Download Lctures Clinical genetics3

Lectures Clinical Genetics
Dr. Aneela Javed
DELETIONS
Types of deletion
Terminal Deletion' - a deletion that occurs towards the end of a
chromosome. Must be caped by telomere for stability….WHY???
Ring chr: epilepsy, dwarfism, mental retardation etc
Interstitial Deletion - a deletion that occurs from the interior of a
chromosome.
microdeletion - a relatively small amount of deletion (up to 5kb that
could include a dozen genes).
Causes include
Losses from translocation
Chromosomal crossovers within a chromosomal inversion
Unequal crossing over
Breaking without rejoining
DUPLICATIONS
less deleterious rather imp for evolution.
recombination is unequal, chromatids that are out of alignment,
Retrotransposition.
new gene carries inappropriate promoters at its 5' end (acquired from
the 11-beta hydroxylase gene) that cause it to be expressed more
strongly than the normal gene. The mutant gene is dominant: results
in high blood pressure ,prone to early death from stroke.
Fragile X Syndrome: CGG
Huntington's disease ,CAG, which adds a string of glutamines (Gln)
INVERSIONS
when a single chromosome undergoes breakage and rearrangement within
itself. Para or peri. may involve gene breakage, dif promotor, etc or no effect
but this will create problems at homologous recombination, looped structure.
REASONS FOR PRENATAL DIAGNOSIS
(1) to enable timely medical or surgical treatment of a condition before
or after birth,
(2) to give the parents the chance to abort a fetus with the diagnosed
condition, and
(3) to give parents the chance to "prepare" psychologically, socially,
financially, and medically for a baby with a health problem or disability,
or for the likelihood of a stillbirth.
(4) Healthcare staff as well as parents can better prepare themselves
for the delivery of a child with a health problem. For example, Down
Syndrome is associated with cardiac defects that may need intervention
immediately upon birth.
Invasiveness
Non-invasive
Non-invasive
Non-invasive
Test
Comments
Based on enrichment of fetal cells
which circulate in maternal blood.
Fetal Cells in Maternal Since fetal cells hold all the genetic
Blood (FCMB)
information of the developing fetus
they can be used to perform prenatal
diagnosis.
Based on DNA of fetal origin
circulating in the maternal blood.
Testing can potentially identify fetal
aneuploidy available in the United
Cell-free Fetal DNA in
States, beginning 2011) and genderof
Maternal Blood
a fetus as early as six weeks into a
pregnancy. Fetal DNA ranges from
about 2-10% of the total DNA in
maternal blood.
During in vitro fertilization (IVF)
procedures, it is possible to sample
cells from human embryos prior the
Preimplantation
implantation. PGD is in itself nonGenetic Diagnosis (PGD)
invasive, but IVF usually involves
invasive procedures such as
transvaginal oocyte retrieval
Time
First trimester
First trimester
prior to
implantation
Examination of the woman's
uterus from outside the body.
Commonly dating scans
(sometimes known as booking
scans) from 7 weeks to confirm
pregnancy dates and look for
twins. The specialised nuchal
scan at 11–13 weeks may be
used to identify higher risks of
Downs syndrome. Later
morphology scans from 18
weeks may check for any
abnormal development.
First or second
trimester
Non-invasive
External examination
Non-invasive
Ultrasound detection
Non-invasive
Fetal heartbeat
Listening to the fetal heartbeat
Non-stress test
Use of cardiotocography during
the third trimester to monitor Third trimester
fetal wellbeing
Non-invasive
First or second
trimester
First or second
trimester
Less invasive
Transcervical
retrieval of
trophoblast cells
Cervical mucus aspiration, cervical
swabbing, and cervical or intrauterine
lavage can be used to retrieve trophoblast
including. Success from 40% to 90%.It can
be used for fetal sex determination and
identify aneuploidies. Antibody markers
First trimester
have proven useful to select trophoblast
cells for genetic analysis and to
demonstrate that the abundance of
recoverable trophoblast cells diminishes
in abnormal gestations, such as in ectopic
pregnancy or anembryonic gestation.
Less invasive
Maternal serum
screening
Including β-hCG, PAPP-A, alpha
First or second
fetoprotein, intact or beta hCG, inhibintrimester
A.
More invasive
More invasive
More invasive
More invasive
Involves getting a sample of the chorionic
Chorionic villus villus and testing it. This can be done
After 10 weeks
sampling
earlier than amniocentesis, but may have a
higher risk of miscarriage, estimated at 1%.
This can be done once enough amniotic
fluid has developed to sample. Cells from
the fetus will be floating in this fluid, and
can be separated and tested. Miscarriage
Amniocentesis
After 15 weeks
risk of amniocentesis is commonly quoted
as 0.06% (1:1600). By amniocentesis is also
possible to cryopreserve amniotic stem
cells.
Though rarely done, these involve putting
Embryoscopy and a probe into a women's uterus to observe
fetoscopy
(with a video camera), or to sample blood
or tissue from the embryo or fetus.
Percutaneous
umbilical cord
blood sampling
REASONS FOR INVASIVE TESTING
going straight for invasive testing.
•Women over the age of 35
•Women who have previously had premature babies or babies with a birth
defect, especially heart or genetic problems
•Women who have high blood pressure, diabetes, asthma, or epilepsy
•Women who have family histories or ethnic backgrounds prone to genetic
disorders, or whose partners have these
•Women who are pregnant with multiples (twins or more)
•Women who have previously had miscarriages
QUALIFYING RISK FACTORS
Because of the miscarriage and fetal damage risks associated with amniocentesis and
CVS procedures, many women prefer to first undergo screening so they can find out if
the fetus' risk of birth defects is high enough to justify the risks of invasive testing. Since
screening tests yield a risk score which represents the chance that the baby has the birth
defect, the most common threshold for high-risk is 1:270. A risk score of 1:300 would
therefore be considered low-risk by many physicians. However, the trade-off between
risk of birth defect and risk of complications from invasive testing is relative and
subjective; some parents may decide that even a 1:1000 risk of birth defects warrants
an invasive test while others wouldn't opt for an invasive test even if they had a 1:10
risk score.
ACOG guidelines currently recommend that all pregnant women, regardless of age, be
offered invasive testing to obtain a definitive diagnosis of certain birth defects.
Therefore, most physicians offer diagnostic testing to all their patients, with or
without prior screening and let the patient decide.
Pregnancy-associated plasma protein A, pappalysin 1, also known
as PAPPA, is a protein used in screening tests for Down syndrome.
Low plasma level of this protein has been suggested as a biochemical marker
for pregnancies with aneuploid fetuses (fetuses with an abnormal number
of chromosomes).For example, low PAPPA may be seen in prenatal
screening for Down syndrome.
In molecular biology, human chorionic gonadotropin (hCG) is
a hormone produced by the syncytiotrophoblast, a component of the fertilized
egg, after conception.Some cancerous tumors produce this hormone.
As of December 6, 2011, the United States FDA has prohibited the sale of
"homeopathic" and over-the-counter hCG diet products and declared them
fraudulent and illegal.
Projects
Hospital visits, pediatric departments for clinical genetic diseases
Or
Transgenders karyotyping
Survey reports for the mothers for invasive and non invasive testing
ETHICAL ISSUES
Fetal screening has also been done to determine characteristics generally
not considered birth defects, and avail for e.g. sex selection. The rise of
designer babies and parental selection for specific traits raises a host of
bioethical and legal issues that will dominate reproductive rights debates in
the 21st century.
Questions of the value of mentally or physically disabled people in society.
Both false positives and false negatives
Diagnostic tests, such as amniocentesis, are considered to be very accurate
for the defects they check for, though even these tests are not perfect, with
a reported 0.2% error rate (often due to rare abnormalities such as mosaic
Down Syndrome where only some of the fetal/placental cells carry the
genetic abnormality).
ADANCED NON INVASIVE TECH
The difference in methylation of specific DNA sequences between mother
and fetus can be used to identify fetal-specific DNA in the blood
circulation of the mother. In a study published in March 6, 2011 online
issue of Nature journal
using this non-invasive technique achieved correct diagnosis of 14 trisomy
21 (Down Syndrome) and 26 normal cases.
9. Mutagenesis and DNA repair
10. Mutations
16. Pedigree drawing
11. The molecular biology of
17. Risk assessment
cancer
18. Dysmorphology
12. Familial cancers
19. Chromosome analysis
13. Immunogenetics
20. Biochemical diagnosis
14. Genetic disorders of the
21. Reproductive genetic counseling
immune system
22. Prenatal sampling
15. Biochemical genetics
23. Clinical application of linkage
16. Clinical applications of
24. DNA profiling
genetics
25. Management of genetic disease
26. Avoidance and prevention of
disease
27. Ethical and social issues in
clinical genetics
Course Contents:
1. The place of genetics in medicine
2. Mendel’s laws
3. Inheritance pattern principles and clinical examples
4. Chromosome structural abnormalities and clinical examples
5. Principles of multi-factorial disease
6. Allele frequency
7. Genetic linkage
8. Gene mapping