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Prof. Lina Basel

Aneuploidy screening in pregnancy - modern approaches. Prof. Lina Basel Director, The Raphael Recanati Genetics Institute, Beilinson hospital, Rabin Medical Center Schneider Children’s Medical Center of Israel Tel Aviv University.

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Prof. Lina Basel

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  1. Aneuploidy screening in pregnancy - modern approaches Prof. Lina Basel Director, The Raphael Recanati Genetics Institute, Beilinson hospital, Rabin Medical Center Schneider Children’s Medical Center of Israel Tel Aviv University

  2. Rabin Medical Center/Schneider Children’s Medical Center of Israel • Pediatric genetics • Adult genetics • Prenatal counseling • Oncogenetics • Genetic screening • Molecular lab • Cytogenetic lab including chromosomal microarray • PGD

  3. Types of genetic disorders Chapter: Chromosomal Karyotype Letter: Single gene mutations Gene sequencing Our genome Sentence: Microdeletions/ microduplications Chromosomal microarray

  4. Role of ObGyn in providing the screening program Beforeand during pregnancy: genetic counseling, population genetic screening Duringpregnancy: fetal US, aneuploidyscreening Afterpregnancy: diagnostic tests

  5. Before and during pregnancy: genetic counseling Before pregnancy During pregnancy Abnormal biochemical screening/NIPT/invasive testing result Fetal abnormalities on the US Family history of genetic disease, ID, autism, recurrent pregnancy loss, infertility, premature ovarian failure

  6. Before and during pregnancy: genetic carrier screening • Gene is known in about 3000 diseases • Carrier tests for prospective parents are recommended for a small number of selected diseases • Common mistake: there is no history of genetic disease in my family, therefore I am not at risk…

  7. Before pregnancy: genetic carrier screening Frequent diseases? SMA, Fragile X, CF, other All diseases? Recent advances in DNA sequencing led for identifying carriers of known mutations that cause more than 400 recessive genetic diseases

  8. Attitude of different populations in Israel towards prenatal testing • Prenatal testing by CVS or amniocentesis; preimplantation genetic diagnosis (pregnancy interruption possible up to birth, even at 40 weeks of pregnancy) • Preimplantation genetic diagnosis (pregnancy interruption possible up to 40 days only – no prenatal testing possible) • Prenatal testing by CVS or amniocentesis; preimplantation genetic diagnosis (pregnancy interruption possible up to 120 days of pregnancy)

  9. Types of genetic screening tests Recommendedbyethnicity Recommendedtoeveryone • Cystic Fibrosis (CF) • Spinal muscular atrophy • Fragile X Syndrome • Canavan • Fanconi Anemia • Familial Dysautonomia • Mucolipidosis type 4 • Bloom Syndrome Covered by Health Insurance and Ministry of Health In Israel – prenatal genetic screening possible due to a large number of founder mutations

  10. http://server.goldenhelix.org/israeli/

  11. Carrier burden of 448 pediatric diseases 22% of literature-cited disease mutations were common SNPs or misannotated Average carrier burden of severe childhood diseases 2.8

  12. Next-generation carrier screening In Israel 1:200 couples both carriers of the same disease

  13. During pregnancy: aneuploidy screening

  14. During Pregnancy: Aneuploidy Screening Tests • High AFP: neural tube defects, congenital nephrotic syndrome, skin diseases • Low uE3: ichthyosis, Smith-Lemli-Opitz syndrome, adrenal axis disorders Amniocenthesis: Isttrimested DS risk >1:200 IIndtrimested DS risk >1:380 Twin pregnancy: NT only IVF: as spontaneous pregnancy

  15. Duringpregnancy: fetal US Relative risk for DS – integrated with biochemical screening 14-15 wk, 21-24 wk Hyperechogenicbowel – X6 Short femur – X2 Lt echogenic intracardiac focus - X1.5 Pyelectasis – X1 Single umbilical artery (SUA) – X1 Chorioid plexus cyst (CPC) - X1

  16. Indications for invasive fetal testing Abnormal biochemical serum screening/NIPT “Soft signs” on the fetal ultrasound- 2 soft signs or combined risk >1:380 Fetal malformations on the ultrasound Parents carriers of genetic disease/affected

  17. Invasive prenatal testing Chorionic villus sampling (CVS) – 10-13 wk Amniocentesis - starting from 16 wks Cordocentesis - starting from 18 wk CVS – 1% confined placental mosaicism Fetal loss: CVS and Amniocentesis: 0.11%

  18. Prenatal invasive testing: chromosomal aberrations • Karyotype • FISH or QPCR for aneuploidy: chromosomes 21, 18, 13, X, Y – 24-48 hours • Chromosomal microarray

  19. Karyotype vs chromosomal microarray (CMA) FISH: specific locus (22q11) CMA: all chromosomes

  20. Chromosomal microarray Trisomy 21

  21. Chromosomal microarray

  22. Current indications for prenatal CMA • U/S – Major fetal malformations • Abnormal de-novo karyotype abnormality (translocation/marker) • Inherited microdeletion/microduplication • U/S – Minor malformations??? • Low risk pregnancy???

  23. Chromosomal microarray: limitations

  24. Databases: normal and abnormal CNVs

  25. Classification of CNVs Benign Pathogenic Uncertain Clinical Significance Known syndrome Polymorphism Likely Pathogenic Likely Benign NOS

  26. PREGNANCIES – LOW RISK PREGNANCIES HIGH RISK – abnormal U/S 1% PATHOGENIC 1% NOS 7% PATHOGENIC 2% NOS

  27. CMA example

  28. CMA example

  29. To test or not to test?

  30. CMA in prenatal diagnosis Why to test for Down syndrome by amniocenthesis (1:380 risk) if every woman has a risk of 1:100-200 for microdeletion or microduplication syndrome in the fetus? Microdeletion/microduplication = frequently intellectual disability Both karyotyping and CMA do not discover monogenic disorders

  31. Non-Invasive Prenatal Testing (NIPT) Cell free fetal (placental) DNA • High risk populations? • Low risk populations?

  32. Comparison of commercially-available NIPTs Curr Genet Med Rep. 2013; 1: 113–121.

  33. NIPT indications according to the American College of Obstetricians and Gynecologists • A woman aged 35 years or older at delivery • Biochemical screening test result shows and increased risk for aneuploidy • A woman has a history of pregnancy with fetal trisomy • An ultrasound shows a fetal abnormality that could be caused by aneuploidy • Parental balanced robertsonian translocation involving 13 and 21 The ACOG and the SMFM do not currently recommend NIPT as a first screening test in low-risk or multiple pregnancies

  34. Comparison of NIPTs

  35. NIPT results • Normal result: no specific follow up necessary, unless ultrasound examination of the fetus reveals anomalies • Test failure: in up to 3% pregnancies not enough fetal DNA • Abnormal NIPT result: amniocentesis or chorion biopsy NIPT is NOT the test of choice when there is : • Fetal anomalies (excluding soft signs) on ultrasound • A triplet pregnancy • Known genetic anomalies that cannot be diagnosed by NIPT NIPT contraindications

  36. NIPT reliability • Phenotype for sex aneuploidies is highly variable • Mosaicism in the fetus is a problem • Mosaicism in the mother is a problem • NIPT for sex aneuploidies is less accurate

  37. NIPT reliability

  38. NIPT reliability

  39. NIPT disadvantages • 50% of cytogenetic abnormalities will not be detected. • <35 years or >35 years: 75 and 43% of cytogenetic abnormalities will be missed. • NIPT is not able to distinguish specific forms of aneuploidy (extra chromosome, Robertsonian translocation or high-level mosaicism (recurrence risk counseling) • Most microdeletions/microduplications will not be detected • NIPT does not screen for open neural tube defects • NIPT does not replace fetal US examination (NT, congenital anomalies) • NIPT has no role in predicting late-pregnancy complications

  40. Microdeletion syndromes/other chromosomes detected by NIPT High false positive rate

  41. The future: Microdeletion syndromes detected by NIPT • Sensitivity 94% • False-positive rate of 3.8% would potentially limit the clinical utility as a stand-alone screening test • Of 55 false-positive samples, 35 were caused by deletions/duplications present in maternal DNA

  42. The future: monogenic disorders detection by NIPT

  43. Detection of monogenic disorders in the fetus

  44. Fetal Exome Sequencing • Congenital abnormalities (e.g. omphalocele and complex cardiac disease) can be associated with chromosomal aneuploidy or related to a single-gene disorder • Knowing the cause of a congenital structural anomaly can aid in making a more accurate diagnosis and provides information about prognosis and recurrence risks for parents

  45. Fetal Exome Sequencing • Exome sequencing on 30 non-aneuploid fetuses with structural abnormalities first identified by prenatal US • Monogenic cause identified in 10% - diagnostic yield comparable to microarray testing

  46. Preimplantationgenetic diagnosis (PGD)

  47. Types of PGD Single gene Cytogenetic • Autosomal Dominant • Autosomal recessive • X – linked disorders • Aneuploidy • Balanced translocation carriers • Inherited CNV syndromes Sex selection HLA - typing • Medical indication • Non- medical indication • Isolated • With Mendelian disease Adult onset diseases • Cancer susceptibility mutation carriers • Full penetrate adult onset (including non-disclosure)

  48. Preimplantation genetic screening 5 or 24 chromosome PGS: FISH or karyomapping

  49. Ethical considerations • When is a disorder “serious” enough to warrant prenatal diagnosis + termination of pregnancy? Or PGD? Hearing loss Gaucher HNPCC Partially penetrant CNVs

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