MCBG Session 16 - Case Studies Flashcards
(37 cards)
What is cytogenetics?
Cytogenetics: 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
I. Identify the syndrome associated with abnormality
II. Account for phenotype
III. Account for pregnancy loss
- Better clinical management – E.g. hormone treatment for Klinefelter syndrome
- Prenatal diagnosis – TOP of affected pregnancy/planning management at birth
- Assess future reproductive risks
I. Risk of live born abnormal child
II. Previous Down’s pregnancy, approx. 1% increase above pop risk of another
The referral reasons for cytogenetics are due to constitutional abnormalities and acquired abnormalities. Outline the former.
- Prenatal diagnosis – Chorionic villus sampling and Amniocentesis
- Birth defects – dysmorphism, congenital malformations, mental retardation, developmental delay (abnormal behaviour, learning difficulties), specific syndromes (Down syndrome, Williams syndrome, DiGeorge syndrome)
- Abnormal sexual development
- Infertility
- Recurrent foetal loss
The referral reasons for cytogenetics are due to constitutional abnormalities and acquired abnormalities. Outline the latter.
- Leukaemia’s
I. Acute diseases – AML/ALL
II. Chronic diseases – CML
III. Myelodysplasia/ Myeloproliferative disorders
- Solid tumours
- Specific translocations/abnormalities can give prognostic information
Outline the chromosome analysis. (incl define karyotyping)
- Karyotyping: the systematic sorting of chromosomes
- Whole genome screen 5-10Mb resolution
- Metaphase chromosome stained, paired up and grouped together
- Abnormalities described using standard nomenclature ISCN
Outline the steps involved in chromosome analysis.
- Count the number of chromosomes
- Identify each chromosome pair
- Assess if there is any missing or extra material – Are the bands in the right place?
- All pairs must be seen at the correct resolution twice
- All chromosomes independently rechecked once
Provide examples of standard nomeclature:
- Normal female
- Normale male
- Female with trisomy 21
- Male with chromosome 7 inversion
- 46,XX – normal female
- 46,XY – normal male
- 47,XX,+21 – female with trisomy 21
- 46,XY,inv(7)(p11.2q11.23) – male with chromosome 7 inversion
Identify some numerical cytogenetic abnormalities (incl. define aneuploidy)
- Aneuploidy – loss and gain of whole chromosomes
- Arise due to errors at cell division in meiosis
I. Trisomies – Down syndrome +21, Patau syndrome +13 and Edwards syndrome +18
II. Monosomies – Turner syndrome 45,X (X inactivation, only full monosomy to be viable)
What is polyploidy?
- Gain of a whole haploid set of chromosomes
- Triploid 3n
- 69, XXX
What are the causes of polyploidy?
- The most common cause of polyploidy is polyspermy: fertilisation of an egg by more than one sperm.
- Triploidy occurs in 2-3% of all pregnancies and ~15% of all miscarriages: term deliveries die shortly after birth
- Tetraploidy is rarer (1-2%) but tetraploid cells are often found at prenatal diagnosis as a cultural artefact
- Diploid/triploid mosaicism seen in livebirths
What are the causes of aneuploidy?
- Originates from non-disjunction at one of the meiotic cell divisions
- Forms gametes with a missing chromosome and an extra chromosome – which chromosomes involved will influence viability.
- Can occur during mitotic cell division – causes mosaicism i.e. two cell populations in an individual
What is anaphase lag?
- Chromosomes can be ‘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?
- Trisomy 21
- Frequency 1:650-1000
- Hypotonia
- Manifestations: characteristic facial features, intellectual disability, heart defects
- Increased prevalence of leukaemia
- Increased incidence of early Alzheimers
What is Edwards syndrome?
- Incidence 1:6000; female predominance
- Maternal meiosis II error
- Modal lifespan 5-15 days
- Nearly all diagnoses made prenatally
- Visual features: Small lower jaw, prominent occiput, low-set ears, rocker bottom feet, overlapping fingers
What is Patau syndrome?
- Trisomy 13
- Incidence 1:12 000
- Majority die in neonatal period
- Holoprosencephaly
- Polydactyly
- Multiple congenital abnormalities
What is X chromosome inactivation?
- Only one X chromosome is ever active in a human cell
- Males only have one X chromosome
- Females have two X chromosomes
- X inactivation ensures individuals have same X chromosome complement that is active
Why is X chromosome inactivation problematic?
- Males only have a single X chromosome.
- However, the X and Y chromosomes have short regions in common at the tips of the long and short arms, allows for pairing during cell division
- Two pseudo-autosomal regions (PAR1 and PAR2)
- Turner syndrome patients will be monosomic for genes in the PARs
- SHOX gene (within PAR) associated with short stature
What is Turner Syndrome?
- Incidence 1:2500
- Majority cases absent paternal X; phenotypic differences depending on parental origin of X
- Visual features: puffy feet, redundant skin at back of the neck
- Manifestations: short stature, heart defects, mild learning difficulties, neck webbing, infertility
Outline what is meant by mosaicism.
- Mosaicism: 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
I. First post zygotic division – no mosaicism looks like a meiotic event
II. Subsequent divisions – 3 cell lines, monosomy cell line usually lost
- Trisomic conceptus ‘rescued’ to give mosaicism – anaphase lag
- Non-disjunction in later cell division
Identify some cytogenetic structural abnormalities.
- Translocations –Reciprocal & Robertsonian
- Inversions – Paracentric & pericentric
- Deletions – incl. microdeletions
- Duplications
- Insertions
- Rings
- Marker chromosomes
- Isochromosomes
Outline recipocial translocations.
- Two break rearrangements
- Usually unique to a family – t(11;22) is an exception
- Carriers produce balanced and unbalanced gametes
- If unbalanced offspring will have an abnormal phenotype dependant on regions of trisomy and monosomy
- Segregation analysis using pachytene diagram to assess this imbalance
Outline robertsonian translocations.
- Two acrocentric chromosomes fused together – 13,14,15 ,21,22
- Mono or dicentric – 13;14 most common
- Chromosome count of 45 in balanced carriers
- Trivalent formed at meiosis – Not very stable
- Aneuploidy risk
I. Females have higher risk than males
II. Homologous carriers can’t have normal pregnancy
Outline the types of segregation in meiosis I.
- Alternate – balanced
- Adjacent I – non homologous centromeres, most common form to give imbalance
- Adjacent 2 – homologous centromeres
- 3:1 non disjunction
- 4:0 non disjunction – all balanced
Outline Alternate segregation.
Alternate – alternate centromeres segregate together
