mutation causes Tay Sachs
Four base insertion/frameshift
81
What is thought to cause turners syndrome
Non dysjcuntion
82
How do you detect Di-George
FISH
83
Why are sex chromosome mutations better tolerated
1. Lyoniztion of all but one x chromosome
2. Small amount of genetic material on the Y chromsome
84
When does X inactivation occur
day 5.5 of embryonic life therefore all females are moasaics
85
Where is the SRY gene located
Distal short arm
86
Implications of more and more X chromosomes
Increased likelihood of intellectual disability
87
What are hormone levels like in Klinefelters
FSH high
Testosterone low
Estradiol high
88
How does klinefelters occur
47XXY
Non dysjunction in first meiosis
89
Risk factor for klinefelters
advanced maternal age
90
3 different types of turners
45X (57%)
Mosaic 29%
Structurally abnormal 14%
91
Frequency of structural abnormalities in turners
Isochromosome - loss of short arm
Deletion of portions of both long and short arms
Deletion of portion of short or long arm
92
4 types of single gene disorders that dont follow mendelian
- Trinucleotide repeat mutations
- Mitochondrial gene mutations
- Genomic imprinting disorders
- Gonadal mosacism
93
When do expansions occur in Hungtingtons and FXs
H - Spermatogenesis
X - OOgeneis
94
HOw does hungtingtons and FXS cause diseae
H - toxic gain or function by protein
X - Toxic gain of function mediated by RNA
95
What are the disease presentations of premutation carrying males and females of FXS
Fragile X associated primary ovarian failure
- Menstrual irregularities and decreased fertiltiy
- Premature ovarian failure
- Decreased AMH
- Increased FSH
Fragile X associated tremor/ataxia
- Intention tremors and cerebellar ataxia, may progress to parkinsonism
96
Example of a mutation in mitochondrial genes
Leber hereditary optic neuropathy
97
What enzymes are encoded in mtDNA
Oxidative phosphorylation enzymes
98
How many genes are in human mtDNA
37
99
What is heteroplasmy and the threshold effect
When not all of the mitochrondria in mtDNA contain the mutation.
The higher the proportion of mutated genes the more likely it'll be passed on (however this occurs randomly)
Threshold effect = minimum number of mutants present before oxidative dysfunction gives rise to disease
100
Explain genomic imprinting and give examples of 2 diseases
In some genes the expression of a particular allele depends on which parent it came from.
Paternal imprinting: Paternal gene silenced
Maternal imprinting: Maternal gene silenced
Occurs in ovum or sperm, before fertilisation.
Loss of the functional gene (not imprinted) allele by deletion gives rise to diseases.
Deletion in chromosome 15
Angelman syndrome
- Maternal
Prader Willi
- Praternal
101
What is gonadal mosaicism and give an example
Phenotypically normal parents have more than one affected child of an autosomal disorder.
Mutation that occurs post-zygotically during early embryonic development.
If the mutation affects only cells destined for the gonads then the gametes carry the mutation but the somatic cels of the individual are normal.
Osteogeneis imperfecta
102
GSSE
flashcards
Decks in class (15)
# Cards
-
CVS physiology165
-
Infectious diseases96
-
Surgical infection83
-
Neoplasia77
-
Cell injury and death79
-
Inflammation12
-
Important cancers190
-
Haemodynamic disorders thrombosis and shock42
-
Genetics102
-
Immunology124
-
Pharmacology20
-
Statistics49
-
Gastro physiology186
-
Neuro physiology100
-
Haemotology100
