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Genetic Screening of Diseases (It’s worth & potential)

Genetic Screening of Diseases (It’s worth & potential). Dr Derakhshandeh. First trimester screening for Down syndrome and trisomy 18. The availability and acceptability of early invasive diagnostic methods (eg, chorionic villus sampling)

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Genetic Screening of Diseases (It’s worth & potential)

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  1. Genetic Screening of Diseases (It’s worth & potential) Dr Derakhshandeh

  2. First trimester screening for Down syndrome and trisomy 18 • The availability and acceptability of early invasive diagnostic methods (eg, chorionic villus sampling) • The continued need for second trimester screening for open fetal neural tube defects

  3. Women with singleton pregnancies underwent: first-trimester combined screening: • measurement of nuchal translucency • pregnancy-associated plasma protein A [PAPP-A] • The free beta subunit of human chorionic gonadotropin (HCG) at 10 weeks 3 days through 13 weeks 6 days of gestation

  4. Nuchal translucency screening involves the measurement by ultrasound of the skin thickness at the back of the neck of a first trimester fetus

  5. Nuchal translucency

  6. Identification about 85-90% of affected fetuses in the first-trimester • maternal age was combined with fetal NT • and maternal serum biochemistry (free β-hCG and pregnancy-associated plasma protein (PAPP-A))

  7. Second-trimester quadruple screening • measurement of: • alpha-fetoprotein • total human chorionic gonadotropin • unconjugated estriol • inhibin A at 15 through 18 weeks of gestation

  8. Maternal blood sampling for fetal blood cells • This is a new technique • use of the phenomenon of fetal blood cells gaining access to maternal circulation through the placental villi • only a very small number of fetal cells enter the maternal circulation in this fashion

  9. Maternal serum alpha-fetoprotein (MSAFP) • fetus has two major blood proteins: • albumin and alpha-fetoprotein (AFP) • Since adults typically have only albumin in their blood • the MSAFP test can be utilized to determine the levels of AFP from the fetus

  10. the gestational age must be known with certainty • the amount of MSAFP increasses with gestational age • the MSAFP can be elevated for a variety of reasons • which are not related to fetal neural tube or abdominal wall defects, so this test is not 100% specific

  11. Neural tube defect • a neural tube defect in the fetus: • from failure of part of the embryologic neural tube to close • there is a means for escape of more AFP into the amniotic fluid

  12. Neural tube defect

  13. Prenatal screening and diagnosis of neural tube defects • Neural tube defects (NTD): second most prevalent congenital anomaly in the United States • Two factors have played a significant role in the prevention of this disorder in developed countries: • Sonographic imaging combined with amniocentesis for diagnosis of affected fetuses • folic acid supplements for prevention of the disorder

  14. Anencephaly (failure of closure at the cranial end of the neural tube)

  15. Spina bifida (failure of closure at the caudal end of the neural tube)

  16. Environmental factors • The frequency of NTDs is increased with exposure to certain environmental factors: • drugs (valproic acid, carbamazepine, Folic acid deficiency) • diabetes mellitus • Obesity • Adequate folate is critical for cell division due to its essential role in the synthesis of: • nucleic • certain amino acids

  17. Genetic factors the observations that NTDs have a high rate: • in monozygotic twins • more frequent among first degree relatives • more common in females than males • The risk of recurrence for NTDs: approximately 2 to 4 percent when there is one affected sibling • With two affected siblings, the risk is approximately: 10 percent • The risk of NTD according to family history: • to be higher in countries such as Ireland where the prevalence if NTDs is high

  18. NOTE: • The genetic polymorphisms : • mutations in the methylene tetrahydrofolate reductase gene • may increase the risk for NTDs • Folate is a cofactor for this enzyme • which is part of the pathway of homocysteine metabolism in cells • The C677T and the A1298C mutations are associated with elevated maternal homocysteine concentrations and an increased risk for NTDs in fetuses

  19. Prevention of neural tube defects • can be accomplished by supplementation of the maternal diet with only 4 mg of folic acid per day • but this vitamin supplement must be taken a month before conception and through the first trimester

  20. Maternal serum beta-HCG • This test is most commonly used as a test for pregnancy • Later in pregnancy: in the middle to late second trimester • the beta-HCG can be used in conjunction with the MSAFP to screen for chromosomal abnormalities, and Down syndrome in particular • An elevated beta-HCG coupled with a decreased MSAFP suggests Downsyndrome

  21. Maternal serum estriol • made by the fetal adrenal glands • Estriol tends to be lower when Down syndrome is present

  22. Inhibin-A • An increased level of inhibin-A is associated with an increased risk for trisomy 21 • A high inhibin-A may be associated with a risk for preterm delivery

  23. The facial features of Down syndrome

  24. overlapping are typical for trisomy 18

  25. BRCA1 AND BRCA2 GENES

  26. BRCA1 AND BRCA2 GENES • Breast cancer develops in about12 percent of women who live to age 90 • a positive family history is reported by 15 to 20 percent of women with breast cancer • Just only 5 to 6 percent of all breast cancers are associated with an inherited gene mutation

  27. Two major susceptibility genes for breast cancer, BRCA1 and BRCA2 • Testing for mutations in these genes, is available • Clinicians and patients must decide when it is appropriate to screen for their presence

  28. The BRCA1 and BRCA2 genes function • As an essential part of the normal mechanisms that repair double-strand DNA breaks (ionizing radiation and DNA cross linking agents such as cisplatin) • through recombination with undamaged, homologous DNA strands

  29. Cisplatin • Cisplatin is a platinum-based chemotherapy drug • used to treat various types of cancers, such as sarcomas, some carcinomas, lymphomas and germ cell tumors

  30. Cisplatin

  31. Cisplatin • works by crosslinking across DNA inter-strands • making it impossible for rapidly dividing cells to duplicate their DNA for cell division (mitosis) • The damaged DNA sets off DNA repair mechanisms which fails to work • so in turn activate cell death processes (apoptosis)

  32. BRCA mutations • The reason why BRCA mutations predispose mainly to breast and ovarian cancers is unclear • intact BRCA1 represents a barrier to transcriptional activation of the estrogen receptor • that functional inactivation could lead to altered hormonal regulation of mammary and ovarian epithelial proliferation

  33. BRCA1 and BRCA2 gene abnormalities • Cancer risk with a high penetrance • women who have inherited mutations • the lifetime risk of breast cancer is between 65 and 85 percent by age 70

  34. Ovarian cancer • Ovarian cancer is also linked to the presence of BRCA mutations • the lifetime risk of ovarian cancer: • between 45 and 50 percent in women who have a deleterious BRCA1 mutation • and 15 to 25 percent for those with a BRCA2 mutation

  35. BRCA1 and BRCA2-associated cancers • prostate cancer • male breast cancer • pancreatic cancer • Although the risk of male breast cancer and pancreatic cancer may be under 10 percent • the risk of prostate cancer in BRCA2 carriers may be as high as 35 to 40 percent

  36. BRCA 1 • The gene Locus for BRCA1: 17q21 • a large gene • 24 exons • encoding a 220 kD • 1863 amino acids • Two recognizable motifs

  37. BRCA2 • BRCA2 (13q12.3) • was identified by Wooster et al. in 1995 • It encodes for 384 kD nuclear protein • 3418 amino acids • BRCA2 bears no homology to any known tumour supressor genes • contains 27 exons • spread over 70 kb of genomicDNA

  38. Breast Cancer Families

  39. Significance of family history • Degree of relatedness to affected relatives • Number of affected relatives • The age of the relative(s) when breast cancer occurred • Laterality of the disease in affected relatives • Whether there is a family history of ovarian cancer

  40. Pedigree of Breast cancer FamilyWith BRCA1 mutation

  41. SSCP AnalysisExon 11pi BRCA1 MS R1347G

  42. Mutations in BRCA1/2 gene

  43. Screening for colorectal cancer

  44. Screening for colorectal cancer • Colorectal cancer (CRC) is • a common • Lethal • preventable disease • It is infrequent before age 40 • the incidence rises progressively to 3.7/1000 per year by age 80

  45. Clinical detection of increased risk • Before deciding how to screen: • clinicians should decide whether the individual patient is at average or increased risk • based on his or her medical and family history • A few simple questions are all that is necessary: • Have you ever had colorectal cancer • or an adenomatous polyp • Have you had inflammatory bowel disease (Crohn disease) • Has a family member had colorectal cancer or an adenomatous polyp • If so, how many • was it a first-degree relative (parent, sibling, or child) • and at what age was the cancer or polyp first diagnosed

  46. Crohn’s disease • an inflammatory bowel disease • causes inflammation of the gastrointestinal tract in both men and women • persistent diarrhea, abdominal pain, fever, and at times rectal bleeding

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