Chromosomal Abnormalities Flashcards
How can miscarriage products be used if they are saved?
They can be cultured to look for chromosome abnormality
What % of successfully cultured miscarriage products have a chromosome abnormality?
50%
How many babies by term have an unbalanced chromosome abnormality?
1 in 250 - therefore there is v effective natural selection against conceptions with chromosome imbalance
What are the three types of chromosome abnormalities?
1) Aneuploidy - too many or too few chromosomes (not divisible by the haploid number)
2) Rearrangements
3) Deletions/duplications
What are the three types of chromosome rearrangements?
1) Translocations (balanced or unbalanced)
2) Inversions
3) Complex chromosome rearrangements (CCRs)
What are the clinical features of trisomy 21?
1) Intellectual disability - mild to moderate learning difficulties
2) Dysmorphic - flat nasal bridge, up slating palpebral fissures, epicanthic folds, protruding tongue, single palmer crease, clinodactyly, sandal gap
3) Cardiac defects (present in 40%) - 50% AV septal defect
What are the clinical features of trisomy 18?
1) Mental disability - severe
2) Dysmorphic - micrognathia (v small chin), prominent occiput, clenched overlapping fingers, prominent heels and rocker-bottom feet
3) Cardiac defects
What are the clinical features of trisomy 13?
1) Mental disability - severe
2) Dysmorphic - cleft lip and palate, holoprosencephaly, post axial polydactyly
3) Renal abnormalities
4) Cardiac defects
How does incidence of whole chromosome aneuploidies change as pregnancy progresses?
Incidence of whole chromosome aneuploidies decreases as pregnancy progresses
What are 5 examples of whole chromosome aneuploidies?
1) T21
2) T18 (Edward’s)
3) T13 (Patau)
4) 45,X (Turner)
5) 47,XXY (Klinefelter)
How does meiotic error (malsegregation) lead to whole chromosome aneuploidy?
Meiotic error during gametogenesis will result in abnormal gametes arising from that meiotic division
How does mitotic error (malsegregation) lead to whole chromosome aneuploidy?
- In the germline this will result in gonadal mosaicism
- In the embryo this will result in a mosaic embryo - the abnormal cell lines may be embryonic, extra embryonic or both dependent on where and when they arise
What are chromosome translocations?
- Exchange of material between chromosomes
- 2 types - Robertsonian and Reciprocal
What are acrocentric chromosomes?
Chromosomes with a short p arm
Describe Robertsonian translocations
- Result from fusion of two acrocentric chromosomes (13,14, 15 (d group) , 21, 22 (g group))
- Prevalence of 1 in 1000
- Most common are der(13;14) (75%) and der(14;21) (10%)
- Balanced carriers phenotypically normal e.g. 45,XX,der(13;14)(q10;q10)
- Balanced carriers have reproductive risks present as recurrent miscarriages, Patau syndrome, Down syndrome and male infertility and are offered prenatal diagnosis
What is an example of a Robertsonian translocation?
- der(13;14)(q10;q10)
- 45 chromosomes but phenotypically normal
Who has a 15% risk of T21 pregnancy?
Female carriers of der(14;21) (can lead to unbalanced translocation)
Describe reciprocal translocations
- Exchange of material between two non-homologous chromosomes
- Prevalence of 1 in 500
- Balanced carriers are generally phenotypically normal
- If we diagnose a de novo balanced reciprocal translocation (it has arisen in that individual) we give ~ 5% risk of developmental delay as there is no family history
What is a balanced reciprocal translocation?
Both der chromosomes
What is an unbalanced reciprocal translocation?
One normal chromosome and one der chromosome
What is an example of a balanced rearrangement reciprocal translocation?
- 46,XX,t(12;17)(p13;p13)
- End of short arms of 12 and 17 have swapped (there is loss of genes at breakpoint) but individuals are normal
What is an example of an unbalanced rearrangement reciprocal translocation?
- 46,XY,der(17)t(12;17)(p13;p13)mat
- 3 copies of top of chromosome 12 and only 1 copy of top of chromosome 17
What is the reproductive risk for balanced reciprocal translocations?
- For most balanced reciprocal translocations, ~ 50% of conceptions will have either normal chromosomes or the balanced translocation
- Unbalanced products result in miscarriage (large segments) and/or dysmorphic delayed child (small segments)
- The risk that a couple will produce a liveborn child with chromosome imbalance due to a balanced reciprocal transaction carried by one parent may vary from <1% to ~40% dependent largely on the size of the imbalanced regions and their genetic content
What are polyploidies?
Multiple sets of chromosomes e.g. triploidy (3 copies of each chromosome instead of 2)
What are examples of unbalanced structure of chromosomes?
- Deletions (generally worse than duplication)
- Duplications
- Inversions
- Translocations
- Often associated with problems
What is the prevalence of T21?
- 1:700 live births
- 1:50 at maternal age 43
- 60% abort spontaneously
Describe whole chromosome aneuploidies
- In theory any of the 24 human chromosomes can occur in the fully aneuploid state i.e. whole chromosome aneuploidy
- However, only a subset is associated with viability when present in the fully aneuploid state - 13, 18, 21, X and Y
How do whole chromosome aneuploidies arise?
Due to malsegregation
1) In the gonad during meiosis leading to abnormal gametes
2) During mitosis in the germline leading to mosaicism in the gonad
3) During mitosis in the early embryo leading to mosaicism in the embryo
Why is whole chromosome aneuploidy generally associated with raised maternal age?
75% of T21 and 90% of T18 arise during female meiosis
What are the causes of T21?
1) Primary T21 (95%) - 47, XX + 21 or 47, XY + 21
2) Translocation (5%) - 46,Xn,der(14;21)(q10;q10),+21
What is the prevalence of T18?
- 1:3000 live births
- 1:500 at maternal age 43
What is the prognosis of T18?
30% die within 1 month, 90% within 1 year
What is the cause fo T18?
Primary T18 - 47,XX + 18 or 47,XY + 18
What is the prevalence of T13?
- 1:5000 live births
- 1:1100 at maternal age 43
What is the prognosis of T13?
45% die within 1 month, 85% within 1 year
What are the causes of T13?
1) Primary trisomy - 47, XX +13
2) Unbalanced translocation 46,Xn,+13,der(13;14)(q10;q10)
How can T21 potentially be treated?
- Down’s syndrome is diagnosed after the first trimester
- At this point, many of the organs have already developed and these abnormalities e.g. cardiac cannot be rescued prenatally
- However, the brain develops throughout embryonic and fatal development (and post-natally)
- Therefore, it may be possible to prevent some of the brain defects by therapeutic treatments in the last 2 trimesters
How can birth defects contribute to long term disability?
e.g. kidney defect - hypertension
Describe deletions and duplications
- Regions of DNA that are deleted or duplicated - may result from aberrant recombination during meiosis or misalignment and crossover between homologues during mitosis
- These imbalances may be recurrent, well characterised and associated with specific syndromes e.g. Prader-Willi syndrome, Angelman syndrome
- Non-recurrent imbalances may be unique to a family and inherited or may arise de novo in an individual
Describe the clinical significance of deletions and duplications
- They may be associated with abnormal clinical phenotype or clinically benign
- Clinical significance may be established by inheritance studies of other family members
- Clinical significance of an imbalance is associated with the gene content and the characteristics of those genes
What is the first test you would do if you had a child with malformation or developmental delay in clinic?
CGH array
What are two examples of a chromosome deletion?
1) DiGeorge syndrome (del22q11.2)
2) William’s syndrome (del7q11)
What are the clinical features of DiGeorge syndrome?
1) CHD - Conotruncal anomaly - heart defects esp. in midline
2) Cleft lip and/or palate
3) Absent thymus leading to immunological disorders
4) Absent parathyroid glands causing hypocalcemic seizures
5) Dysmorphic features - facial, tubular nose - similar width all the way down, hypo plastic nostrils, less flared
6) Learning difficulties
7) Psychological and psychiatric disorders in adulthood
What are the clinical features of William’s syndrome?
1) Heart defects
2) Aortic stenosis
3) Saggy skin/cheeks
4) Wide smiles
5) Very bright blue eyes
6) Characteristic personality (cocktail personality)
What is an example of a disease caused by duplication in a chromosome?
Pallister-Killian syndrome
- Rare genetic multi system disorder due to the presence of the anomalous extra isochromosome 12p in mosaic form (mosaic tetrasomy 12p)
- Part of chromosome 12 is duplicated
- Can detect on US with congenital diaphragmatic hernia
- Can diagnose with amniocentesis and array CGH
- Can lead to termination of pregnancy
