04 Clinical Aspects of Chromosomal Disorders Flashcards
What are some of the first techniques you could use to detect chromosomal disorders?
QF-PCR for chr13, 18, 21, X and Y.
Array CGH (have you got more or less copies than a control) which can either be constitutional arrays (known CNVs causing disease), or SNP arrays (which will contain areas of autozygosity).
What Follow Up Techniques are used to confirm chromosomal disorders? And what advantages are there?
FISH and karyotyping.
Can detect location in these and mosaicism.
What do we define as a chromosomal abnormality?
Well it has to contain >1 gene generally. In either a dosage, or structural/locational manner.
We know that CNVs are normal in that we all have some. What proportion of CNVs are inherited vs de novo?
99% inherited vs 1% de novo
How many CNVs (>1kb) do we all have compared to the reference genome
About 250.
1-3% of us have a pericentric chromosome 9, which may affect fertility, what is this?
Where our centromere of chromosome 9 has been inverted.
CNVs of equal size can have very varying levels of impact, why?
Because of the breakpoints, and gene density varies greatly through the genome. Chr X is very gene dense compared to Chr Y.
How often does miscarriage/spontaneous pregnancy loss (before 24 weeks) occur in 20-24 yr olds and 40-44 yr olds?
11% in 20-24 yr olds.
51% in 40-44 yr olds.
What percentage of couples have >3 miscarriages?
1%
What proportion of born children are affected by chromosomal abnormalities?
0.6%
RCOG say if you’ve had 3 miscarriages then what…?
Your following pregnancies should have cytogenetic analysis
2-5% of recurrent miscarriages are due to what?
One parent having a balanced structural translocation
What can you learn from the Antenatal and Newborn Screening Timeline?
The optimum times for testing pregnancies and newborns. Not just genetic tests.
When are screens for trisomy 13, 18 and 21 done?
1st trimester
What tests are trisomy screening paired with?
Nuchal translucency scan for Down’s syndrome and other abnormalities
What’s the difference between NIPT and NIPD?
NIPT is just a screen, NIPD is diagnostic
Who is offered NIPT analysis?
Pregnancies determined high risk (from age of mother, nuchal translucency etc.)
Some monosomies are viable to full term, true or false?
Only X0. All others cause the death of the child, usually quite early in pregnancy
1 in how many are affected by Down’s syndrome?
1 in 800
3% of downs syndrome cases are what?
Mosaic
What percentage of trisomy 21 babies miscarry?
~60%
What are the symptoms of Down’s syndrome?
Learning disability, cardiac abnormalities, Alzheimers (caused by APP gene), hypothyroidism, obesity.
What are the 3 causes of down’s syndrome?
1-3% ->
4% ->
The rest ->
1-3% -> Mosaicism due to post-zygotic non-disjunction
4% -> Robertsonian translocation
The rest -> Trisomy 21 due to non-disjunction at meiosis
What is Trisomy 13?
Patau syndrome
1 in how many liveborn babies have Patau syndrome (Trisomy 13)?
1 in 5000
What percentage of Patau syndrome affected babies die in the first year?
> 90%
What are some of the symptoms of Patau syndrome
IntraUterine Growth Restriction (IUGR), microcephaly, intellectual disability, facial and feet deformities, extra digits etc.
What is Trisomy 18 called?
Edwards syndrome
1 in how many live born babies are affected by Edwards syndrome
1 in 5000
What percentage of Edward syndrome affecte dbabies die in the first year?
> 80%
What are the symptoms of Edwards syndrome?
IntraUterine Growth Restriction (IUGR), cleft palate, heart defects, microcephaly, low set of ears, other structural abnormalities.
After a NIPT Screening test, what sample might be taken as follow up?
A more invasive test - either a CVS or amniocentesis
How often can invasively checking a pregnancy cause a miscarriage?
1% for CVS, 0.5% for Aminocentesis
What tests are ran on CVS or amnio samples?
QF-PCR and microarray
What is important to consider when dealing with prenatal testing?
Ethics! Eugenics!
1 in how many live born girls have Turner syndrome?
1 in 2000
What are the symptoms of Turner Syndrome?
Webbed neck, low hairline, shield chest, bicuspid aorta, coarctation of aorta, small stature, streak gonads, delayed puberty, hearing loss, high blood pressure, structural kidney issues, autoimmune conditions. Normal intellect but some specific difficulties such as visual/spatial problems
1 in how many live born boys have Klinefelter’s syndrome?
1 in 500-1000 males
What are the symptoms of Klinefelter’s syndrome?
Tall stature, gynaecomastia, hypogonadism/azoospermia, intention tremors, mildly reduced IQ, expressive language problems.
When is Klinefelter’s syndrome usually found?
Either incidentally, or when someone hits puberty
If you ever see a really odd inheritance pattern that you can’t figure, what should you maybe consider?
Maybe a parent has balanced translocation
When you have large balanced translocations, chromosomes can line up in what structure?
A quadrivalent
When assessing a chromosomal abnormality you need to ask if that change fully explains the phenotype. What can you use to do this?
DECIPHER, UNIQUE, medical literature
When comparing your chromosomal abnormality on databases, what do you need to look out for?
That the phenotype is the same in other people. That the breakpoints are the same, specific. How many genes are in the region? Are any morbid genes?
How do large repeat sequences lead to microdeletions and microduplications that you would identify via microarray or FISH?
They are susceptible to non-allelic homologous recombination, usually during meiosis
What syndrome is caused by 22q11.2 deletion?
DiGeorge Syndrome
1 in how many live births are affected by 22q11.2 deletion / DiGeorge syndrome?
1 in 2000-4000
DiGeorge syndrome is the most common cause of what?
cleft palates
There’s lots of variability with DiGeorge syndrome. 75% have what?
Cardiac abnormalities
What are some things we didn’t really touch in this lecture?
Tr_______ and In________,
N___________L_______
Other structural abnormalities: _____________________
Imprinting (like 15q, _______________________)
Translocations and Inversions.
Neurosusceptibility loci
Ring chromsomes, marker chromosomes, isodicentric chromosomes.
Imprinting like 15q, Angelmans and Prader-Willi syndrome
