醫(yī)學(xué)遺傳學(xué)英文教學(xué)課件：Genetic Diagnosis-2 Practical

1、Molecular Classification of Genetic Disease Disorders for which both the gene and mutation are known Disorders for which the gene is known, but not the mutation Disorders for which neither the gene nor the mutation is known Polygenic disorders APPLICATIONS OF MOLECULAR GENETIC TESTING Clinical diagn

2、osis/confirmation Carrier screening Prenatal diagnosis PGD (preimplantation genetic diagnosis)/ PGS (preimplantation genetic screening) Presymptomatic/predisposition diagnosisResources Gene Tests: American College of Medical Genetics: National Society of Genetic Counselors: www.nsg

3、 OMIM: The journals: Molecular Diagnosis, Diagnostic Molecular Pathology, Journal of Molecular Diagnosis, Genetic Testing and Molecular Biomarkers, Prenatal Diagnosis, GeneReviews ContentSummaryDiagnosisClinical DescriptionDifferential DiagnosisManagementGenetic CounselingMol

4、ecular GeneticsResourcesReferences Testing Timelinehttp:/.au/Genetic-testingBlood for Thalassemia & sickle cellAmniocentesis for chromosome & other genetic testingCVS for chromosome & other genetic testingNewborn ScreeningBlood for maternal serum screeningBlood for NIPTPGDThe Father of N

5、ewborn Genetic ScreeningRobert GuthrieRobert Guthrie (1916-1995) Microbiologist, SUNY Buffalo Son with MR/DD and niece with PKU Devised “Guthrie test” originally to monitor PKU therapy Conceptualized NBS for PKU and the “Guthrie spot” Guthrie Test is a bacterial inhibition assay. 2-Thienylalanine（噻吩

6、丙氨酸）（噻吩丙氨酸）is placed in the medium and normally causes the inhibition of Bacillus subtilis（枯草桿菌）（枯草桿菌）growth. However, in the presence of excess of phenylalanine, this inhibition is overridden and bacterial growth occurs. This test is the least expensive screening method available for determining ex

7、cess phenylalanine in the blood, but other tests are used to confirm findings. Disease Targets of Newborn ScreeningPhenylketonuria（苯酮尿癥）（苯酮尿癥）Galactosemia（半乳糖血癥）（半乳糖血癥）Congenital hypothyroidism（先天性甲狀腺功能減退癥）（先天性甲狀腺功能減退癥）Sickle cell/hemoglobinopathiesCystic fibrosisMetabolic screen (TMS。串聯(lián)。串聯(lián)質(zhì)譜篩查法質(zhì)譜篩查

8、法)others?National NBS Status: 2006ACMG NBS Expert Group, 2006 Recommended screening for Core panel of 29 diseases Secondary targets of 25 diseases Total of 54 diseases should be included in NBS test panelsWatson et al. Genet. Med. 2006; 8:1S-11SPrenatal Diagnosis（產(chǎn)前診斷）（產(chǎn)前診斷） The use of tests during

9、a pregnancy to determine whether an unborn child is affected with a particular disorder. Began in 1966.The Principal Indications for Prenatal Diagnosis by Invasive Testing1. Advanced maternal age.2. Previous child with a de novo chromosome abnormality.3. Presence of structural chromosome abnormality

10、 in one of the parents.4. Family history of a genetic disorder that may be diagnosed or ruled out by biochemical or DNA analysis.5. Family history of an X-linked disorder for which there is no specific prenatal diagnostic test.6. Risk of a neural tube defect (NTD).7. Maternal serum screening and ult

11、rasound. Technique Time (Weeks) Disorders Diagnosed Non-Invasive無創(chuàng)性無創(chuàng)性 maternal serum screening -Fetoprotein 16Neural tube defects1618Down syndromeUltrasound 18Structural abnormalities (e.g., central nervous system, heart, kidneys, limbs)Invasive有創(chuàng)性有創(chuàng)性 Amniocentesis 16Fluid Neural tube defectsCells

12、Chromosome abnormalities, metabolic disorders, molecular defects Chorionic villus sampling 10-12Chromosome abnormalities, metabolic disorders, molecular defects Fetoscopy胎兒鏡檢查胎兒鏡檢查 Blood (cordocentesis) Chromosome abnormalities, hematological disorders, congenital infection Liver Metabolic disorders

13、 (e.g., ornithine transcarbamylase deficiency) Skin Hereditary skin disorders (e.g., epidermolysis bullosa) Standard Techniques Used in Prenatal Diagnosis Methods of Noninvasive Testing in Prenatal Diagnosis Maternal serum alpha-fetoprotein Maternal serum screen (MSS) Ultrasonography Isolation of fe

14、tal cells from maternal circulation Screening and Diagnostic Tests for Down Syndrome The triple screen is a noninvasive screening test to determine whether there is an increased risk for Down syndrome. It is only a screening test and not a diagnostic test. Increased risk is associated with the follo

15、wing: Low maternal serum -fetoprotein (MSAFP) Low unconjugated estriol (uE3) Elevated human chorionic gonadotropin (hCG) Diagnostic tests include amniocentesis羊膜穿刺羊膜穿刺, chorionic villus sampling (CVS)絨毛吸取術(shù)絨毛吸取術(shù), and percutaneous umbilical blood sampling (PUBS)臍穿臍穿刺刺. Ultrasound result for a fetus wi

16、th a meningomyelocele脊髓脊膜膨出脊髓脊膜膨出, visible as fluid-filled sacs (arrow) located toward the base of the spinal column. Methods of Invasive Testing in Prenatal Diagnosis Amniocentesis: 15th to 16th weeks Chorionic villus sampling (CVS): 10th to 12th weeks Cordocentesis (PUBS): 19th to 21th weeks Preim

17、plantation genetic diagnosis (PGD): before the fertilization Amniocentesis & CVSAmniocentesis: 15th to 16th weeksPGD (preimplantation genetic diagnosis)ICSI (intracytoplasmic sperm injection)Noninvasive Testing! Maternal serum screen: ? Smear swab: ? Saliva: ? Hair: ?Commonly Utilized Prenatal S

18、creensWeekNT=nuchal translucency 頸項(xiàng)透明層厚度頸項(xiàng)透明層厚度PAPP-A=妊娠相關(guān)蛋白妊娠相關(guān)蛋白AhCG=人絨毛膜促性腺激素人絨毛膜促性腺激素DIA= 抑制素抑制素A二聚體二聚體uE3= 游離雌三醇游離雌三醇AFP= 甲胎蛋白甲胎蛋白Noninvasive Prenatal Testing (NIPT。無創(chuàng)性產(chǎn)前診斷。無創(chuàng)性產(chǎn)前診斷) estimate risks based-on DNA Sources of Fetal DNA in Maternal Bloodcell-free fetal DNA（cffDNA。游離胎兒。游離胎兒DNA）在妊娠第）在妊娠第4周開始周開始經(jīng)胎盤進(jìn)入母體血液循環(huán)，約占