Clinical consequences of chromosomal disorders Flashcards
What are the types of abnormalities that can arise chromosomally?
- Numerical - Too many or too few, either whole chromosomes or partial
- Structural - Genomic rearrangement of one or more chromosomes
Can be present in all cells, or just some cells (mosaic)
Define ploidy
Number of chromosomes in cell nucleus
Gamete = Haploid = 23
Somatic cell = Diploid = 46
What is aneuploidy?
When there is one extra or one less chromosome (47 or 45)
What is triploidy?
Whole extra set of chromosomes, meaning there’s 3n = 69 = XXY
What are microdeletions and microduplications?
Microdeletion - Missing chromosomal material
Microduplication - Extra chromosomal material
Deletions and duplications are the same thing, resulting in partial monosomy or trisomy, these are micro because they cannot be seen under a microscope
NOTE: Monosomy is less/not consistent with life
Define non-disjunction
Failure of chromosomes or sister chromatids to separate/segregate properly during cell division, resulting in daughter cells having abnormal number of chromosomes (aneuploidy)
Define mosaicism
2 or more different cell types present, originating from a single zygote
- Could be chromosome number or structure
- Usually happens in embryo, after conception
- In mistosis, non-disjunction during separation of sister chromatids causes mosaicism or partial trisomic rescue
- May affect multiple tissues, if these are ovaries/testes = Germline mosaicism
- Can also have mosaicism for other abnormalities:
- Translocations
- Duplications/deletions
- Can be difficult to detect:
- Karyotype
- May need tissue other than blood
Describe translocation
Rearrangement of chromosomes, can be balanced or unbalanced
Balanced - Healthy, normal, individual will still end up with the correct amount of genetic material. At risk of unbalanced offspring (miscarriages, infertility, children with developmental, growth, physical problems).
Unbalanced - Depends on size and position, individual ends u0p with incorrect amount of genetic matieral. Often developmental, growth, physical problems
Describe reciprocal translocations
- Balanced translocations
- 2-way exchange of genetic material b/w non-homologous chromosomes
- May be inherited or de novo
- Recurrence risk dependent on specific translocation (important to test parents and other family members)
Describe roberstoninan translocations
- Caused by fusion of acrocentric chromsomes (13,14,15, 21, 22)
- Non-reciprocal
- 2 long arms fuse, short arms lost
- Usually b/w non-homologous chromosomes
- Often familial
- Written 45XX rob(14;21) q(10;10)
What are the clinical features of Down’s syndrome?
Down’s syndrome = Trisomy 21
- Facial:
- Epicanthic folds - Skin fold of upper eyelid, covers inner corner of eye
- Flat nasal bridge
- Macroglossia
- Hands and feet - Small:
- Single palmar crease
- Sandal gap
- Other:
- Hypotonia
- Short stature
- Developmental delay and intellectual disability
- Cardiac malformations (40-50%)
- Hypothyroidism (20-40%)
- 20x increase in leukaemia
- Dementia
What are the clinical features of Edward syndrome?
Edward syndrome = Trisomy 18
- Usually maternal meiotic non-disjunction
- Strong maternal age effect
- Presentation antenatally:
- Raised nuchal, or abnormal maternal screening
- Intrauterine growth restriction (IUGR)
- Multiple congenital anomalies
- Cardiac, renal malformations
- Exomphalos
- Overlapping fingers and rocker bottom feet
- Micrognathia, prominent occiput
- Severe-profound intellectual disability
- Severe feeding problems
- Poor survival rate
What are the clinical features of Patau syndrome?
Patau syndrome = Trisomy 13
- 90% material meiosis 1 non-disjunctoin
- 5-10% caused by translocations usually t13;14
- Presentation antenatally:
- Raised nuchal or high risk maternal screening
- IUGR
- Multiple congenital anomalies
- Holoprosenchephaly
- Cleft lip/palate
- Cardiac, renal malformations
- Polydactyly
- Exomphalos
- Cutis aplasia
- Severe-profound intellectual disability
- Poor survival
What are the clinical features of Turner syndrome?
45, X = Turner syndrome
- 50% 45,X (paternal meiotic errors)
- 41% mosaicism
- 9% abnormal X (translocations, deletions, inversions)
- Presentation antenatally:
- Raised nuchal
- Foetal oedema/hydrops
- Congenital anomalies (e.g. cardiac, renal)
- Broad, webbed neck
- Low hairline
- Cardiac malformation (coarctation of aorta)
- Renal anomalies
- Short stature
- Primary ovarian failure - Absent puberty, infertility
- IQ in normal range
- Mosaic - 45X, 46XY - Gonadoblastoma risk
What are the clinical features of Klinefelter syndrome?
47, XXY = Klinefelter syndrome
- Increased with maternal age, non-disjunction of maternal X
- Phenotypically male
- Relatively normal IQ
- Infertile
- Normal life expectancy
- Tall (mean 186cm)
- Female fat distribution
- Gynaecomastia
- Hypergonadotrophic hypogonadism
- Small testes
- Infertility
- Increased risk of breast cancer
- Behaviour phenotype - Higher autism and ADHD rates
Describe 47 XYY
47 XYY:
- Paternal meiotic non-disjunction
- Tall (mean 188cm)
- IQ often normal, need learning support
- No significant medical problems
- Puberty and fertility normal
- Behavioural issues
What is CNV?
Copy number variation - Sections of genome are repeated and number of repeats in genome varies b/w individuals. May be normal, but some associated with disease
What are the clinical features of 22q11.2?
22q11.2 = Deletion syndrome
- Velo-cardio-facial/ DiGeorge/ Sphrintzen syndrome
- 93% de novo (spontaneous)
- 7% inherited
- AD - 50% recurrence risk
- Features are:
- Characteristic face
- Cardiac malformations
- Cleft palate
- Hypocalcaemia
- Immune deficiency
- Velopharyngeal insufficiency
- Developmental delay and intellectual disability
- Psychiatric problems (adult)
What are the clinical features of 7q11.2?
7q11.2 = Deletion = Williams syndrome
- 1.55Mb deletion is most common
- Features:
- Characteristic face
- Supravalvular aortic stenosis
- Mild-severe intellectual disability
- Hypercalcaemia
Describe the role of roberstonian translocations in occurrence of Down’s syndrome
Robertsonian translocations involving chromosome 21 e.g. rob(14;21) can be a cause of recurrent Down’s syndrome in a family
What are the clinical features of mosaic trisomy 8?
- Complete trisomy 8 is not compatible with life
- Deep palmar/plantar creases
- Facial dysmorphism
- Congenital heart disease
- Structural abnormalities
- Learning difficulties
- Very variable
What is the function of qf-PCR and what are the pros and cons?
- Target polymorphic microsatellite DNA repeats to identify and quantify specific chromosomes
- At each marker, number of repeats on chromosome of a pair likely to be different and therefore, the different copies of chromosome appear as separated peaks
- DOES NOT provide information about position or balanced rearrangements
- Applications:
- Prenatal qPCR aneuploidy testing - First line (invasive) test for high risk T21 pregnancies
- T21, T18, T13 +/- sex chromosomes
- Fetal sexing
- Pros - Quick, cheap, accurate
- Cons - Limited number of uses (only picks up aneuploidies)
How can Down’s syndrome be diagnosed?
Using qf-PCR
Karyotype of baby/feotus can be used to determine origin of T21, which is important for measuring the risk of recurrence.
Parental karyotypes can also be measured if there’s translocation/rearrangement, for the same above reason
- 95% - Meiotic non-disjunction
- 2% - Robertsonian translocation
- 2% - Mosaicism
- 1% - Chromosome rearrangements
Describe the use of array-CGH and the pros and cons
- Comparitive method, compares patient’s DNA to reference/control DNA
- Identifies deletions or duplications
-
First line chromsome test for:
- Developmental delay
- Learning difficulties
- Structural abnormalities
- Dysmorphic features
- Larger difference b/w patient and control is worse, and deletions are more deleterious than duplications
- Pros- Uses DNA, quicker than karyotype, no hypothesis required
- Cons:
- Copy number variants of uncertain significance challenging to interpret
- Prenatal samples often required for interpretation
- Risk of incidental findings
- Breakpoints only represent first and last probe (beware of genes adjacent to breakpoints)
- Will not reliably detect:
- Balanced translocations
- Triploidy
- Microdeletions/microduplications
- Mosaicism
- Location of abnormality
Describe the use of SNP array
- No direct comparison with control genome, just uses control data set for reference
- Uses differentially labelled probes for Single Nucleotide Polymorphisms (SNPs) located across genome
- SNP - Genetic variation b/w individuals at a single nucleotide
- Quantifies number of SNPs by comparing intensity of signals
- Gives genotype information by comparing ratios of detected SNPs
- First line chromsome test for:
- Developmental delay
- Learning difficulties
- Structural abnormalities
- Dysmoprhic features
- Can detect uniparental disomy (UPD), loss of heterozygosisty (may indicate consanguinity), non-paternity if follow up in parent
Describe the use of karyotype and FISH and their pros and cons
Karyotype:
- Visual inspection of chromosomes
- Blood, skin, bone marrow, prenatal (CVS or amniotic fluid)
- Cells cultured, arrested at metaphase, harvested for analysis, mounted onto slides, banded (stained) and viewed under light microscope
- Applications:
- Rearrangements (translocations) e.g. inferility or recurrent miscarriage
- Mosaicism
- Pros - Balanced translocations, best test for mosaicism
- Cons - Hard to interpret
FISH:
- Useful for positional informations
- Uses probe that’s complementary to strand of DNA being identified. Labelled probe hybridises to single stranded target DNA whilst still in natural position on chromosome.
- Applications:
- Clarification of chromosome translocations
- Confirmation of array CGH findings
- Mosaicism
- Haemato-oncology applications
- Pros - Better resolution than karyotype
- Cons - Needs hypothesis, won’t pick up tandem CNVs or very small CNVs or translocations
Describe the use of antenatal testing
- First trimester screen: ‘Combined’ screening test (nuchal translucency, BhCG and PAPP-A)
- If high risk, offered:
- Invasive test - CVS/aminocentesis (1-2% miscarriage risk)
- qf-PCR
- Array
- Non-invasive test:
- Detects free foetal DNA in maternal circulation which originates from trophoblast (placenta)
- Can meausre from around 10/40 weeks via blood test
- Offerred as secondary screening test after high-risk first trimester screen, tests for T21, 18 and 13.
- Normal NIPT avoid need for invasive test
- Abnormal NIPT - Needs confirmation with invasive test before TOP
- Invasive test - CVS/aminocentesis (1-2% miscarriage risk)
What test is the first line used?
Array - CGH - High resolution, quicker
