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IMS > Clinical genetics- Chromosome and chromosomal abnormalities and molecular techniques > Flashcards

Clinical genetics- Chromosome and chromosomal abnormalities and molecular techniques Flashcards

1
Q

Penetrance

A

Proportion individuals carrying particular allele in population

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2
Q

Expressivity

A

Degree to which genotype (alleles) expressed in individual

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3
Q

Gene dosage

A

Number of copies of a particular gene present in a genome

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4
Q

Categories of genetic disease- multifactorial

A

multifactorial (common)- “environmental” influences (eg. drugs, infections) + genetic predisposition = susceptibility to a disease

- variants in genes cause alteration of function
- one organ system affected
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5
Q

Types of genetic disorders- chromosomal

A

Chromosomal-thousands of genes may be involved and chromosomal imbalance causes alteration in gene dosage

  • multiple organ systems affected at multiple stages in gestation (the process of carrying or being carried in the womb between conception and birth)
  • usually de novo (trisomies, deletions, duplications)
    • in rare cases, can be inherited (translocations)
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6
Q

Types of genetic disorders- single gene

A
  • dominant/recessive pedigree patterns (Mendelian inheritance)
  • mutations in single genes (often cause loss of function)-can affect structural proteins, enzymes, receptors, transcription factors
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7
Q

Syndrome

A

A collection of clinical features

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8
Q

Down’s syndrome- clinical features

A
  • round face
  • protruding tongue
  • up slanting palpebral fissures (abnormal folds of eye lid)
  • epicanthic folds (abnormal folds of eye lid)
  • developmental delay
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9
Q

Ultrasound features of +21

A
  • short femurs
  • nuchal translucency (collection of fluid under the skin at the back of your baby’s neck)-cardiovascular abnormalities
  • echogenic bowel (unusually bright appearance of the baby’s bowel on an ultrasound)
  • choroid plexus cyst (cysts that occur within choroid plexus of the brain)
  • sandal gap- abnormal gap on scan between toe and other toes
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10
Q

What can cause Down Syndrome

A
  • Trisomy 21
  • Robertson translocation
  • Mosaicism with normal and trisomy 21 cell lines (occurs postzygotically)
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11
Q

Other chromosomal anomalies: microdeletions

A
  • chromosomal region is lost: too small to be observed microscopically
  • identified by use of specific molecular cytogenetic techniques
  • DiGeorge syndrome
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12
Q

Williams-Beuren syndrome (WBS)- micro deletion

A
  • bright eyes, stellate irides
  • wide mouth, upturned nose, long philtrum, flattened nasal bridge
  • heart defects
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13
Q

Single gene disorders- dominant, recessive, X-linked

A

Dominant-heterozygotes with one copy of the altered gene are affected

Recessive-homozygotes with two copies of the altered gene are affected

X-linked-males with one copy of the altered gene on the X-chromosome are affected

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14
Q

Single gene disorder- Huntington disease symptoms

A

Involuntary movements of the head, face and loss of tissue in the brain.

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15
Q

Single gene disorder-Cholesterol deposition in patients heterozygous for familial hypercholesterolemia

A

Tendon xanthomata (irregular yellow patch), and (c) corneal arcus (lipid in cornea)-Major problem is high risk of cardiovascular disease

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16
Q

Single gene disorder- CF

A

Fluid and mucus build up in lungs

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17
Q

Single gene disorder-Duchenne muscular dystrophy

A

Weak proximal muscles, invasion of fibrous tissue and complete absence of dystrophin

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18
Q

What is autosomal dominant inheritance?

A

Heterozygotes with one copy of the mutated gene are affected.

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19
Q

What is autosomal recessive inheritance?

A

Homozygotes with two copies of the mutated gene are affected.

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20
Q

What is X-linked inheritance?

A

Males with one copy of the mutated gene on the X chromosome are affected.

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21
Q

Mitochondrial inheritance

A

Relies on mitochondrial DNA which comes from the mum.

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22
Q

Example of mitochondrial inheritance

A

Leber hereditary optic neuropathy

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23
Q

The genetic basis of sporadic cancer

A
  • dominantly inherited familial cancer syndromes
  • both alleles of a gene become inactivated in a particular somatic cell leading to loss of control of growth and unchecked cell proliferation
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24
Q

Determining the mode of inheritance: complications and problems

A
  • genetic heterogeneity-deafness-AD/AR/X-linked/mitochondrial
  • reduced penetrance-neurofibromatosis
  • variable expressivity-tuberous sclerosis
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25
Q

Determining the mode of inheritance: complications and problems- problem of expressivity- what disease?

A

Neurofibromatosis – same gene is mutated but can cause two different diseases

Neurofibromatosis type 1 (NF1)- six or more café au lait spots

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26
Q

Determining the mode of inheritance: complications and problems- problem of penetrance- what disease?

A

Huntington’s disease

The size of the CAG repeat increases in size.

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27
Q

Phenylketonuria- what it is and what are the symptoms?

A

Most prevalent inherited defect in amino acid metabolism.

  • phenylalanine plasma levels >20 mg/dL
  • epilepsy (in 50%)
  • extrapyramidal manifestations (eg Parkinsonism)
  • musty or mousy odour
  • fair skin and hair: impaired melanin synthesis
  • eye abnormalities (eg hypopigmentation)
28
Q

Mitosis

A

Cell division to ensure growth of the organism

29
Q

Meiosis- function

A

• used only for production of sperm and eggs
• reduction division to 23 chromosomes per gamete
• ensures that every gamete is genetically unique (reassortment of genes) by
-crossing-over/recombination
-independent segregation of chromosomes

30
Q

Meiosis- mechanism

A

• each homologue (“chromosome”) replicates to give two sister chromatids
• the maternal and paternal homologues pair together
• exchange of material between non-sister chromatids by crossing-over (recombination)
-chiasma (visible cytologically) are the physical manifestations of crossing-over

31
Q

Stages of meiosis

A

Two successive cell divisions producing four daughter cells.

  • Homologous pair parental chromosomes
    • Meiosis I – each chromosome duplicates  2 sister chromatids
  • Crossing over – recombination
  • Meiosis II to 4 gametes with half number original cell
32
Q

Locus

A

Position of a gene or genetic marker

33
Q

Anatomy of metaphase chromosomes

A 
Light bands
•	Replicate early S phase
•	Less condensed chromatin
•	Transcriptionally active
•	GC-rich
Centromere
•	Joins sister chromatids 
•	Essential chromosome segregation
•	Repetitive DNA – non specific + specific chromosomal 
Dark (G) bands
•	Replicate late
•	Condensed chromatin
•	AT rich
Telomere 
•	DNA + protein cap – ensures replication of tip 
•	Tethers to nuclear membrane
34
Q

Chromosome anomalies- What is it and what are trisomies and amonosomy?

A
  • cause their effects by altering the amounts of products of the genes involved:
  • altered amounts may cause anomalies directly or may alter the balance of genes acting in a pathway
  • often affect many organ systems at once
  • three copies of genes (trisomies) = 1.5 times normal amount
  • one copy of genes (deletions or monosomy)= 0.5 times normal amount.
35
Q

Polyploidy

A

State of a cell or organism having more than two paired (homologous) sets of chromosomes.

36
Q

Aneuploidy

A

The presence of an abnormal number of chromosomes in a cell

37
Q

De novo

A

Mutation first time in family line

38
Q

Classification of chromosomal anomalies-numerical usually due to de novo error in meiosis

A

Aneuploidy-monosomy, trisomy

Polyploidy- triploidy

39
Q

Classification of chromosomal anomalies-structural usually de novo error in meiosis but can be inherited

A
  • translocations- reciprocal and Robertsonian (centric fusion)
  • deletions
  • duplications
  • inversions
40
Q

Classification of chromosomal anomalies-different cell lines

A

-Mosaicism

41
Q

Karyotype

A

The number and visual appearance of the chromosomes in the cell nuclei of an organism or species.

42
Q

How to understand a karyotype

A

e.g. 46,XX,dup(2)(p13p22) describes a female with 46 chromosomes and a duplication of the short arm of chromosome 2 from bands 13 -22.

43
Q

Most frequent numerical anomalies in liveborn- autosomes

A 
Down syndrome (trisomy 21: 47,XX,+21)
Edwards syndrome (trisomy 18: 47,XX,+18) 
Patau syndrome (trisomy 13: 47,XX+13)
44
Q

Most frequent numerical anomalies in liveborn- Sex chromosomes

A

Turner syndrome 45,X

Klinefelter syndrome 47,XXY

45
Q

Most frequent numerical anomalies in liveborn- All chromosomes

A

Triploidy (69 chromosomes)

46
Q

What is gametogenesis?

A
  • Age 15 – every spermatogonium in testes is the result of 30 previous cell divisions
    • Continues to divide
  • Every 16 days from puberty – spermatogonium divides into 4 spermatozoa
  • Age 25 – 310 cell divisions occurred to produce a particular sperm
47
Q

Number cell divisions for human egg cell

A
  • 22 mitotic cell divisions by 5 months gestation produce 2,600,000 oocytes
  • Each month – 1 oocyte is ovulated
  • Meiosis 1 completed at ovulation
    • Lengthy interval between onset and completion of meiosis (up to 50 yrs.)
  • Meiosis 2 completed at fertilisation
    • Damage to repair mechanisms of primary oocyte increases risk of non-disjunction.
48
Q

Meiotic non-disjunction

A

The failure of one or more pairs of homologous chromosomes or sister chromatids to separate normally during nuclear division, usually resulting in an abnormal distribution of chromosomes in the daughter nuclei- so each daughter cell contains double the amount of DNA it should

49
Q

Mosaicism

A
  • this is mitotic non-disjunction
  • after fertilisation of a normal egg, the embryo may undergo abnormal separation of chromosomes in one of its cells
  • this results in a fetus with two (or more) populations of cells
  • the proportion of abnormal cells depends on when during early embryonic development the non-disjunction event occurred and this influences the severity of phenotypic expression
50
Q

Edwards syndrome

A

Edwards syndrome (trisomy 18)
• 1 in 3000 births
• multiple malformations (especially heart, kidneys)
• clenched hands with overlapping fingers

51
Q

Patau syndrome

A

Patau syndrome (trisomy 13)
• 1 in 5000 births
• multiple malformations
• affects midline structures particularly:
incomplete lobation of brain; cleft lip; congenital heart disease

52
Q

Anomalies of sex chromosome number

A

• more common than autosomal chromosomal anomalies as problems not as severe chromosome anomalies
• problems relating to sexual development and fertility
• present at puberty or later, sometimes during investigations for infertility
• caused by abnormal gametes with unusual complements of sex chromosomes:
– abnormal sperm with XY or 0
– abnormal ova with XX or XXX or 0

53
Q

Anomalies of sex chromosome number- Klinefelter syndrome

A

Klinefelter syndrome
– 47,XXY
– 1 in 850 live male births
– infertility (atrophic testes do not produce sperm)
– in some, poorly developed 2ndy sexual characteristics (pubic and facial hair, deepened voice due to lack of testosterone)
– gynaecomastia (male breast enlarged) and osteoporosis
– tall

54
Q

Anomalies of sex chromosome number- Turner syndrome

A

Turner syndrome
– 45,X
– 1 in 3000 live female births
– 99% are lost spontaneously in pregnancy
– short stature, wide carrying angle of arms
– primary amenorrhoea (ovaries involute before birth)
– congenital heart disease (coarctation of aorta) 20%

55
Q

Chromosomal structural anomalies- two types of chromosome translocations

A

Centric fusion (Robertsonian)- Breakage of two chromosomes at or close to their centromeres, with subsequent fusion of their long arms so short arms are lost

Reciprocal-Breakage of two non-homologous chromosomes with exchange of the fragments

56
Q

Acquired cytogenetic abnormalities

A

Genetic change associated with a neoplastic (a new and abnormal growth of tissue in a part of the body) or cancer disease process

57
Q

Karyotype analysis of chromosomes

A

Karyotype represents the cytogenetic characteristics of the individual person and is an arrangement of the chromosomes in descending order of size.

58
Q

Male chromosome spread with chromosomes shown by bright field G-banding

A
  • G-banding involves trypsin digestion of chromosomes followed by DNA staining with Giemsa; G bands stain darkly with Giemsa
  • Can identify every chromosome
  • Prometaphase chromosomes
59
Q

Chromosomes can be classified by their topography

A
  • size
  • centromere position
  • chromomere and heterochromatin patterns
  • high resolution band patterns produced by different stains
  • genes highlighted by DNA probes using fluorescence in situ hybridization- FISH
60
Q

Chromosome painting (spectral karyotyping)

A
  • Spectral karyotyping and multicolour-FISH paint each human chromosome in one of 24 colours.
  • Outline of the spectral karyotyping (SKY) protocol. SKY and multicolour fluorescence in situ hybridization (M-FISH) differ only in the method used to measure the spectral characteristics of each pixel in the image.
61
Q

Fluorescence in situ hybridization (FISH)

A

• analysis of chromosomes at the DNA or gene level of resolution
• can be performed on dividing (metaphase) and non-dividing (interphase) cells
• can identify numerical and structural abnormalities
• three types of FISH probe:
– repetitive sequences
– DNA segments that will bind to and cover the entire length of a particular chromosome
– DNA segments from specific genes or regions on a chromosome that have been previously mapped or identified

62
Q

Comparative genome hybridization (CGH)

A

This technique reveals the loss or gain of chromosomal regions in test samples (for example, derived from a tumour) relative to normal controls.

63
Q

Uses of cytogenetics

A

The study of inheritance in relation to the structure and function of chromosomes.

  • pregnant women with increased risk of aneuploidy such as Down syndrome/trisomy 21
  • pregnant women with serum screening results indicative of trisomy 21
  • children with phenotypic problems and/or developmental delay
  • couples with reproductive problems
  • families with known translocations etc
  • microdeletion syndromes
  • diagnosis, prognosis and monitoring of many cancers
64
Q

DNA mutation analysis: Sanger and clonal sequencing- when you don’t know the mutation

A

“Chain termination” chemistry (Sager sequencing)

  • starting material is a single DNA fragment (usually produced by PCR)
  • anneal a specific oligonucleotide primer and synthesize a new strand that is complementary to the template
  • strand synthesis is catalysed by a DNA polymerase, and requires deoxynucleotides to form the new strand
  • BUT a small amount of each dideoxynucleotide is also incorporated in DNA strand (ddTTP etc.) strand causing it to be terminated prematurely
  • strands are synthesized that are all different lengths, each ending in a ddTTP – termination occurs randomly 3
65
Q

Detection of unknown mutations: DNA sequencing

A

The ultimate method of finding mutations in the diagnosis of genetic disease is to detect changes in the sequence of the gene
• mutations can be detected by simpler (and cheaper) methods, but they do not characterize the nature or position of a novel mutation
– sequencing determines the exact position of the mutation within the gene
– determines the type of the mutation (including single base changes)

66
Q

What DNA is sequenced by clonal sequencing?

A
  • PCR products
  • “long” PCR product covering a part or the whole of a gene
  • panels of selected genes known to be mutated for a particular phenotype
  • very large “exome” panels, based on all coding genes in the human genome
  • analysis is restricted to genes of clinical relevance

IMS (13 decks)

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