S14) Chromosomal Mutations Flashcards
What is cytogenetics?
Cytogenetics is the study of the genetic constitution of cells through the visualisation and analysis of chromosomes
What are the benefits of cytogenetic analysis?
- Accurate diagnosis/prognosis of clinical problems
- Better clinical management e.g. hormone treatment for Klinefelter syndrome
- Prenatal diagnosis
- Assess future reproductive risks
In terms of constitutional abnormalities, identify some referral reasons for cytogenetic analysis
- Prenatal diagnosis
- Birth defects
- Abnormal sexual development
- Infertility
- Recurrent foetal loss
In terms of acquired abnormalities, identify some referral reasons for cytogenetic analysis
- Leukaemia’s (acute/chronic diseases)
- Solid tumours
- Specific translocations/abnormalities
Identify and describe two prenatal diagnostic methods
Identify 4 birth defects
- Dysmorphism
- Congenital malformations
- Mental retardation
- Developmental delay
Which three biochemical techniques are used in cytogenic analysis?
- Karyotyping
- Fluorescent in situ hybridisation (FISH)
- Microarray comparative genomic hybridisation (aCGH)
Briefly describe the process of karyotyping (chromosome analysis)
Karyotyping is the systematic sorting of chromosomes:
⇒ Whole genome screen
⇒ Metaphase chromosomes stained, paired up, grouped together
⇒ Abnormalities described using standard nomenclature
Outline the steps involved in chromosome analysis
⇒ Count the number of chromosomes
⇒ Identify each chromosome pair
⇒ Assess any missing/extra material
⇒ Recheck all chromosomes independently
Provide examples of standard nomeclature for the following:
- Normal female
- Normale male
- Female with trisomy 21
- Male with chromosome 7 inversion
- Normal female – 46,XX
- Normal male – 46,XY
- Female with trisomy 21 – 47,XX,+21
- Male with chromosome 7 inversion – 46,XY,inv(7)(p11.2q11.23)
Aneuploidy is a numerical cytogenetic abnormality.
Define it
Aneuploidy is the loss/ gain of whole chromosomes and arise due to errors at cell division in meiosis
Identify some examples of aneuploidy where whole chromosomes are lost and identify their associated diseases
- Trisomies – Down syndrome +21, Patau syndrome +13 and Edwards syndrome +18
- Monosomies – Turner syndrome 45,X (X inactivation)
What is polyploidy?
Polyploidy is the gain of a whole haploid set of chromosomes (an example of aneuploidy) eg. triploid 3n – 69, XXX
What are the causes of polyploidy?
The most common cause of polyploidy is polyspermy i.e. fertilisation of an egg by more than one sperm
Aneuploidy is due to non-disjunction during cell division.
Describe how this occurs
What is anaphase lag?
- Anaphase lag is when chromosomes are ‘left behind’ at cell division because of defects in spindle function or attachment to chromosomes
- The lagging chromosomes may be lost entirely in mitosis or meiosis
What is Down syndrome?
- Down Syndrome is a genetic condition arising due to trisomy 21 (third copy of chromosome 21)
- It manifests with characteristic facial features, intellectual disability, heart defects and increased prevalence of leukaemia
What is Edwards syndrome?
- Edwards syndrome is a genetic condition arising due to trisomy 18 (third copy of chromosome 18) in maternal meiosis II
- Babies survive for 5-15 days and it manifests with a small lower jaw, prominent occiput, low-set ears, rocker bottom feet and overlapping fingers
What is Patau syndrome?
- Patau syndrome is a genetic condition arising due to trisomy 13 (third copy of chromosome 13)
- Majority die in neonatal period and it manifests with holoprosencephaly, polydactyly and multiple other congenital abnormalities
What is Turner’s Syndrome?
- Turner syndrome is a genetic condition occurring when one normal X chromosome is present in a female’s cells and the other sex chromosome is missing / structurally altered (X inactivation)
- It presents with puffy feet, short stature, heart defects, mild learning difficulties, neck webbing, infertility
What is mosaicism?
- Mosaicism is the presence of 2/more cell lines in an individual, usually caused by mitotic non-disjunction
- Occurs throughout the body or tissue limited & degree of mosaicism depends on when the error occurred
Identify 5 cytogenetic structural abnormalities
- Translocations
- Inversions
- Deletions
- Duplications
- Insertions
What are recipocial translocations?
- Reciprocal translocations are usually an exchange of material between nonhomologous chromosomes wherein carriers produce balanced and unbalanced gametes
- If unbalanced offspring will have an abnormal phenotype dependant on regions of trisomy and monosomy
What are robertsonian translocations?
- Robertsonian translocations are a rare form of chromosomal rearrangement wherein acrocentric chromosomes break at their centromeres and the long arms fuse to form a single, large chromosome with a single centromere.
- Ther is a chromosome count of 45 in balanced carriers and homologous carriers can’t have normal pregnancy
Identify the types of segregation which occur in meiosis I
- Alternate
- Adjacent-1
- Adjacent-2
Describe alternate segregation
Describe adjacent-1 segregation
Describe adjacent-2 segregation
What is FISH?
Fluorescent in situ hybridisation is a molecular cytogenetic technique wherein probes are used for specific chromosomes or loci
Outline 5 steps ocurring in FISH
⇒ Select target material
⇒ Specific DNA probe (fluorescent label)
⇒ Denaturation & hybridisation
⇒ Washing
⇒ Visualisation
What are the different types of FISH probes?
Describe the use of microarray comparative genomic hybridisation (aCGH)
- Examines the whole genome at high resolution
- Uses patient DNA not chromosomes
- Compares normal control DNA to patient DNA
- Can’t detect balanced rearrangements
- Not used for mutation detection
What are the aCGH referral groups?
- Learning difficulties
- Developmental delay
- Multiple congenital abnormalities
- Normal karyotype
- Balanced / unbalanced karyotype
What are the advantages and disadvantages of aCGH?
- Advantages: examines entire genome, detailed information on genes in del/dup region
- Disadvantages: more expensive than karyotyping, doesn’t detect balanced rearrangements, mosaicism may be missed
