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Semester 3 Revision > MCBHD > Flashcards

MCBHD Flashcards

1
Q

What is meant by autosomal dominant?

A
  • manifests in HETEROZYGOUS form
  • multiple generations affected
  • male to male transmission
  • 50% risk to offspring
  • only need a mutation in one copy of the gene to manifest symptoms
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2
Q

What are characteristics of autosomal inheritance patterns?

A
  • most individuals have an affected parent (not everyone because of cases of new mutations or incomplete penetrance)
  • males and females are equally likely to inherit the allele and be affected
  • risk for each child of an affected parent is 0.5
  • if an affected individual’s siblings/children are not affected, and they do not carry the mutation they cannot pass it on to their own offspring
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3
Q

What is the definition of PENETRANCE?

A

The percentage of individuals expressing the disorder to any degree (sever or mild) - many dominant disorders show age dependent penetrance

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4
Q

What is EXPRESSIVITY?

A

Variation in the severity if a disorder tween individuals with the same mutation

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5
Q

What is the new mutation rate?

A

‘De novo’ mutation rate varies considerably between different AD conditions

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6
Q

What is reproductive fitness?

A

In some AD disorders mutations carriers do not reproduce - the disorder is maintained in the population by new mutations

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7
Q

What is somatic mosaicism?

A

A new mutation arising at an early state in embryogenesis - present only in some tissues/cells

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8
Q

What is germ-line mosaicism?

A

(Gonadal mosaicism) a new mutation arises during oogenesis or spermatogenesis - the mutation is present in a variable proportion of the gametes and can be transmitted to the offspring

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9
Q

What is paternal age effect?

A

The chance of a new mutation increases with advancing paternal age

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10
Q

What is ANTICIPATION?

A

Worsening of disease severity in successive generations - characteristically occurs in triplet repeat disorders

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11
Q

What is AUTOSOMAL RECESSIVE inheritance?

A
  • manifests in homozygous/compound heterozygous form
  • carriers are not affected
  • usually one generation affected
  • May be consanguinity - eg cousin marriages
  • need to have mutations in both copies to be affected
  • carriers have a normal copy which is sufficient to prevent symptoms
  • unless it is a common disorder, or there is consanguinity, normally only a single generation is affected
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12
Q

What are characteristic patterns of autosomal excessive inheritance?

A
  • males and females are equally likely to be affected
  • the trait is often found in clusters of siblings but not in their parents and offspring
  • the more rare a trait in the general population, the greater ten chance it was a consanguineous mating
  • recurrence risk is 1/4 for each sibling of an affected person
  • carrier probability of 2/3 of normal siblings of an affected person
  • all offspring of an affected person are OBLIGATE CARRIERS
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13
Q

About x-linked inheritance…

A

Women have 2 X chromosomes –> two copies of x-linked genes
Men have 1 X and 1 Y –> only a single copy of x-linked genes

Can be…
RECESSIVE: women are carriers, no make to make transmission
DOMINANT: women are affected, males more severely affected/lethal

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14
Q

What are patterns of x-linked inheritance?

A
  • x-linked genes are never passed from father to son
  • males are never carriers
  • makes are more likely to be affected because they only have one copy to the gene
  • affected males get the disease from their mothers (or are new mutations)
  • all of the daughters of affected males are obligate carriers
  • children of carrier females have a 50% chance of receiving the mutant allele
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15
Q

What is skewed x-inactivation?

A

Normally the majority of genes on one of a woman’s x-chromosomes are inactivated. This is generally random but ~10% of women have uneven or skewed x-inactivation >80:20%

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16
Q

What are manifestation carriers?

A

Some women do have symptoms in x-linked recessive conditions eg cardiomyopathy in DMD - unfavourable skewing of x-inactivation may help to explain this

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17
Q

About mitochondrial inheritance…

A
  • rare
  • small circular molecule
  • exclusively maternally inherited/transmitted
  • there may be:
    Homoplasmy: only one type of mtDNA
    Heteroplasmy: more than one type of mtDNA

Threshold effect: normal mitochondrial function below a proportion of abnormal mtDNA but abnormal above it

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18
Q

What is heteropasmy?

A

The presence of more than one type of organelles genome (mtDNA) within a cell of individual. It is an important factor in considering the severity of mitochondrial diseases.

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19
Q

What is the basics if mitosis and meiosis?

A

Daughter cells created after mitosis are generally identical to parent cells.

Meiosis is the type of cell division by which eggs and sperm are produced. Meiosis involves a reduction in the amount of genetic material

  • comprises two successive nuclear divisions with only one round of DNA replication
  • one parent cell produces four daughter cells
  • daughter cells have half the number of chromosomes found in the original parent cell and with crossing over, are genetically different.
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20
Q

How do we look at chromosomes?

A
  • blood same or CVS/amnio
  • culture cells (lymphocytes)
  • arrest cells in metaphase
  • burst cells to release chromosomes
  • mount on a slide and stain
21
Q

What are methods of chromosome identification?

A
  • G-banded ideogram: giemsa stain, most common
  • FISH
  • array - comparative genome hybridisation (Array-CGH)
22
Q

What is FISH?

A

Fluorescence in situ hybridisation
Specific DNA probe used to identify a region if interest (gene, locus, centromere, etc)
cultured cells, metaphase spread
microscopic (5-10 Mb)

23
Q

What is aneuploidy?

A

HAPLOID: one set of chromosomes (n=23) as in a normal gene
DIPLOID: cell contains two sets of chromosomes (normal in human)
POLYPLOID: multiple of the haploid number
ANEUPLOID: chromosome number which is not an exact multiple if the haploid number - due to extra or missing chromosome(s)

Changes can be in the germline or be as a result of mosaicism

24
Q

What is mosaicism?

A

The presence of two or more genetically different cell lines derived for a single zygote

25
Q

About Down’s syndrome

A 
Trisomy 21
95% patients NDJ (usually maternal meiosis I)
5% robertsonian chromosome
~2% mosaic
'Order egg model' - maternal age effect
26
Q

What are the clinical features of Down’s syndrome?

A

1 in 650-1000 live births
Most common cause of mental retardation
Hypotonia, particularly in newborn period
Developmental delay
Cardiac abnormalities; AV canal defects most common
GI abnormalities; duodenal stenosis/atresia, imperforate anus, Hischsprung disease
ALL/AML - 10-20 x relative risk
Conductive hearing loss
Features of Alzheimer’s >40 years

27
Q

About Edwards syndrome…

A 
Trisomy 18
Incidence ~1 in 6000 live births
Intrauterine growth retardation
Micrognathia
Cleft lip +\- palate
Short palpebral fissures
Fixed flex ion deformities of fingers
Heart defect >95% - VSD/ASD/PDA
Inguinal/diaphragmatic hernias
Renal malformations
28
Q

About Patau syndrome…

A

Trisomy 13 - primary or secondary robertsonian translocation
~1 in 10,000 live births
Midline defects: hyotelorism, holoprosencephaly,midline cleft lip/palate, scalp defect
Post axial polydactyly
Heart defects/renal abnormalities
Survival - most die by 1 month

29
Q

What are the basic rules of pedigree drawing?

A
  • males are squares
  • females are circles
  • partners have a line between them
  • siblings have a line above them
  • there is a line down for children
  • affected people are shaded in
  • carriers have dots in
30
Q

About turner syndrome…

A
  • incidence 1/4000 female births
  • 45X0 or mosaic (45X0/46XX, 45 XO/47XXX, 45X0/46XY)
  • > 60% miscarry
  • high incidence in spontaneous abortions (9-10%)
  • raised at nuchal translucency/cystic hygroma
  • at birth: oedema of hands and feet, neck webbing, coarctation of aorta, renal malformation
  • short stature
  • infertility secondary to gonadal dysgenesis
  • intellectually normal
31
Q

What is turner mosaicism?

A
  • 45X/46XY mosaicism - usually normal male (90%), but with potential for gonadoblastoma
  • mosaicism with ring or isochromosome Xq results in variant Turner syndrome
32
Q

What is Klinefelter syndrome?

A
  • 47XXY
  • incidence 1/1000 male live births
  • phenotype mild and variable - some cases undetected
  • Barr body present
  • NDJ paternal meiosis I (50%), others NDJ maternal meiosis or zygotic mitotic error (mosaic)
  • variants 48,XXYY, 48,XXXY etc
33
Q

What are clinical symptoms of Klinefelter syndrome?

A
  • may present prenatally, during childhood with behavioural problems, or adulthood with infertility
  • tall stature
  • eunuchoid body habitus
  • some behavioural and minor learning difficulties
  • lack of secondary sexual characteristics - treat with testosterone
  • infertility
34
Q

About structural rearrangements…

A

Approximately 1/400 newborns have a structural rearrangement
BALANCED: no net gain or loss of genetic material
UNBALANCED: net gain or loss of genetic material
RECIPROCAL or ROBERTSONIAN
usually no deleterious phenotype unless breakpoint affects regulation of a gene

35
Q

What is reciprocal translocation?

A
  • two afrocentric chromosomes join near centromere with the loss of p arms
  • balanced carrier has 45 chromosomes
  • if 46 chromosomes present including Robertsonian then must be unbalanced
  • P arms encode rRNA (multiple copies so not deleterious to lose some)
  • 13q14q and 14q21q relatively common
36
Q

About deletions…

A
  • breakage and loss of eccentric fragment
  • terminal or interstitial
  • monosomic region - haploinsufficiency of some genes
  • phenotype usually abnormal and specific for size and place of deletion
  • 1/7000 live births
37
Q

About microdeletions/duplications…

A
  • many patients has no abnormality visible on metaphase spread
  • high resolution banding, FISH and now CGH showed ‘micro’ deletions
  • only a few genes may be lost or gained - contiguous gene syndrome
  • areas of low copy number repeat sequences - recombination error?
38
Q

What happens in a cytogenetics laboratory?

A

chromosome analysis
pre and post-natal testing, adult testing: foetal blood, amniotic fluid, CVS biopsy, solid tissue; venous blood, tumour tissue

WHY?: ambiguous genetalia/indeterminate gender, known familial chromosome rearrangement, multiple miscarriages
HOW?: G-banding, FISH, QF-PCR, array-CGH

39
Q

About G-banding…

A
  • giemsa stain
  • metaphase
  • line up based on size, banding and centromere position

uses a chemical stain, uses metaphase chromosomes, takes several days at least, looks for aneuploidies, translocations and very large deletions

40
Q

Why do you get chromosome banding?

A

Chromatin: 2 different sorts: euchromatin and heterochromatin, euchromatin = GC-rich; loosely packed; genes active, heterochromatin = AT-rich; tightly packed; genes inactive, stain differently

41
Q

what are the steps of FISH testing?

A
  1. fluorescent probe
  2. denature probe and target DNA
  3. mix probe and target DNA
  4. probe binds to target
42
Q

What are examples of FISH tests?

A
  • 22q deletion syndrome
  • prader-willi syndrome (chromosome 15)
  • cri-du-chat (chromosome 5)

You have to know what causes a disease in order to be able to test for it by standard FISH, because you have to be able to design a specific probe.

43
Q

What is QF-PCR?

A
  • quantitative fluorescence PCR
  • triremes 13, 18 and 21
  • uses microsatellites
  • looks at how many copies of a chromosome the patient has
  • uses fluorescent probes for specific micro satellite markers on specific chromosomes
  • uses extracted DNA
  • quick (~48 hours)
  • looks for aneuploidies
  • need to know what you’re looking for
44
Q

What are micro satellites?

A

di, tri, tetra, penta, hexa nucleotide sequence with a variable number of repeats

  • number of repeats is constant within an individual
  • number of repeats varies between individuals
45
Q

What is array-CGH?

A
  • comparative genomic hybridisation
  • sub-microscopic chromosome abnormalities (~60kb)
  • micro deletions, micro duplications, CNVs
  • main indication = developmental problems, dysmorphia
  • uses fluorescent probes to differentiate between patient and control
  • uses extracted DNA
  • looks for deletions and duplications
46
Q

What are Copy Number Variations (CNVs)?

A
  • deletions/duplications
  • 10kb-5000kb
  • can protect e.g. from HIV
  • can be detrimental e.g. autism and schizophrenia
  • many do nothing
  • ~12% of the genome = CNV
47
Q

What is the process of array-CGH?

A
  1. extract DNA
  2. test DNA labelled with fluorescent dye
  3. control DNA labelled with different fluorescent die
  4. mix DNA tighter
  5. apply denatured DNA to array –> hybridise
  6. measure relative fluorescence
48
Q

What is the sequence of sanger sequencing?

A
  • DNA isolation and amplification (generally each exon separately)
  • denature
  • anneal primer
  • extend
  • terminate
  • denature
  • read; sort fragments and determine sequence

DNA fragments are drawn through the capillary; the smaller fragments pass through more quickly than larger fragments

49
Q

What is NextGen sequencing?

A
  • targeted
  • whole exome
  • whole genome

Looks at each base and identifies small substitutions and small indels. It can look at ALL the genes at once and uses different chemistry from Sanger sequencing.

Semester 3 Revision (7 decks)

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