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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