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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 diagnosis/confirmation Carrier screening Prenatal diagnosis PGD(preimplantation genetic diagnosis)/PGS(preimplantation genetic screening)Presymptomatic/predisposition diagnosisResources Gene Tests:www.genetests.org American College of Medical Genetics: National Society of Genetic Counselors:www.nsgc.org OMIM:http:/www.omim.org The journals:Molecular Diagnosis,Diagnostic Molecular Pathology,Journal of Molecular Diagnosis,Genetic Testing and Molecular Biomarkers,Prenatal Diagnosis,GeneReviews ContentSummaryDiagnosisClinical DescriptionDifferential DiagnosisManagementGenetic CounselingMolecular 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 Newborn 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（噻吩丙氨酸）（噻吩丙氨酸）is placed in the medium and normally causes the inhibition of Bacillus subtilis（枯草杆菌）（枯草杆菌）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 excess phenylalanine in the blood,but other tests are used to confirm findings.Disease Targets of Newborn ScreeningPhenylketonuria（苯酮尿症）（苯酮尿症）Galactosemia（半乳糖血症）（半乳糖血症）Congenital hypothyroidism（先天性甲状腺功能减退症）（先天性甲状腺功能减退症）Sickle cell/hemoglobinopathiesCystic fibrosisMetabolic screen(TMS。串联。串联质谱筛查法质谱筛查法)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（产前诊断）（产前诊断）The use of tests during 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 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 ultrasound.Technique Time(Weeks)Disorders Diagnosed Non-Invasive无创性无创性 maternal serum screening-Fetoprotein 16Neural tube defects1618Down syndromeUltrasound 18Structural abnormalities(e.g.,central nervous system,heart,kidneys,limbs)Invasive有创性有创性 Amniocentesis 16Fluid Neural tube defectsCells Chromosome abnormalities,metabolic disorders,molecular defects Chorionic villus sampling 10-12Chromosome abnormalities,metabolic disorders,molecular defects Fetoscopy胎儿镜检查胎儿镜检查 Blood(cordocentesis)Chromosome abnormalities,hematological disorders,congenital infection Liver Metabolic disorders(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 fetal 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 following: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)绒毛吸取术绒毛吸取术,and percutaneous umbilical blood sampling(PUBS)脐穿脐穿刺刺.Ultrasound result for a fetus with 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 Preimplantation 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 ScreensWeekNT=nuchal translucency 颈项透明层厚度颈项透明层厚度PAPP-A=妊娠相关蛋白妊娠相关蛋白AhCG=人绒毛膜促性腺激素人绒毛膜促性腺激素DIA=抑制素抑制素A二聚体二聚体uE3=游离雌三醇游离雌三醇AFP=甲胎蛋白甲胎蛋白Noninvasive Prenatal Testing(NIPT。无创性产前诊断。无创性产前诊断)estimate risks based-on DNA Sources of Fetal DNA in Maternal Bloodcell-free fetal DNA（cffDNA。游离胎儿。游离胎儿DNA）在妊娠第）在妊娠第4周开始周开始经胎盘进入母体血液循环，约占孕妇血浆游离经胎盘进入母体血液循环，约占孕妇血浆游离DNA的的10%。cffDNA片段可代表胎儿的全基因组。胎儿出生之后，片段可代表胎儿的全基因组。胎儿出生之后，cffDNA迅迅速在母体内被清除。速在母体内被清除。Performance ComparisonFPR=false positive rate 1976：1st DNA diagnosis(Prof.Yuet Wai Kan,UCSF)The 1st Genetic Testing in China Prof.吴冠芸吴冠芸(1924-,PUMC):-thalassemia,1981.
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